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• Review Article
• Published: 03 January 2017

Disease tolerance and immunity in host protection against infection

• Miguel P. Soares 1 ,
• Luis Teixeira 1 &
• Luis F. Moita 1  

Nature Reviews Immunology volume  17 ,  pages 83–96 ( 2017 ) Cite this article

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• Antimicrobial responses
• Inflammation
• Lymphoid tissues

Disease tolerance is an evolutionarily conserved defence strategy against infection that does not exert a direct negative effect on the host pathogen load.

Disease tolerance relies on tissue damage control mechanisms.

Tissue damage control mechanisms rely on stress and damage responses.

Innate and adaptive components of the immune system regulate tissue damage control mechanisms and contribute to the establishment of disease tolerance to infection.

Host–commensal microorganism interactions regulate disease tolerance against pathogens.

Pharmacological targeting of tissue damage control mechanisms induces disease tolerance to infection.

The immune system probably evolved to limit the negative effects exerted by pathogens on host homeostasis. This defence strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues during infection, without exerting a direct negative effect on pathogens. This defence strategy, known as disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from immunopathology and disease. In this Review, we provide a unifying view of resistance and disease tolerance in the framework of immunity to infection.

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Soares, M. P., Gozzelino, R. & Weis, S. Tissue damage control in disease tolerance. Trends Immunol. 35 , 483–494 (2014).

Article   CAS   PubMed   Google Scholar  

Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160 , 816–827 (2015).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Chovatiya, R. & Medzhitov, R. Stress, inflammation, and defense of homeostasis. Mol. Cell 54 , 281–288 (2014). References 1–3 provide an overview of how different stress and damage reponses contribute to re-establishment of homeostasis after infection and other pathological conditions.

Fauci, A. S. & Morens, D. M. The perpetual challenge of infectious diseases. N. Engl. J. Med. 366 , 454–461 (2012).

Schneider, D. S. & Ayres, J. S. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat. Rev. Immunol. 8 , 889–895 (2008).

Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335 , 936–941 (2012). References 5 and 6 provide a conceptual overview of disease tolerance to infection, bridging its initial description in plants and insects to mice and possibly humans.

Schaefer, J. F. Tolerance to plant disease. Annu. Rev. Phytopathol. 9 , 235–252 (1971).

Article   Google Scholar  

Caldwell, R. M., Schafer, J. F., Compton, L. E. & Patterson, F. L. Tolerance to cereal leaf rusts. Science 128 , 714–715 (1958).

Ayres, J. S., Freitag, N. & Schneider, D. S. Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics 178 , 1807–1815 (2008).

Teixeira, L., Ferreira, A. & Ashburner, M. The bacterial symbiont Wolbachia induces resistance to RNA viral infections in Drosophila melanogaster . PLoS Biol. 6 , e2 (2008). References 9 and 10 are the first demonstrations of disease tolerance in insects, suggesting that this host defence strategy against infection, identified originally in plants, can be extrapolated to animals. Reference 10 also demonstrates that host symbiotic interactions modulate disease tolerance to pathogens.

Article   PubMed   CAS   Google Scholar  

Raberg, L., Sim, D. & Read, A. F. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318 , 812–814 (2007). This is the original demonstration of disease tolerance in mammals.

Seixas, E. et al. Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc. Natl Acad. Sci. USA 106 , 15837–15842 (2009). This is the first mechanistic study on disease tolerance in mammals using the same experimental model as in reference 11.

Gozzelino, R. et al. Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12 , 693–704 (2012).

Rodrigue-Gervais, I. G. et al. Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival. Cell Host Microbe 15 , 23–35 (2014).

Jamieson, A. M. et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 340 , 1230–1234 (2013). This is the first mechanistic demonstration of how deregulation of disease tolerance affects the pathological outcome of co-infections.

Larsen, R. et al. A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl Med. 2 , 51ra71 (2010).

Figueiredo, N. et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 39 , 874–884 (2013).

Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511 , 184–190 (2014).

Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 11 , 275–288 (2011).

Ferreira, A. et al. Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145 , 398–409 (2011).

Pamplona, A. et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13 , 703–710 (2007).

Ayres, J. S. Cooperative microbial tolerance behaviors in host-microbiota mutualism. Cell 165 , 1323–1331 (2016).

Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529 , 307–315 (2016).

Ayres, J. S. & Schneider, D. S. Tolerance of infections. Annu. Rev. Immunol. 30 , 271–294 (2012).

Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118 , 229–241 (2004). This seminal article demonstrates that PRRs sense components of the gut microbiota and help to maintain a homeostatic balance in host–microbiota interactions. The article also suggests that PRRs contribute to tissue damage control in the host gut epithelium.

Ayres, J. S. Inflammasome-microbiota interplay in host physiologies. Cell Host Microbe 14 , 491–497 (2013).

Sykiotis, G. P. & Bohmann, D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci. Signal. 3 , re3 (2010).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Hayes, J. D. & Dinkova-Kostova, A. T. The NRF2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39 , 199–218 (2014).

Jeney, V. et al. Control of disease tolerance to malaria by nitric oxide and carbon monoxide. Cell Rep. 8 , 126–136 (2014).

Ferreira, A., Balla, J., Jeney, V., Balla, G. & Soares, M. P. A central role for free heme in the pathogenesis of severe malaria: the missing link? J. Mol. Med. 86 , 1097–1111 (2008). This article proposes that labile haem generated through haemolysis functions as a central component in the pathogenesis of severe forms of malaria. The article also proposes how physiological mechanisms that control the pathogenic effects of labile haem counteract the pathogenesis of severe forms of malaria.

Gozzelino, R., Jeney, V. & Soares, M. P. Mechanisms of cell protection by heme oxygenase-1. Annu. Rev. Pharmacol. Toxicol. 50 , 323–354 (2010).

Soares, M. P. & Ribeiro, A. M. NRF2 as a master regulator of tissue damage control and disease tolerance to infection. Biochem. Soc. Trans. 43 , 663–668 (2015).

Thimmulappa, R. K. et al. NRF2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Invest. 116 , 984–995 (2006).

Athale, J. et al. NRF2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice. Free Radic. Biol. Med. 53 , 1584–1594 (2012).

Kobayashi, E. H. et al. NRF2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7 , 11624 (2016).

Eichenfield, D. Z. et al. Tissue damage drives co-localization of NF-κB, SMAD3, and NRF2 to direct Rev-erb sensitive wound repair in mouse macrophages. eLife 5 , e13024 (2016).

Article   PubMed   PubMed Central   Google Scholar  

Greer, S. N., Metcalf, J. L., Wang, Y. & Ohh, M. The updated biology of hypoxia-inducible factor. EMBO J. 31 , 2448–2460 (2012).

Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345 , 1250684 (2014).

Kelly, B. & O'Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25 , 771–784 (2015).

Matak, P. et al. Myeloid HIF-1 is protective in Helicobacter pylori -mediated gastritis. J. Immunol. 194 , 3259–3266 (2015).

Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166 , 1512–1525.e12 (2016).

Jantsch, J. et al. Cutaneous Na + storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. Cell Metab. 21 , 493–501 (2015).

Kino, T. et al. Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5. Sci. Signal. 2 , ra5 (2009).

PubMed   PubMed Central   Google Scholar  

Brocker, C., Thompson, D. C. & Vasiliou, V. The role of hyperosmotic stress in inflammation and disease. Biomol. Concepts 3 , 345–364 (2012).

Kuper, C., Fraek, M. L., Muller, H. H., Beck, F. X. & Neuhofer, W. Sepsis-induced urinary concentration defect is related to nitric oxide-dependent inactivation of TonEBP/NFAT5, which downregulates renal medullary solute transport proteins and aquaporin-2. Crit. Care Med. 40 , 1887–1895 (2012).

Qiu, Y., Hansen, P. J., Zhang, M. & Yang, D. in Experimental Biology 2016 Meeting Faseb Journal. 30 , (Suppl.) 920.10 (2016).

Google Scholar  

Linster, C. L., Van Schaftingen, E. & Hanson, A. D. Metabolite damage and its repair or pre-emption. Nat. Chem. Biol. 9 , 72–80 (2013). This article proposes a new concept — metabolite damage.

Franklin, B. S., Mangan, M. S. & Latz, E. Crystal formation in inflammation. Annu. Rev. Immunol. 34 , 173–202 (2016). This article provides a detailed conceptual and mechanistic framework for phase transition as a universal 'danger signal' sensed by PRRs.

Gutteridge, J. M. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin. Chem. 41 , 1819–1828 (1995).

Binder, C. J., Papac-Milicevic, N. & Witztum, J. L. Innate sensing of oxidation-specific epitopes in health and disease. Nat. Rev. Immunol. 16 , 485–497 (2016).

Imai, Y. et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133 , 235–249 (2008). This article shows the extremely potent pathological effect exerted by lipid peroxidation via TLR4 signalling.

