Helminth-Tuberculosis Co-infection: An Immunologic Perspective

Abstract

Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth-TB coinfection.

Figure 1. Cytokine Regulation of Tuberculosis Infection by Helminths

The cytokine responses engendered by relatively acute (early) and chronic helminth infections are depicted on the left, while the cytokine responses induced in latent or active tuberculosis is shown on the right. Type 1 cytokines are represented in red, type 2 cytokines in blue and regulatory cytokines in black. The size of the box represents the magnitude of the response. Thus, helminth infections predominantly induce type 2 and regulatory responses, while tuberculosis infection and disease is predominantly type 1, or pro-inflammatory, with different degrees of magnitude. IFN: Interferon, TGF, Transforming growth factor; TNF, Tumor necrosis factor

Figure 2. Modulation of Immune Response to Tuberculosis Infection by Helminths Based on Murine Models

Helminth parasites (for example Ascaris Lumbricoides) induce the release of alarmin cytokines, including thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 from barrier cells including epithelial cells. These cytokines then activate a variety of secondary cell types. In addition, helminth parasites or their excretory-secretory products can directly interact with dendritic cells, macrophages, basophils and eosinophils to induce activation and initiation of the type 2 immune response. This subsequently modulates the T cell response to effect influence on Mycobacterium tuberculosis (Mtb) infection and disease through a variety of mechanisms described. TSLP, thymic stromal lymphopoietin; Arg-1, arginase-1; IDO, indoleamine 2,3 dioxygenase; DC-SIGN, dendritic cell specific intracellular adhesion molecule-3 grabbing non-integrin; PD-1, programmed cell death protein -1; CTLA-4, cytotoxic T lymphocyte associated protein-4, TNF: tumor necrosis factor, TGF: transforming growth factor