Immunological Interactions between Intestinal Helminth Infections and Tuberculosis

Abstract

Helminth infections are among the neglected tropical diseases affecting billions of people globally, predominantly in developing countries. Helminths' effects are augmented by coincident tuberculosis disease, which infects a third of the world's population. The role of helminth infections on the pathogenesis and pathology of active tuberculosis (T.B.) remains controversial. Parasite-induced suppression of the efficacy of Bacille Calmette-Guerin (BCG) has been widely reported in helminth-endemic areas worldwide. T.B. immune response is predominantly proinflammatory T-helper type 1 (Th1)-dependent. On the other hand, helminth infections induce an opposing anti-inflammatory Th2 and Th3 immune-regulatory response. This review summarizes the literature focusing on host immune response profiles during single-helminth, T.B. and dual infections. It also aims to necessitate investigations into the complexity of immunity in helminth/T.B. coinfected patients since the research data are limited and contradictory. Helminths overlap geographically with T.B., particularly in Sub-Saharan Africa. Each disease elicits a response which may skew the immune responses. However, these effects are helminth species-dependent, where some parasites have no impact on the immune responses to concurrent T.B. The implications for the complex immunological interactions that occur during coinfection are highlighted to inform government treatment policies and encourage the development of high-efficacy T.B. vaccines in areas where helminths are prevalent.

Keywords: Bacille Calmette-Guerin; Mycobacterium tuberculosis; coinfection; helminths; immune response; vaccination.

Figure 1

PRISMA flow diagram of the search strategy and the research design process.

Figure 2

Immune response profiles during helminth infection. Migration of helminths damages epithelial barrier cells and tissues, triggering an immune response. Helminths produce damage and pathogen-associated molecular patterns (DAMPS and PAMPS). DAMPS and PAMPS activate various cells, such as epithelial, which release alarmins such as Thymic stromal lymphopoietin (TSLP), IL-25 and IL-33. Alarmins stimulate innate lymphoid cells (ILCs), aiding collagen deposition and tissue repair, and are a source of IL-5 required for eosinophil activation. Eosinophils enter tissues during helminth infection-induced inflammation. Eosinophilia is a crucial feature of the host response to helminth infection. Alarmins promote B cell activation and induction of alternatively activated macrophages (AAMs). AAMs stimulate IL-10 and TGF-β, which reduce the host’s immune response to pathogens to avoid damaging the host and maintain normal tissue homeostasis. Classically activated macrophages, stimulated by IFN-γ produce proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-12 and TNF-α).

Figure 3

Immune response profiles during tuberculosis infection. Mycobacteria encounter alveolar macrophages where they are phagocytosed, kept inside phagosomes and exposed to antimicrobial peptides and degrading lysosomal enzymes (lysozyme). However, pathogenic mycobacteria have developed strategies to subvert the host’s defenses. Th1-cell activity (IFN-γ, IL-12 and TNF-α) is required for Mycobacterium tuberculosis immunity. IFN-γ activation of macrophages promotes bacterial killing by forming toxic reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). An array of cytokines and chemokines, including tumor necrosis factor (TNF-α), induces a proinflammatory response and direct immune cells to the infection site. Dendritic cells migrate to draining lymph nodes, where they encounter many immature T cells. In the presence of proinflammatory cytokines such as IFN-γ and IL12, T cells become activated, multiply and differentiate into T helper (Th)1 cells. IFN-γ stimulates macrophages and triggers the potent antimicrobial activities of the primed Th1 cells.