Suzuki, T., Motohashi, H. & Yamamoto, M. Toward clinical application of the KEAP1-NRF2 pathway. Trends Pharmacol. Sci. 34 , 340–346 (2013).

Bettigole, S. E. & Glimcher, L. H. Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33 , 107–138 (2015).

Lindquist, S. The heat-shock response. Annu. Rev. Biochem. 55 , 1151–1191 (1986).

Mohri-Shiomi, A. & Garsin, D. A. Insulin signaling and the heat shock response modulate protein homeostasis in the Caenorhabditis elegans intestine during infection. J. Biol. Chem. 283 , 194–201 (2008).

Singh, V. & Aballay, A. Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc. Natl Acad. Sci. USA 103 , 13092–13097 (2006).

Murapa, P., Ward, M. R., Gandhapudi, S. K., Woodward, J. G. & D'Orazio, S. E. Heat shock factor 1 protects mice from rapid death during Listeria monocytogenes infection by regulating expression of tumor necrosis factor-α during fever. Infect. Immun. 79 , 177–184 (2011).

Richardson, C. E., Kooistra, T. & Kim, D. H. An essential role for XBP-1 in host protection against immune activation in C. elegans . Nature 463 , 1092–1095 (2010).

Filone, C. M. et al. The master regulator of the cellular stress response (HSF1) is critical for orthopoxvirus infection. PLoS Pathog. 10 , e1003904 (2014).

Weitzman, M. D. & Weitzman, J. B. What's the damage? The impact of pathogens on pathways that maintain host genome integrity. Cell Host Microbe 15 , 283–294 (2014).

Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14 , 197–210 (2013).

Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13 , 722–737 (2013).

Orvedahl, A. et al. Autophagy protects against sindbis virus infection of the central nervous system. Cell Host Microbe 7 , 115–127 (2010).

Maurer, K. et al. Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin. Cell Host Microbe 17 , 429–440 (2015).

Medzhitov, R. Origin and physiological roles of inflammation. Nature 454 , 428–435 (2008). This article is a 'must read' and probably the best succinct review so far on inflammation.

Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517 , 311–320 (2015).

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 , 1060–1072 (2012).

Fridman, J. S. & Lowe, S. W. Control of apoptosis by p53. Oncogene 22 , 9030–9040 (2003).

Ashida, H. et al. Cell death and infection: a double-edged sword for host and pathogen survival. J. Cell Biol. 195 , 931–942 (2011).

Gillet, G. & Brun, G. Viral inhibition of apoptosis. Trends Microbiol. 4 , 312–317 (1996).

Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510 , 92–101 (2014).

Lee, T. S. & Chau, L. Y. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat. Med. 8 , 240–246 (2002).

Chen, Y. C. et al. Nitric oxide and prostaglandin E2 participate in lipopolysaccharide/interferon-gamma-induced heme oxygenase 1 and prevent RAW264.7 macrophages from UV-irradiation-induced cell death. J. Cell. Biochem. 86 , 331–339 (2002).

Otterbein, L. E. et al. Carbon monoxide mediates anti-inflammatory effects via the mitogen activated protein kinase pathway. Nat. Med. 6 , 422–428 (2000).

Brouard, S. et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J. Exp. Med. 192 , 1015–1026 (2000). This is the original description of the cytoprotective effects exerted by the gasotransmitter carbon monoxide.

Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10 , 826–837 (2010).

Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81 , 1–5 (2007).

Mustafa, A. K., Gadalla, M. M. & Snyder, S. H. Signaling by gasotransmitters. Sci. Signal. 2 , re2 (2009).

Wegiel, B. et al. Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation. J. Clin. Invest. 124 , 4926–4940 (2014). This article proposes that the gasotransmitter carbon monoxide, produced by macrophages via haem catabolism by HO1, provides metabolic sensing of microbes and adjusts macrophage antimicrobial responses accordingly.

Soares, M. P. & Hamza, I. Macrophages and iron metabolism. Immnunity 44 , 492–504 (2016).

Article   CAS   Google Scholar  

Beg, A. A. & Baltimore, D. An essential role for NF-kB in preventing TNFα -induced cell death. Science 274 , 782–784 (1996).

Buchon, N., Broderick, N. A., Poidevin, M., Pradervand, S. & Lemaitre, B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe 5 , 200–211 (2009). This is the original finding of the crucial part played by regenerative responses of the gut epithelium as a defence strategy against enteric pathogens.

Hochmuth, C. E., Biteau, B., Bohmann, D. & Jasper, H. Redox regulation by KEAP1 and NRF2 controls intestinal stem cell proliferation in Drosophila . Cell Stem Cell 8 , 188–199 (2011).

Bonfini, A., Liu, X. & Buchon, N. From pathogens to microbiota: how Drosophila intestinal stem cells react to gut microbes. Dev. Comp. Immunol. 64 , 22–38 (2016).

Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517 , 293–301 (2015).

Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12 , 1045–1054 (2011).

Turner, J. E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210 , 2951–2965 (2013).

Monticelli, L. A. et al. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc. Natl Acad. Sci. USA 112 , 10762–10767 (2015).

Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528 , 560–564 (2015).

Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30 , 531–564 (2012).

Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155 , 1282–1295 (2013).

Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162 , 1078–1089 (2015). References 91 and 92 are the original descriptions of an unsuspected physiological role for tissue-resident T reg cells in conferring tissue damage control and disease tolerance to infections (reference 92).

Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513 , 564–568 (2014).

Noel, S. et al. T lymphocyte-specific activation of NRF2 protects from AKI. J. Am. Soc. Nephrol. 26 , 2989–3000 (2015).

Cramer, T. et al. HIF1α is essential for myeloid cell-mediated inflammation. Cell 112 , 645–657 (2003).

Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146 , 772–784 (2011).

McFall-Ngai, M. et al. Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl Acad. Sci. USA 110 , 3229–3236 (2013).

Ayres, J. S. & Schneider, D. S. The role of anorexia in resistance and tolerance to infections in Drosophila . PLoS Biol. 7 , e1000150 (2009).

Jamieson, A. M., Yu, S., Annicelli, C. H. & Medzhitov, R. Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection. Cell Host Microbe 7 , 103–114 (2010).

Cunnington, A. J., de Souza, J. B., Walther, M. & Riley, E. M. Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization. Nat. Med. 18 , 120–127 (2012). References 99 and 100 are the original findings that disease tolerance to one class of pathogens can compromise immune-driven resistance to co-infections by another class of pathogens.

Kara, E. E. et al. Tailored immune responses: novel effector helper T cell subsets in protective immunity. PLoS Pathog. 10 , e1003905 (2014).

Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 15 , 271–282 (2015).

Allen, J. E. & Wynn, T. A. Evolution of TH2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog. 7 , e1002003 (2011).

Soares, M. P. & Weiss, G. The Iron age of host-microbe interactions. EMBO Rep. 16 , 1482–1500 (2015).

Murray, P. J. Amino acid auxotrophy as a system of immunological control nodes. Nat. Immunol. 17 , 132–139 (2016).

Sahoo, M., Del Barrio, L., Miller, M. A. & Re, F. Neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with Burkholderia species. PLoS Pathog. 10 , e1004327 (2014).

Gimblet, C. et al. IL-22 protects against tissue damage during cutaneous leishmaniasis. PLoS ONE 10 , e0134698 (2015).

Robinson, K. M., Kolls, J. K. & Alcorn, J. F. The immunology of influenza virus-associated bacterial pneumonia. Curr. Opin. Immunol. 34 , 59–67 (2015).

Castiglia, V. et al. Type I interferon signaling prevents IL-1β-driven lethal systemic hyperinflammation during invasive bacterial infection of soft tissue. Cell Host Microbe 19 , 375–387 (2016).

Sullivan, G. W., Fang, G., Linden, J. & Scheld, W. M. A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J. Infect. Dis. 189 , 1897–1904 (2004).

Escobar, D. A. et al. Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J. Surg. Res. 194 , 262–272 (2015).

Mulchandani, N. et al. Stimulation of brain AMP-activated protein kinase attenuates inflammation and acute lung injury in sepsis. Mol. Med. 21 , 637–644 (2015).

Rialdi, A. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352 , aad7993 (2016).

Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180 , 5771–5777 (2008).

Muhl, H. et al. IL-22 in tissue-protective therapy. Br. J. Pharmacol. 169 , 761–771 (2013).

Vilaplana, C. et al. Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis. J. Infect. Dis. 208 , 199–202 (2013).

Carey, M. A. et al. Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection. J. Immunol. 175 , 6878–6884 (2005).

Hideko Tatakihara, V. L. et al. Effects of cyclooxygenase inhibitors on parasite burden, anemia and oxidative stress in murine Trypanosoma cruzi infection. FEMS Immunol. Med. Microbiol. 52 , 47–58 (2008).

