Regulation of the host immune system by helminth parasites
Authors: Rick M. Maizels, Henry J. McSorley
Journal: Journal of Allergy and Clinical Immunology (2016)

Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research. Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Helminths are highly prevalent metazoan worm parasites, which have evolved a spectrum of sophisticated means to regulate and evade the host immune system.1McSorley H.J. Maizels R.M. Helminth infections and host immune regulation.Clin Microbial Rev. 2012; 25: 585-608Crossref PubMed Scopus (0) Google Scholar Helminths appear to act as successful xenotransplants into the mammalian body, neutralizing immune pathways that would otherwise expel them and resetting the thresholds of immune reactivity.2Johnston C.J. McSorley H.J. Anderton S.M. Wigmore S.J. Maizels R.M. Helminths and immunological tolerance.Transplantation. 2014; 97: 127-132Crossref PubMed Scopus (15) Google Scholar In so doing, they also dampen responses to unrelated bystander specificities, such as allergens and autoantigens, in a manner that might in fact benefit the host.1McSorley H.J. Maizels R.M. Helminth infections and host immune regulation.Clin Microbial Rev. 2012; 25: 585-608Crossref PubMed Scopus (0) Google Scholar, 3Mishra P.K. Palma M. Bleich D. Loke P. Gause W.C. Systemic impact of intestinal helminth infections.Mucosal Immunol. 2014; 7: 753-762Crossref PubMed Scopus (39) Google Scholar Only a dozen or so species of helminths are widespread in human subjects, but together, they infect some 2 billion persons, nearly one third of the human population.4Hotez P.J. Brindley P.J. Bethony J.M. King C.H. Pearce E.J. Jacobson J. Helminth infections: the great neglected tropical diseases.J Clin Invest. 2008; 118: 1311-1321Crossref PubMed Scopus (660) Google Scholar Their extraordinary prevalence bears witness to their success at defeating host defenses and suggests we have much to learn from how these parasites modulate our own immune system. Although helminths establish in a range of tissue and intestinal niches, in nearly all cases they do not multiply within the host but produce eggs or larvae to infect new hosts; hence they tend to establish stable chronic infections that can endure for surprisingly long (up to 20 years) in an individual host. In this setting almost every facet of the immune system is modified or even recalibrated, with infected subjects displaying a state of immune hyporesponsiveness that can be considered a form of immunologic tolerance.5Nutman T.B. Kumaraswami V. Ottesen E.A. Parasite-specific anergy in human filariasis. Insights after analysis of parasite antigen-driven lymphokine production.J Clin Invest. 1987; 79: 1516-1523Crossref PubMed Google Scholar, 6Maizels R.M. Lawrence R.A. Immunological tolerance: the key feature in human filariasis?.Parasitol Today. 1991; 7: 271-276Abstract Full Text PDF PubMed Google Scholar, 7King C.L. Kumaraswami V. Poindexter R.W. Kumari S. Jayaraman K. 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Regulatory T cells: key controllers of immunologic self-tolerance.Cell. 2000; 101: 455-458Abstract Full Text Full Text PDF PubMed Google Scholar As discussed below, a strong link has emerged between long-term helminth infection and Treg cell activity, particularly in the asymptomatic or hyporesponsive state.17Maizels R.M. Smith K.A. Regulatory T cells in infection.Adv Immunol. 2011; 112: 73-136Crossref PubMed Scopus (0) Google Scholar, 18Ludwig-Portugall I. Layland L.E. TLRs, Treg, and B cells, an interplay of regulation during helminth infection.Front Immunol. 2012; 3: 8Crossref PubMed Scopus (14) Google Scholar, 19Metenou S. Nutman T. Regulatory T cell subsets in filarial infection and their function.Front Immunol. 2013; 4: 305Crossref PubMed Scopus (23) Google Scholar Immune downregulation by helminths further extends into many local and systemic settings, with modulation of responses to a variety of unrelated bystander specificities.3Mishra P.K. Palma M. Bleich D. Loke P. Gause W.C. Systemic impact of intestinal helminth infections.Mucosal Immunol. 2014; 7: 753-762Crossref PubMed Scopus (39) Google Scholar One example is that polyclonal immune responses to childhood vaccines can be compromised in heavily infected subjects.20Labeaud A.D. Malhotra I. King M.J. King C.L. King C.H. Do antenatal parasite infections devalue childhood vaccination?.PLoS Negl Trop Dis. 2009; 3: e442Crossref PubMed Scopus (101) Google Scholar In addition, helminths can undermine host defenses against other major pathogens, such as Mycobacterium tuberculosis.3Mishra P.K. Palma M. Bleich D. Loke P. Gause W.C. Systemic impact of intestinal helminth infections.Mucosal Immunol. 2014; 7: 753-762Crossref PubMed Scopus (39) Google Scholar, 21Salgame P. Yap G.S. Gause W.C. 