Abstract
Successful immune control of Mycobacterium tuberculosis (MTB) requires robust CD4+ T cell responses, with IFNγs as the key cytokine promoting killing of intracellular mycobacteria by macrophages. By contrast, helminth infections typically direct the immune system toward a type 2 response, characterized by high levels of the cytokines IL-4 and IL-10, which can antagonize IFNγ production and its biological effects. In many countries with high burden of tuberculosis, helminth infections are endemic and have been associated with increased risk to develop tuberculosis or to inhibit vaccination-induced immunity. Mechanistically, regulation of the antimycobacterial immune response by helminths has been mostly been attributed to the T cell compartment. Here, we review the current status of the literature on the impact of helminths on vaccine-induced and natural immunity to MTB with a focus on the alterations enforced on the capacity of macrophages to function as sensors of mycobacteria and effector cells to control their replication.
Highlights
Innate Recognition of Mycobacterium tuberculosis (MTB)The innate immune system detects incoming mycobacteria during phagocytosis by alveolar macrophages in the lung
Reviewed by: Subash Babu, International Centers for Excellence in Research (NIH), India Thomas Jacobs, Bernhard-Nocht-Institut für Tropenmedizin, Germany
The hydrophobic mycobacterial cell wall contains a large number of lipids, glycolipids, and lipoglycans that act as pathogen-associated molecular patterns (PAMPs), which are recognized by several classes of pattern recognition receptors (PRRs) [for review, see Ref. [1]]
Summary
The innate immune system detects incoming mycobacteria during phagocytosis by alveolar macrophages in the lung. The endosomal TLR7 and TLR8 (the later only in humans, but not in mice) sense single-stranded RNA [13], while CpG-rich DNA was initially purified as the immunostimulatory principle of Bacille Calmette–Guerin (BCG) treatment and later explained by activation of TLR9 [14] Independent of their localization on the cell surface or in the phagosome, TLR2, TLR7/8, and TLR9 require the adapter protein Myd to activate gene expression. DCAR (Clec4b1), another FcRγ-coupled CLR, was revealed to bind to PIM of the cell wall, to induce MCP-1 expression by macrophages, and to induce Th1 responses [30] All of these CLR signal via the SykCard9-Bcl10-Malt pathway to activate NFκB and upregulate expression of multiple chemokines, cytokines and inflammatory mediators causing inflammation and directing developing adaptive immune responses [31, 32]. Beyond a simple lack of correlation between IFNγ levels and protection in MTB infection, there is even evidence that IFNγ production has to be tightly controlled to prevent damage to the host, the lung tissue, during infection [48]
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