Stanley, E. D., Jackson, G. G., Panusarn, C., Rubenis, M. & Dirda, V. Increased virus shedding with aspirin treatment of rhinovirus infection. JAMA 231 , 1248–1251 (1975).

Tauber, S. C. & Nau, R. Immunomodulatory properties of antibiotics. Curr. Mol. Pharmacol. 1 , 68–79 (2008).

Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497 , 451–457 (2013).

Cai, Y., Cao, X. & Aballay, A. Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways. mBio 5 , e01235–14 (2014).

Billingham, R. E., Brent, L. & Medawar, P. B. Actively acquired tolerance of foreign cells. Nature 172 , 603–606 (1953).

Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447 , 972–978 (2007).

Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345 , 1251086 (2014).

Netea, M. G., Latz, E., Mills, K. H. & O'Neill, L. A. Innate immune memory: a paradigm shift in understanding host defense. Nat. Immunol. 16 , 675–679 (2015). Reference 124 provides a mechanistic basis for lipopolysaccharide tolerance in macrophages, which was later expanded to other PRR agonists and coined as 'trained immunity' (references 125 and 126).

Dionne, M. S., Pham, L. N., Shirasu-Hiza, M. & Schneider, D. S. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila . Curr. Biol. 16 , 1977–1985 (2006).

Raberg, L., Graham, A. L. & Read, A. F. Decomposing health: tolerance and resistance to parasites in animals. Phil. Trans. R. Soc. B 364 , 37–49 (2009).

Article   PubMed   Google Scholar  

Simms, E. L. Defining tolerance as a norm of reaction. Evol. Ecol. 14 , 563–570 (2000).

Schneider, D. S. Tracing personalized health curves during infections. PLoS Biol. 9 , e1001158 (2011). This is the original description of disease curves and their interpretation as a novel way to understand host–pathogen interactions.

Torres, B. Y. et al. Tracking resilience to infections by mapping disease space. PLoS Biol. 14 , e1002436 (2016).

Hedges, L. M., Brownlie, J. C., O'Neill, S. L. & Johnson, K. N. Wolbachia and virus protection in insects. Science 322 , 702 (2008).

Moreira, L. A. et al. A Wolbachia symbiont in Aedes aegypti limits infection with dengue, chikungunya, and Plasmodium . Cell 139 , 1268–1278 (2009).

Dutra, H. L. et al. Wolbachia blocks currently circulating zika virus isolates in Brazilian Aedes aegypti mosquitoes. Cell Host Microbe 19 , 771–774 (2016).

Pan, X. et al. Wolbachia induces reactive oxygen species (ROS)-dependent activation of the Toll pathway to control dengue virus in the mosquito Aedes aegypti . Proc. Natl Acad. Sci. USA 109 , E23–E31 (2012).

PubMed   Google Scholar  

Caragata, E. P. et al. Dietary cholesterol modulates pathogen blocking by Wolbachia . PLoS Pathog. 9 , e1003459 (2013).

Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108 , 5354–5359 (2011).

Zeng, Melody, Y. et al. Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens. Immunity 44 , 647–658 (2016).

Yilmaz, B. et al. Gut microbiota elicits a protective immune response against malaria transmission. Cell 159 , 1277–1289 (2014).

Villarino, N. F. et al. Composition of the gut microbiota modulates the severity of malaria. Proc. Natl Acad. Sci. USA 113 , 2235–2240 (2016). Articles 137–140 provide mechanistic demonstrations of how symbiotic interactions with different bacteria in the microbiota modulate resistance to infections by different blood-borne pathogens.

Schieber, A. M. et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 350 , 558–563 (2015).

Zele, F., Nicot, A., Duron, O. & Rivero, A. Infection with Wolbachia protects mosquitoes against Plasmodium-induced mortality in a natural system. J. Evol. Biol. 25 , 1243–1252 (2012).

Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453 , 620–625 (2008).

Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514 , 638–641 (2014).

Brestoff, J. R. & Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 14 , 676–684 (2013).

Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331 , 337–341 (2011).

Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13 , 790–801 (2013).

Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5 , 2177–2189 (2007).

Sun, H., Kamanova, J., Lara-Tejero, M. & Galan, J. E. A. Family of Salmonella type III secretion effector proteins selectively targets the NF-κB signaling pathway to preserve host homeostasis. PLoS Pathog. 12 , e1005484 (2016).

Chau, T. A. et al. Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat. Med. 15 , 641–648 (2009).

Naquet, P., Giessner, C. & Galland, F. Metabolic adaptation of tissues to stress releases metabolites influencing innate immunity. Curr. Opin. Immunol. 38 , 30–38 (2016).

Dal Peraro, M. & van der Goot, F. G. Pore-forming toxins: ancient, but never really out of fashion. Nat. Rev. Microbiol. 14 , 77–92 (2016).

Nathan, C. & Shiloh, M. U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl Acad. Sci. USA 97 , 8841–8848 (2000).

Beckman, J. S. & Koppenol, W. H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271 , C1424–C1437 (1996).

Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13 , 251–262 (2012).

Eijkelenboom, A. & Burgering, B. M. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 14 , 83–97 (2013).

Becker, T. et al. FOXO-dependent regulation of innate immune homeostasis. Nature 463 , 369–373 (2010).

Ahn, H. M., Lee, K. S., Lee, D. S. & Yu, K. JNK/FOXO mediated peroxiredoxin V expression regulates redox homeostasis during Drosophila melanogaster gut infection. Dev. Comp. Immunol. 38 , 466–473 (2012).

Seiler, F. et al. FOXO transcription factors regulate innate immune mechanisms in respiratory epithelial cells. J. Immunol. 190 , 1603–1613 (2013).

Reed, S. A., Sandesara, P. B., Senf, S. M. & Judge, A. R. Inhibition of FOXO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. FASEB J. 26 , 987–1000 (2012).

Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13 , 397–411 (2013).

Ip, W. K. & Medzhitov, R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat. Commun. 6 , 6931 (2015).

Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440 , 237–241 (2006).

Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 , 1357–1361 (2010).

Idzko, M., Ferrari, D. & Eltzschig, H. K. Nucleotide signalling during inflammation. Nature 509 , 310–317 (2014).

Mahamed, D. A., Toussaint, L. E. & Bynoe, M. S. CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection. Infect. Immun. 83 , 721–729 (2015).

Alam, M. S. et al. CD73 is expressed by human regulatory T helper cells and suppresses proinflammatory cytokine production and Helicobacter felis -induced gastritis in mice. J. Infect. Dis. 199 , 494–504 (2009).

Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414 , 916–920 (2001).

Madenspacher, J. H. et al. p53 Integrates host defense and cell fate during bacterial pneumonia. J. Exp. Med. 210 , 891–904 (2013).

Okabe, Y. & Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol. 17 , 9–17 (2015).

Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14 , 986–995 (2013).

Song, X. et al. Growth factor FGF2 cooperates with interleukin-17 to repair intestinal epithelial damage. Immunity 43 , 488–501 (2015).

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Acknowledgements

The authors thank J. Thompson and F. Brazza for insightful comments and S. Ramos for careful review and editing of the manuscript (Instituto Gulbenkian de Ciência). M.P.S. is supported by Fundação Calouste Gulbenkian, Fundação para a Ciência e Tecnologia (FCT; PTDC/SAU-TOX/116627/2010 and HMSP-ICT/0022/2010) and the European Community 7th Framework program (ERC-2011-AdG 294709-DAMAGECONTROL). L.F.M. is an Fundação para a Ciência e Tecnologia Investigator and is supported by the European Community Horizon 2020 (ERC-2014-CoG 647888-iPROTECTION). L.T. is supported by Fundação Calouste Gulbenkian and Fundação para a Ciência e Tecnologia PTDC/BEX-GMG/3128/2014.

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Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for fig. 3, powerpoint slide for fig. 4.

Maintenance of a stable physiological 'internal' state in multicellular organisms via feedback mechanisms that allow physiological functions to proceed despite variations in the 'external' environment.

Refers to a breakdown of homeostasis in which immunity functions as the main cause of disease.

Any variations in the 'external' environment that disrupt the maintenance of a stable physiological environment in which biological processes are allowed to proceed.

(ATM kinase). A serine and threonine protein kinase that is recruited and activated by DNA double-strand breaks and that has an important role in the activation of DNA damage responses.

A specific form of programmed cell death mediated via a genetically encoded mechanism involving receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and the mixed lineage kinase domain-like (MLKL) pseudokinase.

Genetically encoded form of programmed cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and by the accumulation of lipid hydroperoxides.

Endogenous molecules released from damaged cells and sensed by receptors of the immune system that alert for tissue dysfunction or damage, associated with disruption of homeostasis.

An evolutionarily conserved resistance mechanism against infection based on the host's ability to withhold nutrients, such as iron, from pathogens.

A class of red aromatic polyketide drugs derived from Streptomyces spp. bacteria that intercalate into DNA, arresting transcription and cell division, a property widely used therapeutically against cancers.