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Helminth parasites clearly establish hyporesponsiveness in the naive adult in model systems, but in endemic settings it is common for offspring to be born to infected mothers, become infected at a very early age, or both. Maternal infection boosts tolerance in the newborn, so that offspring of Haitian mothers with the filarial infection Wuchereria bancrofti were 2- to 3-fold more likely to become infected themselves while showing a lower level of T-cell reactivity to parasite antigens than children of uninfected mothers.27Lammie P.J. Hitch W.L. Walker Allen E.M. Hightower W. Eberhard M.L. Maternal filarial infection as risk factor for infection in children.Lancet. 1991; 337: 1005-1006Abstract PubMed Scopus (0) Google Scholar In a remarkable study in the Cook Islands, it was confirmed that even at 17 years of age, subjects born to infected mothers mounted substantially weaker T-cell responses to parasite antigens.28Steel C. Guinea A. McCarthy J.S. Ottesen E.A. 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Sparwasser T. et al.Schistosoma mansoni-mediated suppression of allergic airway inflammation requires patency and Foxp3+ Treg cells.PLoS Negl Trop Dis. 2013; 7: e2379Crossref PubMed Scopus (0) Google Scholar They also play a vital role protecting the host from pathology because Treg cell depletion can exacerbate inflammatory responses with lethal results.48Sawant D.V. Gravano D.M. Vogel P. Giacomin P. Artis D. Vignali D.A.A. Regulatory T cells limit induction of protective immunity and promote immune pathology following intestinal helminth infection.J Immunol. 2014; 192: 2904-2912Crossref PubMed Scopus (19) Google Scholar, 49Smith K.A. Filbey K.J. Reynolds L.A. Hewitson J.P. Harcus Y. Boon L. et al.Low level regulatory T cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths.Mucosal Immunol. 2016; 9: 428-443Crossref PubMed Google Scholar, 54D'Elia R. Behnke J.M. Bradley J.E. Else K.J. Regulatory T cells: a role in the control of helminth driven intestinal pathology and worm survival.J Immunol. 2009; 182: 2340-2348Crossref PubMed Scopus (0) Google Scholar Thus although partial Treg cell depletion can strengthen the TH2 response required for parasite expulsion, in their total absence an inflammatory storm prevails, preventing a coherent protective immune response.49Smith K.A. Filbey K.J. Reynolds L.A. Hewitson J.P. Harcus Y. Boon L. et al.Low level regulatory T cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths.Mucosal Immunol. 2016; 9: 428-443Crossref PubMed Google Scholar Treg cells are also implicated in the weakened defenses against other parasites, and in human subjects in vitro T-cell proliferative responses to BCG and malaria are attenuated in helminth-infected patients but recover if Treg cells are removed from the test cultures.55Wammes L.J. Hamid F. Wiria A.E. de Gier B. Sartono E. Maizels R.M. et al.Regulatory T cell in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum.Eur J Immunol. 2010; 40: 437-442Crossref PubMed Scopus (0) Google Scholar Similarly, BCG vaccination of helminth-infected subjects elicits poor inflammatory cytokine responses to purified protein derivative antigen in contrast to significant TGF-β production; anthelmintic treatment reverses this scenario, suggesting that interference with vaccine responses might be due to the presence of immunosuppressive cytokines.56Elias D. Britton S. Aseffa A. Engers H. Akuffo H. Poor immunogenicity of BCG in helminth infected population is associated with increased in vitro TGF-β production.Vaccine. 2008; 26: 3897-3902Crossref PubMed Scopus (0) Google Scholar Supporting this, a recent study reported that tuberculosis-infected migrants in the United Kingdom who were coinfected with helminths had higher Treg cell frequencies than those with tuberculosis alone but that anthelmintic treatment decreased Treg cell numbers while increasing TH1 effector populations.57Toulza F. Tsang L. Ottenhoff T.H. Brown M. Dockrell H.M. Mycobacterium tuberculosis-specific CD4+ T-cell response is increased, and Treg cells decreased, in anthelmintic-treated patients with latent TB.Eur J Immunol. 2016; 46: 752-761Crossref PubMed Scopus (0) Google Scholar Often overshadowed by their T-cell counterparts, regulatory B (Breg) cells are also crucially important in control of the immune response during helminth infection.58Hussaarts L. van der Vlugt L.E. Yazdanbakhsh M. Smits H.H. Regulatory B-cell induction by helminths: implications for allergic disease.J Allergy Clin Immunol. 2011; 128: 733-739Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar B cells from Heligmosomoides polygyrus–infected mice can suppress experimental autoimmune encephalomyelitis and airway allergy when transferred to recipient mice.59Wilson M.S. Taylor M.D. O'Gorman M.T. Balic A. Barr T.A. Filbey K. et al.Helminth-induced CD19+CD23hi B cells modulate experimental allergic and autoimmune inflammation.Eur J Immunol. 2010; 40: 1682-1