New Players in Immunity to Tuberculosis: The Host Microbiome, Lung Epithelium, and Innate Immune Cells

Abstract

Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Efforts to control and eradicate TB are hampered by the rapid emergence of drug resistance and limited efficacy of the only available vaccine, BCG. Immunological events in the airways and lungs are of major importance in determining whether exposure to Mycobacterium tuberculosis (Mtb) results in successful infection or protective immunity. Several studies have demonstrated that the host microbiota is in constant contact with the immune system, and thus continually directs the nature of immune responses occurring during new infections. However, little is known about its role in the eventual outcome of the mycobacterial infection. In this review, we highlight the changes in microbial composition in the respiratory tract and gut that have been linked to the alteration of immune responses, and to the risk, prevention, and treatment of TB. In addition, we summarize our current understanding of alveolar epithelial cells and the innate immune system, and their interaction with Mtb during early infection. Extensive studies are warranted to fully understand the all-inclusive role of the lung microbiota, its interaction with epithelium and innate immune responses and resulting adaptive immune responses, and in the pathogenesis and/or protection from Mtb infection. Novel interventions aimed at influencing the microbiota, the alveolar immune system and innate immunity will shape future strategies of prevention and treatment for TB.

Keywords: alveolar immune system; innate lymphoid cells; microbiota/microbiome; mucosa-associated invariant T; tuberculosis.

Figure 1

Multiple players in Mycobacterium tuberculosis (Mtb) infection and immunity: lung microbiota, lung epithelium, gut–lung axis, gut microbiota, innate and adaptive lymphocytes. (A) The upper (oro/nasopharyngeal) and lower respiratory (lung) microbiota. (B) Alveolar epithelial cells secrete cytokines, opsonins, and antimicrobial peptides upon mycobacterial infection. Alveolar macrophages/interstitial macrophages constitute the first line of immune defense and also the first port of entry during mycobacterial infection, but their interaction with lung microbiota is not yet known. Innate lymphocytes, such as MAIT, NK, NKT, γδ T cells, and innate lymphoid cells (ILCs) become activated, and their coordination leads to subsequent expansion/modulation of adaptive T and B cells. Dendritic cells transport Mtb antigens to draining lymph nodes to promote Mtb-specific immunity. (C). In a healthy state, the gut microbiota regulates lung immunity and influences the lung microbiota. Dysbiosis caused by anti-TB therapy in the gut can lead to dysregulation of immune responses in the lung. (D). The intestinal microbes and their metabolites regulate ILCs directly, or through cytokines produced by gut epithelium or DCs. ILCs and DCs in turn regulate adaptive T and B cells in the gut which migrate systemically and to lungs. Also, a combination of signals from microbes leads to migration of DCs to the draining lymph nodes, where DCs promote activation of various T cell subsets and B cells. During mycobacterial infection, cells activated in gut-associated lymphoid tissue (GALT) and mesenteric lymph nodes migrate to the lungs where they promote protective immunity and influence the lung microbiota. Bacterial metabolites are also directly transported to the lungs to influence the lung immunity against mycobacterial infection. The exact pathways of interactions between the components of (A–D) are still being explored.