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Soares, M., Teixeira, L. & Moita, L. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17 , 83–96 (2017). https://doi.org/10.1038/nri.2016.136

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General Mechanisms of Tissue Injury in Parasitic Infections

• First Online: 01 January 2013

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• Claudio M. Lezama-Davila BSc, MSc, PhD 3 , 4 ,
• Abhay R. Satoskar MSc, MD, PhD 5 &
• Angelica P. Isaac-Marquez BSc, MSc 6  

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Parasitic infections represent a serious health problem recognized by the World Health Organization. Most mechanisms of tissue injury during these types of infections are directly related to immunological processes. There are several immunologically based responses of tissue damage triggered by chronic parasite infections. Apoptosis, cytokines, and nitric oxide production constitute some of the most important pathways of protection against infection, but when unproperly regulated, they can induce tissue damage to infected hosts. In this review, we analyze different mechanisms of tissue damage triggered for some of the most important parasitic diseases recognized by the World Health Organization (WHO).

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Pathogenesis of Parasitic Diseases

Pathophysiology of parasitic disease.

Modabber F. The leishmaniasis. Eighth program report of the UNDP/World Bank/WHO. In: Maurice J, Pearce AM, editors. Tropical disease research: a global partnership. Geneva: WHO; 1987. p. 99–112.

Google Scholar  

Actor JK, Shirai M, Kullberg MC, Buller RM, Sher A, Berzofsky JA. Helminth infection results in decreased virus-specific CD8 + cytotoxic T-cell and Th1 cytokine responses as well as delayed virus clearance. Proc Natl Acad Sci U S A. 1993;90:948–52.

Article   PubMed   CAS   Google Scholar  

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.

PubMed   CAS   Google Scholar  

Mosmann TR, Coffman RL. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–73.

Mosmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–47.

Lezama-Dávila CM, Williams D, Gallagher G, Alexander J. Cytokine control of Leishmania infection in the BALB/c mouse: enhancement and inhibition of parasite growth by local administration of IL2 or IL4 is species and time dependent. Parasite Immunol. 1992;14:37–48.

Article   PubMed   Google Scholar  

Lezama-Dávila CM, Gallagher G. CD4 + , CD8 + and CD4 - CD8 - T cell-subsets can confer protection against Leishmania m . mexicana infection. Mem Inst Oswaldo Cruz. 1995;90:51–8.

Lezama-Dávila CM, Isaac-Márquez AP. Inmunobiología de las leishmaniosis. Campeche: Universidad Autónoma de Campeche (ED); 1995. ISBN 9686585362.

Liew FY. Functional heterogeneity of CD4 + T cells in leishmaniasis. Immunol Today. 1989;10:40–5.

Lezama-Dávila CM, Isaac-Márquez AP, Padierna-Olivos J, Aguilar-Torrentera R, Chapa-Ruiz R. Immunomodulation of Chiclero’s ulcer. Role of eosinophils, T cells, tumor necrosis factor and interleukin-2. Scand J Immunol. 1998;47:502–8.

Finkelman FD, Pearce EJ, Urban Jr JF, Sher A. Regulation and biological function of helminth-induced cytokine responses. Immunol Today. 1991;12:A62–6.

Romagnani S. Human Th1 and Th2 subsets: doubt no more. Immunol Today. 1991;12:256–7.

Romagnani S. Induction of Th1 and Th2 responses: a key role for the ‘natural’ immune response? Immunol Today. 1992;13:379–81.

Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol. 1994;12:227–57.

Romagnani S. Biology of human Th1 and Th2 cells. J Clin Immunol. 1995;15:121–9.

Romagnani S, Maggi E, Del Prete G. HIV can induce a Th1 to Th0 shift, and preferentially replicates in CD4+ T-cell clones producing Th2-type cytokines. Res Immunol. 1994;14:611–8.

Article   Google Scholar  

Yoshida H, Miyazaki Y, Wang S, Hamano S. Regulation of defense responses against protozoan infection by interleukin-27 and related cytokines. J Biomed Biotechnol. 2007;2007:79401.

Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:133–1141.

Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.

Patera AC, Pesnicak L, Bertin J, Cohen JI. Interleukin 17 modulates the immune response to vaccinia virus infection. Virology. 2002;299:56–63.

Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol. 2002;2:845–58.

Sher A, Coffman RL. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol. 1992;10:385–409.

Zwingenberger K, Hohmann A, de Brito MC, Ritter M. Impaired balance of interleukin-4 and interferon-gamma production in infections with Schistosoma mansoni and intestinal nematodes. Scand J Immunol. 1991;34:243–51.

Dixon H, Blanchard C, Deschoolmeester ML, Yuill NC, Christie JW, Rothenberg ME, et al. The role of Th2 cytokines, chemokines and parasite products in eosinophil recruitment to the gastrointestinal mucosa during helminth infection. Eur J Immunol. 2006;36:1753–63.

Inobe J, Slavin AJ, Komagata Y, Chen Y, Liu L, Weiner HL. IL-4 is a differentiation factor for transforming growth factor-beta secreting Th3 cells and oral administration of IL-4 enhance oral tolerance in experimental allergic encephalomyelitis. Eur J Immunol. 1998;28:2780–90.

Peltz G. A role for CD4 + T-cell subsets producing a selective pattern of lymphokines in the pathogenesis of human chronic inflammatory and allergic diseases. Immunol Rev. 1991;123:23–35.

Leung DY, Martin RJ, Szefler SJ, Sher ER, Ying S, Kay AB, et al. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med. 1995;181:33–40.

Del Prete GF, De Carli M, D’Elios MM, Maestrelli P, Ricci M, Fabbri L, et al. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol. 1993;23:1445–9.

Secrist H, DeKruyff RH, Umetsu DT. Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type. J Exp Med. 1995;181:1081–9.

Xu D, Liu H, Komai-Koma M, Campbell C, McSharry C, Alexander J, et al. CD\4 + CD25 + regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J Immunol. 2003;170:394–9.

Aseffa A, Gumy A, Launois P, MacDonald HR, Louis JA, Tacchini-Cottier F. The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4 + CD25 + T cells. J Immunol. 2002;169:3232–41.

Satoskar A, Brombacher F, Dai WJ, McInnes I, Liew FY, Alexander J, et al. SCID mice reconstituted with IL-4-deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis. J Immunol. 1997;159:5005–13.

Vanloubbeeck Y, Ackermann MR, Jones DE. Late cutaneous metastases in C3H SCID mice infected with Leishmania amazonensis . J Parasitol. 2005;91:226–8.

Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J, et al. Expression of FoxP3, a key molecule in CD4 + CD25 + regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol. 2004;126:81–4.

Vorob’ev AA, Bykovskaia SN, Pashkov EP, Bykov AS. The role of regulatory cells CD4 + CD25 + in the development of chronic infective diseases. Vestn Ross Akad Med Nauk. 2006;9–10:24–9.

PubMed   Google Scholar  

Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003;85:85–95.

Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest. 2006;116:485–94.

Yamamura M, Wang XH, Ohmen JD, Uyemura K, Rea TH, Bloom BR, et al. Cytokine patterns of immunologically mediated tissue damage. J Immunol. 1992;149:1470–5.

Mitchell GF, Curtis JM, Handman E, McKenzie IF. Cutaneous leishmaniasis in mice: disease patterns in reconstituted nude mice of several genotypes infected with Leishmania tropica. Aust J Exp Biol Med Sci. 1980;58:521–32.

Mitchell GF. Responses to infection with metazoan and protozoan parasites in mice. Adv Immunol. 1979;28:451–511.

Jong EC, Chi EY, Klebanoff SJ. Human neutrophil-mediated killing of schistosomula of Schistosoma mansoni : augmentation by schistosomal binding of eosinophil peroxidase. Am J Trop Med Hyg. 1984;33:104–15.

Chitkara RK, Krishna G. Parasitic pulmonary eosinophilia. Semin Respir Crit Care Med. 2006;27:171–84.

Ellis TN, Beaman BL. Interferon-γ activation of polymorphonuclear neutrophil function. Immunology. 2004;112:2–12.

Padigel UM, Stein L, Redding K, Lee JJ, Nolan TJ, Schad GA, et al. Signaling through Galphai2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larval Strongyloides stercoralis in mice. J Leukoc Biol. 2007;81:1120–6.

Negrao-Correa D. Importance of immunoglobulin E (IgE) in the protective mechanism against gastrointestinal nematode infection: looking at the intestinal mucosae. Rev Inst Med Trop Sao Paulo. 2001;43:291–9.

Stassen M, Hultner L, Schmitt E. Classical and alternative pathways of mast cell activation. Crit Rev Immunol. 2002;22:115–40.

Campos MA, Gazzinelli RT. Trypanosoma cruzi and its components as exogenous mediators of inflammation recognized through Toll-like receptors. Mediators Inflamm. 2004;13:139–43.

