Effect of helminth-induced immunity on infections with microbial pathogens

Abstract

Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ from and potentially antagonize host protective responses to microbial pathogens. In this Review we focus on the three main killers in infectious disease-AIDS, tuberculosis and malaria-and critically assesses whether helminths adversely influence host control of these diseases. We also discuss emerging concepts for how M2 macrophages and helminth-modulated dendritic cells can potentially influence the protective immune response to concurrent infections. Finally, we present evidence advocating for more efforts to determine how and to what extent helminths interfere with the successful control of specific concurrent coinfections.

Figures

Figure 1

World map showing the geographic distribution of coinfection with helminths together with tuberculosis, malaria and/or HIV infection of adults. This simplified map (constructed for illustrative purposes) includes only data obtained from the following sources: for helminths, lymphatic filariasis, onchocerciasis, schistosomiasis or soil-transmitted helminthiasis; for tuberculosis (TB), incidence rates; for malaria, the countries and territories affected; and for HIV, the reported prevalence in adults. Countries with fewer than 25–49 new cases of tuberculosis per 100,000 people and with a prevalence of HIV infection below 0.5% have not been included here. Because of that cutoff for HIV, many parts of the world (such as India and South America) are not presented here as regions with coinfection with helminths and HIV, although there is a substantial HIV burden in those countries.

Figure 2

Mechanisms of helminth-induced inhibition of effector CD4+ T cells and macrophages required for protective immunity to microbial pathogens. Specific stimuli characteristic of helminth invasion trigger different aspects of the overall type 2 immune response. (a) Induction of tissue injury by helminths induces the release of cytokine alarmins (IL-33, IL-25 and TSLP), which promote the production of TH2 cytokines by ILC2 cells and TH2 cells and also by eosinophils and basophils. Exposure of macrophages to IL-4 or IL-13 suppresses classical (M1) activation of macrophages and diverts their differentiation toward the M2 phenotype. (b) Excretory-secretory (ES) molecules produced and shed by worms can shut down DC synthesis of proinflammatory cytokines, chemokines and costimulatory molecules and also promote DC production of the immunoregulatory molecules IL-10 and TGF-β. (c) Helminth infection has also been shown to induce the in vivo differentiation of a CD103−CD11Clo population of regulatory DCs, which are inefficient in priming effector T cells and instead favor the generation of Treg cells. Together all these mechanisms act in synergy to produce a helminth-modulated immunoregulatory environment that compromises TH1 and TH17 responses and favors Treg cell activities.