Dosreis GA, Barcinski MA. Apoptosis and parasitism: from the parasite to the host immune response. Adv Parasitol. 2001;49:133–61.

Erwing LP, Henson PM. Immunological consequences of apoptotic cell phagocytosis. Am J Pathol. 2007;171:2–8.

Liew FY, Cox FE. Nonspecific defence mechanism: the role of nitric oxide. Immunol Today. 1991;12:A17–21.

Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992;256:225–8.

Fang FC. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol. 2004;2:820–32.

Schofield L. Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis. Immunol Cell Biol. 2007;85:130–7.

Soares MB, Santos RR. Immunopathology of cardiomyopathy in the experimental Chagas disease. Mem Inst Oswaldo Cruz. 1999;94 Suppl 1:257–62.

Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol. 2007;85:148–54.

Nüssler NC, Stange B, Hoffman RA, Schraut WH, Bauer AJ, Neuhaus P. Enhanced cytolytic activity of intestinal intraepithelial lymphocytes in patients with Crohn’s disease. Langenbecks Arch Surg. 2000;385:218–24.

Honma J, Mitomi H, Murakami K, Igarashi M, Saigenji K, Toyama K. Nodular duodenitis involving CD8 + cell infiltration in patients with ulcerative colitis. Hepatogastroenterology. 2001;48:1604–10.

Baughman R. Diagnostic quiz. Case no. 1: central giant cell granuloma. Todays FDA. 2007;19:20–2.

Asashi H, Stadecker MJ. Analysis of egg antigens inducing hepatic lesions in schistosome infection. Parasitol Int. 2003;52:361–7.

Barbi J, Oghumu S, Rosas LE, Carlson T, Lu B, Gerard C, et al. Lack of CXCR3 delays the development of hepatic inflammation but does not impair resistance to Leishmania donovani. J Infect Dis. 2007;195:1713–7.

Stanley CA, Engwerda CR. Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol. 2007;85:138–47.

Schofield L. Rational approaches to developing an anti-disease vaccine against malaria. Microbes Infect. 2007;9:784–91.

de Walick S, Amante FH, McSweeney KA, Randall LM, Stanley AC, Haque A, et al. Conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria. J Immunol. 2007;178:6033–7.

Nobl T, de Veer MJ, Schofield L. Stimulation of innate immune responses by malarial glycosylphosphatidylinositol via pattern recognition receptors. Parasitology. 2005;130(Suppl):S45–62.

Taylor-Robinson AW. Vaccination against malaria: targets, strategies and potentiation of immunity to blood stage parasites. Front Biosci. 2000;5:E16–29.

Hunt NH, Stocker K. Heme moves to center stage in cerebral malaria. Nat Med. 2007;13:667–9.

Kret M, Arora R. Pathophysiological basis of right ventricular remodeling. J Cardiovasc Pharmacol Ther. 2007;12:5–14.

Savino W, Villa-Verde DM, Mendes-da-Cruz DA, Silva-Monteiro E, Perez AR, Aoki Mdel P, et al. Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi. Cytokine Growth Factor Rev. 2007;18:107–24.

Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A. Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol. 2006;177:3515–9.

Drennan MB, Stijlemans B, Van Den Abbeele J, Quesniaux VJ, Barkhuizen M, Brombacher F, et al. The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent. J Immunol. 2005;175:2501–9.

Yoshihara K, Morris A, Iraqi R, Naessens J. Cytokine mRNA profiles in bovine macrophages stimulated with Trypanosoma congolense. J Vet Med Sci. 2007;69:421–3.

Finkelman FD, Urban JF. The other side of the coin: the protective role of the Th2 cytokines. J Allergy Clin Immunol. 2001;107:772–80.

Reiman RM, Thompson RW, Feng CG, Hari D, Knight R, Cheever AW, et al. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun. 2006;74:1471–9.

Whal SM, Frazier-Jessen M, Jin WW, Kopp JB, Sher A, Cheever AW. Cytokine regulation of schistosome-induced granuloma and fibrosis. Kidney Int. 1997;51:1370–5.

McKee AS, Pearce EJ. CD25 + CD4 + cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol. 2004;173:1224–31.

Abouel-Nour MF, Lofty M, Attallah AM, Doughty BL. Schistosoma mansoni major egg antigen Smp40: molecular modeling and potential immunoreactivity for anti-pathology vaccine development. Mem Inst Oswaldo Cruz. 2006;101:365–72.

Stadecker MJ, Hernandez HJ, Asashi H. The identification and characterization of new immunogenic egg components: implications for evaluation and control of the immunopathogenic T cell response in schistosomiasis. Mem Inst Oswaldo Cruz. 2001;96(Suppl):29–33.

Gottstein B, Nash TE. Antigenic variation in Giardia lamblia: infection of congenitally athymic nude and scid mice. Parasite Immunol. 1991;13:649–59.

Roberts-Thomson IC, Mitchel GF. Giardiasis in mice. I. Prolonged infections in certain mouse strains and hypothymic (nude) mice. Gastroenterology. 1978;75:42–6.

Scott KG-E, Logan MR, Klammer GM, Teoh DA, Buret AG. Jejunal brush border microvillous alterations in Giardia muris -infected mice: role of T lymphocytes and interleukin-6. Infect Immun. 2000;68:3412–8.

Farting MJ. Diarrhoeal disease: current concepts and future challenges. Pathogenesis of giardiasis. Trans R Soc Trop Med Hyg. 1993;87 Suppl 3:17–21.

Scott KG, Yu LC, Buret AG. Role of CD8+ and CD4+ T lymphocytes in jejunal mucosal injury during murine giardiasis. Infect Immun. 2004;72:3536–42.

Heyworth MF, Carlson JR, Ermark TH. Clearance of Giardia muris infection requires helper/inducer T lymphocytes. J Exp Med. 1987;165:1743–8.

Müller N, von Allmen N. Recent insights into the mucosal reactions associated with Giardia lamblia infections. Int J Parasitol. 2005;35:1339–47.

Melgar S, Bas A, Hammarström S, Hammarström ML. Human small intestinal mucosa harbours a small population of cytolytically active CD8 + αβ T lymphocytes. Immunology. 2002;106:476–85.

Belosevic M, Faubert GM, MacLean JD. Disaccharidase activity in the small intestine of gerbils (Meriones unguiculatus) during primary and challenge infections with Giardia lamblia. Gut. 1989;30:1213–9.

Teoh DA, Kamieniecki D, Pang G, Buret AG. Giardia lamblia rearranges F-actin and alpha-actinin in human colonic and duodenal monolayers and reduces transepithelial electrical resistance. J Parasitol. 2000;86:800–6.

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Pathology Department, The Ohio State University Medical Center, 320 10th West Avenue, Starling Loving, M408, Columbus, OH, 43210, USA

Claudio M. Lezama-Davila BSc, MSc, PhD

Department of Microbiology, The Ohio State University, 320 10th West Ave, Starling Loving, M408, Columbus, OH, 43210, USA

Pathology Department, Ohio State Medical Center, 320 10th West Avenue, Starling Loving, M408, Columbus, OH, 43210, USA

Abhay R. Satoskar MSc, MD, PhD

Centro de Investigaciones en Enfermedades Tropicales, University of Campeche, Av. Patricio Trueba Regil s/n, Campeche, 24090, Mexico

Angelica P. Isaac-Marquez BSc, MSc

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Lezama-Davila, C.M., Satoskar, A.R., Isaac-Marquez, A.P. (2013). General Mechanisms of Tissue Injury in Parasitic Infections. In: Barrios, R., Haque, A. (eds) Parasitic Diseases of the Lungs. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-37609-2_3

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The Parasites that Transformed Our Immune System

University of utah health.

• U Health Plans

Sophia Friesen

Summer is near, flowers are blooming, and more than one in four Americans have seasonal allergies. But what most people don’t know is that the part of the immune system that causes allergies has been shaped from day one by the most successful human pathogens on the planet: a group of parasitic worms called helminths.   Keke Fairfax, PhD, believes that the best way to understand the human immune system is to understand how it’s evolved to deal with pathogens, especially helminths. “There has never been mammalian immunity without helminths,” explains Fairfax, an associate professor in the Department of Pathology at the Spencer Fox Eccles School of Medicine at the University of Utah. The Type 2 immune system, which is involved in allergic reactions and wound healing, evolved in response to parasitic worms, Fairfax says. “By studying the interaction between the immune system and these pathogens, you can actually understand how the mammalian immune system evolved to function.”

While helminth infections are relatively rare in the U.S., they’re extremely common worldwide, currently affecting more than 1.5 billion people. They cause chronic diseases such as schistosomiasis, which can lead to malnutrition, liver failure, and death. These diseases present an enormous public health burden globally.   But their relative absence in the U.S. may be causing unexpected negative health consequences. “It’s very clear that helminths drive the development of very specific cells in the immune system, and without that, the immune system does not necessarily develop properly,” Fairfax says.    Parasitic worms produce many chemicals that reduce the activity of the immune system, which helps the worms maintain a chronic infection in their host. For millions of years, our immune systems have evolved to work in the presence of these immune-suppressing chemicals; without them, people may be at increased risk of autoimmune and inflammatory diseases, including asthma and diabetes, Fairfax says. She adds that many immunologists believe that the lower rate of helminth exposure in the U.S. may contribute to the increasing prevalence of these conditions.   But parasitic worms’ immune-suppressing effects can cause problems, too. Worm infection can make some vaccines less effective . And these changes can last long-term—in some cases, even across generations. If someone is infected while pregnant, it can tamp down their kids’ immune responses to measles vaccination.

Revealing long-term health changes

Fairfax’s lab is trying to unravel the complex relationship between helminth infection and the immune system, uncovering long-lasting health changes that depend on what stage of life the infection occurs in. “There are specific windows in the development of an individual where different cell types are open for reprogramming,” Fairfax explains.    Her lab’s research has identified how, in mice, schistosomiasis infection during pregnancy alters some of the immune signals in the next generation , changing the number of some immune cells and weakening the response to vaccination. She’s also uncovered sex-specific differences in how helminth infection affects metabolism , helping explain why worm infection can protect against metabolic diseases. 

Transforming human health

Because helminth infection is less common in the global North, Fairfax adds, it tends to be understudied relative to its importance. But the relatively small community of scientists investigating helminths have made an outsized impact on human health. Research on the interactions between the immune system and helminths was foundational to the development of drugs that affect Type 2 immunity, including the asthma drugs dupilumab/Dupixent and omazilumab/Xolair.   Fairfax says that these translational discoveries underscore the importance of basic science to lead to discoveries that transform human health. “One of the tenets of basic science is that you actually never know, 20 years from now, what a specific finding is going to lead to,” she says. “It’s really hard to predict.”    What’s certain is that, like the helminths she studies, Fairfax has found her niche. She knew she wanted to pursue science at age 6 and started researching pathogens in high school. “Then, in grad school, I found worms,” Fairfax says. “And I haven’t looked back.”

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Helminth parasites and immune regulation

Pedro h. gazzinelli-guimaraes.

1 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Building 4, Room 211, Bethesda, MD, 20892, USA

Thomas B. Nutman

Helminth parasites are complex metazoans that belong to different taxonomic families but that collectively share the capacity to downregulate the host immune response directed toward themselves (parasite-specific immunoregulation). During long-standing chronic infection, these helminths appear able to suppress immune responses to bystander pathogens/antigens and atopic, autoimmune, and metabolic disorders. Helminth-induced immunoregulation occurs through the induction of regulatory T cells or Th2-type cells (or both). However, secreted or excreted parasite metabolites, proteins, or extracellular vesicles (or a combination of these) may also directly induce signaling pathways in host cells. Therefore, the focus of this review will be to highlight recent advances in understanding the immune responses to helminth infection, emphasizing the strategies/molecules and some of the mechanisms used by helminth parasites to modulate the immune response of their hosts.

Introduction

Helminth parasites belong to a diverse group of complex metazoans from different taxonomic families. Collectively, helminth infections are a major public health problem worldwide, and recent estimates suggest that 1.5 billion people have one or more of the common helminth infections ( Table 1 ), most of whom reside in low- and middle-income countries in the endemic areas of Asia, Latin America, the Caribbean, and sub-Saharan Africa 1 .

N/A, not applicable. There is no development of adult worms in humans.

These many helminths each have significant differences in their biological life cycles along with marked variation in tissue tropism. These differences are reflected in the differences in clinical outcomes seen among the helminth parasites. Pathologic consequences of most helminth infection have been associated with both the parasite intensity (or burden) and the relative acuteness or chronicity of the infection.

Despite these helminth species-specific differences, helminths as a group have been shown to modulate/regulate the host response to themselves (parasite-specific immunoregulation) 2 – 4 . However, with long-standing chronic infection, these parasites can alter the immune response to bystander pathogens/antigens 5 , 6 , including vaccines 7 , 8 , and allergens 9 , 10 . In addition, they have been associated with modulation of the severity of inflammatory bowel disease (IBD) 11 , diabetes 12 , and arthritis 13 .

Because of the helminths’ capacity to regulate the host immune response, a regulation that can be partially reversed by anthelmintic therapy, there has been widespread interest in understanding the mechanisms underlying helminth-induced immune regulation along with those parasite-encoded molecules that may be driving such regulation. In particular, the so-called excretory/secretory (ES) products from helminth parasites have gained the most attention, as they may be targets for anthelmintic vaccines, diagnostics, and drugs or they could be useful as potential therapeutics for inflammatory and autoimmune disorders. Therefore, the focus of this review will be to highlight recent advances in understanding the immune responses to helminth infection, emphasizing the strategies/molecules used by helminth parasites to modulate the immune response of their hosts.

Acuteness and chronicity of infection drive distinct immune profiles

The complexity of the life cycles of helminth parasites that have multiple developmental stages of the parasite each with a distinct antigenic repertoire and often distinct tropisms for particular organ systems (for example, intestinal and airway mucosa in larval Ascaris lumbricoides and hookworm infections; skin/subcutaneous tissue and draining lymph nodes in Onchocerca volvulus infection; the hepatic portal system for Schistosoma mansoni ; and the muscle and the brain for Taenia solium cysticerci) makes it difficult to generalize about helminths as a single group 2 . Normally, however, infection occurs through the ingestion of eggs or exposure to infective larvae. Once in contact with their mammalian hosts, the parasite progressively develops during the migration of the larval stages through the host’s systems/organs that culminate in their maturation into adult worms within a specific habitat that reflects each helminth’s tropism for a particular anatomical niche. As these developmental transitions and migration occur over a period of time (from weeks to years, depending on the parasite and its particular mammalian host), immune responses are often regulated differently on the basis of the resident tissue or perhaps by the life span of the parasite.

One example of the complex developmental and migratory processes that occur following helminth infection is that caused by the roundworms A. lumbricoides , a parasite that, by current estimates, is harbored by more than 800 million people worldwide 14 . Human infection occurs following the ingestion of parasite eggs containing the third-stage infective larvae (L3) that hatch in the small intestine. After penetrating the intestine at the level of the caecum or proximal colon, these L3 migrate through the portal vessels to the liver and subsequently to the lungs. There they migrate through the lung parenchyma and penetrate into the alveolar spaces, causing a range of symptoms, including wheezing, dyspnea, cough, and substernal pain 15 , 16 . This early/acute phase of infection has been called larval ascariasis 17 . These migrating Ascaris larvae induce a local inflammatory response in the lungs of humans (causing a Löffler’s-like syndrome 18 ) and of experimentally infected mice. In mice, the inflammation has been characterized as a type 2 response (dominated by IL-4 and IL-13 and some IL-5). Tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels are also seen in the lung induced by larval migration. At the peak of Ascaris larval migration (~8 days post-infection), there is a marked production of IL-6, thought to be related to the prominent neutrophil infiltration 19 . When the larvae start to leave the lung tissue to migrate back to the small intestine to complete their life cycle, the neutrophil infiltrate in the lung is replaced by both alternatively activated (or M2) macrophages (AAM) (Fizz1+, Arginase-I+) and eosinophils that play a key role in tissue remodeling and prevention of re-infection 20 . Once back in the small intestine, the larvae mature into adult worms, establishing a long-term chronic infection characterized by a profoundly diminished helminth-specific response 21 , 22 .

Over the last 20 years, several experimental studies using intestinal nematodes of rodents such as Heligmosomoides polygyrus or Nippostrongylus brasiliensis have provided a detailed description of a “protective” immune response associated with worm expulsion 23 – 26 . Although the mechanisms of larval killing are less well-studied, it is known that early in infection, prior to adult worm development and establishment, mucosal epithelial sensor cells secrete a group of alarmins—for example, IL-25, thymic stromal lymphopoietin (TSLP), and IL-33—that promote the activation and differentiation of innate and adaptive type 2 cells, leading to the secretion of a myriad of cytokines, including IL-4, IL-5, IL-9, and IL-13 26 , 27 . These type 2-associated cytokines result in goblet cell hyperplasia, mucus hyper-secretion, and smooth muscle contraction and other immunological changes such as eosinophilia and the differentiation of AAM macrophages 26 , 28 .

Recently, a novel subset of epithelial cells, termed tuft cells, was identified in the small intestine. These tuft cells constitutively express IL-25. Von Moltke et al . 29 and Gerbe et al . 30 showed that after infection by the rodent hookworm N. brasiliensis , tuft cells produce IL-25 that in turn activates type 2 innate lymphoid cells (ILC2s) to produce IL-13 that subsequently acts on epithelial crypt progenitors to promote differentiation and increased frequency of both tuft and goblet cells. As reviewed by Grencis and Worthington 31 , this tuft cell–ILC2 circuit loop orchestrates a rapid and effective anti-helminth immune effector response that leads to worm expulsion.

For helminth infection in humans, the immune response during the early/acute phase of infection involves the induction of type 2-associated cytokines (IL-4, IL-5, IL-9, and IL-13) first by innate lymphocytes (ILC2) and later by effector antigen-specific polyfunctional CD4 T cells 32 . This relatively early phase also induces high antigen-specific IgG4 and IgE levels as well as peripheral and tissue eosinophilia and expanded populations of AAM 33 , 34 .

In peripheral blood, this polarized type 2 response occurs at the time of patency when egg laying (for example, S. mansoni ) 35 or microfilarial release (for example, Wuchereria bancrofti ) from adult females occurs 36 , resulting in a significant modulation of Th1 responses (IL-2 and interferon-gamma [IFN-γ]). However, this persistent dominant Th2 response over the course of the helminth infection also induces expansion of natural 37 – 39 and helminth-induced 40 , 41 regulatory T (Treg) cells and immunoregulatory monocytes 42 – 44 ; this same response drives B-cell class-switching to IgG4 45 . This new regulatory environment, characterized by low parasite antigen-specific lymphocyte proliferation, higher antigen-specific IgG4/IgE ratios, and increased levels of the regulatory cytokines IL-10 and transforming growth factor-beta (TGF-β), is the hallmark of an asymptomatic, chronic infection 46 – 49 .

In chronic filarial infections, microfilaremia is observed in clinically asymptomatic patients. Interestingly, T cells from these filarial-infected asymptomatic patients show the following: a muted/anergic parasite-specific lymphoproliferative response 50 – 52 ; an increased parasite-specific IL-4/IFN-γ ratio 46 ; dysfunctional antigen-presenting cells (APCs) 53 , 54 ; expanded natural Treg (nTreg) cells expressing CTLA-4, PD-1, and GITR (molecules associated with regulatory functions on nTreg cells) 55 ; and elevated IL-10 levels 48 , 56 . In contrast, infected patients with progressive and often symptomatic infection, such as elephantiasis, fail to suppress (or be tolerant to) filarial antigen-driven inflammation. This relative immune hyper-responsiveness is associated with microfilarial clearance but also consequent morbidity 56 . Furthermore, anthelmintic therapy that leads to clearance of the microfilariae or in vitro blockade of IL-10 can result in a recovery of many of the parasite antigen-specific responses, suggesting that they were actively inhibited in the presence of the parasites or of circulating parasite antigens 56 , 57 .

Traditionally, it has been shown that, beyond attenuating parasite-specific response, helminths can suppress the immunity to bystander pathogens or to vaccines 7 , 58 . It is known that the induction of the regulatory response by helminths is associated with the downmodulation of Th1 response 3 , 59 , 60 , considered crucial for the immunological control of viral, bacterial, or protozoal infections ( Figure 1 ). Immuno-epidemiological studies suggest that coincident infection with helminths has a strong potential to significantly influence the course of viral or protozoan infections, especially in those infections where protective immunity depends on a strong Th1/Th17 immune response 61 – 63 . In addition, several recent studies have provided insight into how helminths and helminth-derived molecules (ES products) regulate some of the inflammatory responses that underlie allergic, autoimmune, or metabolic disorders.

Early in infection, normally during the larval migration through the lungs or intestinal mucosa, prior to adult worm development and establishment, epithelial cells secrete a group of alarmins—thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33), including IL-25-producing tuft cells—that promote the activation and differentiation of type 2 innate lymphoid cells (ILC2) and polyfunctional CD4 T helper 2 (Th2) cells, leading to the secretion of a myriad of cytokines, including IL-4, IL-5, and IL-13. These type 2-associated cytokines result in goblet cell hyperplasia, mucus hyper-secretion, peripheral and tissue eosinophilia, and differentiation of M2 macrophages and also induce high antigen-specific IgG1 and IgE levels. Helminth early/acute responses generally associate with an allergy-like response. The persistent exposure to helminth parasites and helminth-derived excretory/secretory (ES) antigens over the course of the infection lead to a modified type 2 response resulting in a significant modulation of T helper 1 (Th1) response—IL-2 and interferon-gamma (IFN-γ)—and also induce the expansion of natural regulatory T (nTreg) cells expressing CTLA-4, PD-1, GITR, and regulatory dendritic cells (regDCs) and monocytes, which are all sources of IL-10. This same response drives B-cell class-switching to IgG4. Chronic infection with helminth also alters the composition of intestinal bacterial communities leading to more microbial-derived short chain fatty acids (SCFAs) that also activate and promote the expansion of Treg cells. Collectively, this new regulatory environment is the signature for the establishment of an asymptomatic chronic long-standing infection, characterized by a muted/anergic parasite-specific lymphoproliferative response but also a suppressed immunity to bystander pathogens, allergens, vaccines, or non-related inflammatory, autoimmune—inflammatory bowel diseases (IBDs) and type 1 diabetes (T1DM)—or metabolic diseases. DC, dendritic cell; EOS, eosinophil; EV, extracellular vesicle; TGF-β, transforming growth factor beta.

Helminth-derived excretory/secretory products: the era of the extracellular vesicles

Helminth-induced immune responses have long been postulated to be directed at the ES products from living parasite stages during the infection. Some of the soluble proteins, lipids, and carbohydrates present in the ES products have been shown to have immunomodulatory activity 64 , 65 . The list of helminth-derived immunomodulatory molecules that evoke a regulatory phenotype among innate and adaptive immune cells has been increasing over the last decade 9 , 10 , 41 , 64 – 66 .

The relatively recent discovery of extracellular vesicles (EVs) secreted by helminths has suggested a new paradigm in the study of host–parasite interaction 67 , 68 . EVs are released from most cell types and from a diverse group of pathogens, including parasitic helminths 69 , 70 . At homeostasis, EVs represent a mechanism by which cell-to-cell communication occurs through the transfer of genetic material, proteins, and lipids 68 . In parasitic infections, EVs can function by transmitting signals between parasites, from parasite to host cells, or from the host to the environment 68 .

In general, it is felt that helminth EVs have immunoregulatory effects on host cells 71 , 72 . For a group of helminths, the analysis of the composition of these EVs has identified proteins previously described in ES products along with microRNAs (miRNAs), a highly conserved group of small, non-coding RNA molecules that can control gene expression. Among the proteins identified as components of helminth EVs are cysteine protease inhibitors (cystatins), serine protease inhibitors (serpins), metabolic enzymes such as enolase, GAPDH, and aldolase, and the well-known exosome components Hsp70, Hsp90, and annexins 73 .

Recently, it has been shown that EVs secreted by both the parasite and the host can influence the outcome of an infection. With an experimental murine model for a chronic helminth infection ( H. polygyrus ), it was shown that EVs secreted by the H. polygyru s are internalized by murine macrophages and, as a consequence of this internalization, suppress the activation of both M1 and M2 macrophages 72 . In contrast, with the infective stage of the filarial parasite Brugia malayi , it has been shown that these parasites secrete EVs containing parasite protein and miRNAs, which are also internalized by macrophages but which elicit/induce macrophage (M1) activation 74 . Finally, with H. polygyru s and rodent filarial nematode Litomosoides sigmodontis , it was shown that these parasites secrete EVs containing miRNAs, which when administered prior to allergic sensitization in an experimental allergy-asthma model in mice actually suppressed the allergen-induced type 2 innate immune response in vivo 71 .

Notwithstanding the data demonstrating EV-induced suppression of host inflammation and immune response, some groups have advocated the use of helminth-derived EVs for the identification of targets to be used in vaccines against some helminth infections 69 , 73 , 75 . Indeed, EVs isolated from the ES products of Trichuris muris (a whipworm of mice) can induce protective immunity, reducing about 60% of parasite burden, in a murine model when administered as a vaccine without adjuvant, generating a strong EV-specific antibody response 76 . Moreover, helminth-derived EVs induced protection to H. polygyrus larval challenge in mice 72 .

Interestingly, there has been a suggestion that helminth-derived EVs could be used as therapeutics to regulate inflammation in the context of allergic, autoimmune, and metabolic disorders 71 , 77 , 78 . As suggested by Siles-Lucas et al . 78 , specific molecules from helminth exosomes could be delivered in artificial exosomes to host cells with the aim of regulating pathologic inflammatory responses. How to target specific cells, to stabilize these EVs, and to find the correct dosage are challenges that will need to be addressed.

Allergic diseases and helminth infection

Allergies are inflammatory disorders that result generally from inappropriate immune responses to environmental allergens. Allergic sensitization or atopy is driven by allergen-specific responses initiated by CD4 + Th2 cells that ultimately drive the production of allergen-specific IgE 79 . Although the hygiene hypothesis suggests that the lack of exposure in children early in their development to helminth parasites or other microbial products (as seen in high- and middle-income countries) may drive the increased incidence of allergic diseases seen in these countries, there are conflicting sets of studies in humans and in experimental models 80 – 83 that have called this particular hypothesis into question. Leonardi-Bee et al . 84 demonstrated, in a meta-analysis, that chronic infection by the hookworm Necator americanus protects against asthma but that A. lumbricoides infection aggravates the clinical symptoms of this allergic condition. Interestingly, children living in a helminth-endemic region of Ecuador had a lower risk of allergies when compared with non-parasitized children in the same region 85 . Moreover, repetitive anthelmintic treatment in endemic areas has been shown to increase the prevalence of allergen skin test reactivity in children 86 .

The differences among these studies likely reflect differences in the timing of parasite infection in relationship to immune maturation or sensitization, although the species of the helminth, the intensity of the helminth infection, or the nature of the allergic disease assessed (or a combination of these) may also play a role in driving the outcomes seen. The most compelling explanation relates to the relative acuteness of the helminth parasitic infection, with early exposure to helminths driving an enhanced allergic inflammatory response 32 and long-term chronic infections attenuating the host allergic response 58 .

Among the various hypotheses put forward to explain the modulatory influence of helminth infection on allergic effector responses in humans and murine models, the IL-10-induced suppression of Th2-effector responses and the expansion of natural and parasite-induced Treg cells 9 , 87 , 88 have been the leading candidates. One possible mechanism is the IL-10-induced inhibition of IgE signaling (key players in allergic diseases) in basophils 89 , 90 . Over the last decade, it has been shown that, in human parasitic infection and in experimental models of helminth infection, helminth parasites can induce B cells to differentiate into IL-10-producing regulatory B cells that may play a role in the suppression of the immune response that leads to an expansion of Treg cells 91 , 92 .

Other studies have suggested that helminths potentiate the functional effect of Treg cells by the secretion of parasite-derived TGF-β mimics. Helminth-derived TGF-β-like molecules can bind to TGF-β receptors and trigger FoxP3 + Treg cell expansion 93 – 96 . These data notwithstanding, new data suggest (based on H. polygyrus infection in mice) that the suppression of the type 2 allergic immune response in helminths is driven by a Hp-secreted protein (HpARI) that actively inhibits IL-33 release, thereby inhibiting the allergic response 97 .

As reviewed recently, the ability of helminths to induce parasite-reactive Treg cells and IL-10 production may occur through parasite ES products 64 . In addition, these helminth-derived products likely modulate bystander inflammatory responses, particularly the development of allergy 9 , 10 , 64 . The molecular basis of this suppression has yet to be defined.

Recently, a novel mechanism underlying the helminth suppression of the allergic response has been suggested that implicates an interaction between helminth-derived proteins and the local microbiome 98 . This concept stems from the “barrier regulation hypothesis of allergy” whereby, in the healthy state, a microbiome replete with mucosa-associated taxa stimulates the intestinal mucosa (mediated by IL-22) to produce a protective mucous layer and to produce anti-microbial peptides 99 that, in turn, regulate the abundance of particular bacterial communities. These bacteria-induced barrier-protective functions reduce the ability of allergens to cross the epithelial barrier 99 . Compositional shifts within bacterial communities through dietary changes or antibiotic use can induce alterations in these bacteria-induced barrier-protective responses, thereby driving allergen-induced ILC2- or Th2-associated inflammation or both 100 . A slight variation on this theme suggests that in an environment with chronic microbial exposure, the lung and gut microbiome stimulates the formation of regulatory dendritic cells that promote the differentiation of allergy-specific Treg cells that suppress allergen-induced Th2-associated inflammation 79 .

Whether it is the helminth infection per se or helminth-derived proteins, changes in microbial composition/abundance/diversity appear to contribute indirectly to the modulation of the allergic response in the host 100 . Indeed, it has been shown that chronic infection with H. polygyrus altered the intestinal bacterial communities 101 and, in so doing, increased the amount of microbial-derived short chain fatty acids (SCFAs) that in turn suppressed house dust mite-induced allergic inflammation 98 .

Helminth infections and autoimmune and metabolic disorders

Epidemiologic evidence demonstrates that while the prevalence of helminth infections is declining worldwide, the prevalence of autoimmune diseases—including IBDs and type 1 diabetes (T1DM)—and metabolic disorders is increasing rapidly. This phenomenon has led many to infer that there is a relationship between exposure to helminth infection and protection from autoimmune diseases—for example, Crohn’s disease (CD), ulcerative colitis (UC), and multiple sclerosis—and metabolic disorders. But how helminths regulate the group of varied inflammatory disorders, autoimmune diseases, and metabolic disorders remains unknown.

Using experimental model approaches, many authors have shown that helminth infection itself or treatment with helminth ES products is sufficient to suppress inflammation in numerous models of inflammatory diseases, including the dextran sodium sulfate (DSS)-induced colitis model in mice. ES products of Ancylostoma ceylanicum (human, cat, dog, and rodent hookworm) 102 , A. caninum (dog hookworm) 103 , Trichinella spiralis (carnivorous animal roundworm) 104 , and S. japonicum (human blood fluke) have each been shown to attenuate the severity of DSS-induced colitis in mice 105 . In addition, EVs of N. brasiliensis and T. muris 77 and the recombinant B. malayi protein rBmALT2 and cystatin 106 , 107 have been shown to modulate colitis in experimental animal models. A common aspect of all of these studies has been the presence of increased levels of Th2-associated and regulatory cytokines (IL-10 and TGF-β) and a concomitant reduction in the inflammatory cytokines IL-6, IL-1β, IFN-γ, and IL-17a, known to be associated with the colitis-induced pathology. Concomitantly, two major species of helminths have been tested in more than 10 placebo-controlled clinical trials that have looked at Trichuris suis ova for the treatment of active UC and CD 108 or infection with N. americanus for the treatment of celiac disease in humans 11 , 109 , 110 . As recently reviewed by Smallwood et al . 111 , the results of the clinicals trials in humans are still controversial depending on the nature of the IBD or parasite evaluated, but, for some of them, there was some clinical improvement 108 , 109 , 112 .

It has been shown that helminth infection can prevent T1DM based on the non-obese diabetic (NOD) mouse model. The data suggest that the immune switch from a Th1 to either a Th2 or a regulatory response is the primary mechanism through which T1DM is ameliorated 12 , 113 . In addition, it has been shown that helminth-derived proteins inhibit the initiation of autoreactive T-cell responses and prevent diabetes in the NOD mouse model 114 . Interestingly, it has been postulated that the presence of these type 2 or regulatory cells in the pancreas of NOD mice has to take place before the bulk of beta cell mass is compromised by autoimmune attack 115 . With a filarial infection in IL-4-deficient NOD mice, it was demonstrated that, despite the absence of a type 2 immune shift, filarial infection in IL-4-deficient NOD mice prevented the onset of T1DM and was accompanied by increases in CD4 + CD25 + Foxp3 + Treg cells 40 . Moreover, blocking TGF-β signaling prevented the beneficial effect of helminth infection on T1DM, suggesting that skewing the immune response to a Th2 and regulatory environment could elicit suppression of the diabetogenic Th1 response.

Finally, when investigators evaluated the beneficial impact of helminth on protecting against the development of metabolic disorders, including obesity and dyslipidemia, commonly associated with insulin resistance and type 2 diabetes, parasite‐induced IL‐10 and the type 2 immune responses seem to act to improve insulin sensitivity 116 , thereby ameliorating the metabolic syndrome (MetS)-associated morbidity 117 . In this context, it has been shown that helminths have an important beneficial role by skewing this inflammatory response toward one with IL-4-producing eosinophils, M2 macrophages, and Treg cells that maintain insulin signaling and sensitivity 118 .

Future directions

Helminths are potent regulators of type 1 immune response induced by bystander pathogens or inflammatory disorders or both. Understanding the mechanisms underlying this interaction and identifying the potential molecular targets are the current challenges and areas that need to be investigated further to develop novel strategies to prevent or delay allergic, inflammatory, autoimmune, or metabolic disorders in humans.

Abbreviations

AAM, alternatively activated macrophages; CD, Crohn’s disease; DSS, dextran sodium sulfate; ES, excretory/secretory; EV, extracellular vesicle; IBD, inflammatory bowel disease; IFN-γ, interferon-gamma; IL, interleukin; ILC2, innate lymphoid cell type 2; miRNA, microRNA; NOD, non-obese diabetic; nTreg, natural regulatory T; T1DM, type 1 diabetes; TGF-β, transforming growth factor-beta; Treg, regulatory T; UC, ulcerative colitis

[version 1; referees: 2 approved]

Funding Statement

This work was supported by the Division of Intramural Research of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

• Padraic Fallon , Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland No competing interests were disclosed.
• Rick M. Maizels , Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK No competing interests were disclosed.