Abstract
Human genetic control is thought to affect a considerable part of the outcome of infection with Mycobacterium tuberculosis (Mtb). Most of us deal with the pathogen by containment (associated with clinical “latency”) or sterilization, but tragically millions each year do not. After decades of studies on host genetic susceptibility to Mtb infection, genetic variation has been discovered to play a role in tuberculous immunoreactivity and tuberculosis (TB) disease. Genes encoding pattern recognition receptors (PRRs) enable a consistent, molecularly direct interaction between humans and Mtb which suggests the potential for co-evolution. In this review, we explore the roles ascribed to PRRs during Mtb infection and ask whether such a longstanding and intimate interface between our immune system and this pathogen plays a critical role in determining the outcome of Mtb infection. The scientific evidence to date suggests that PRR variation is clearly implicated in altered immunity to Mtb but has a more subtle role in limiting the pathogen and pathogenesis. In contrast to ‘effectors’ like IFN-γ, IL-12, Nitric Oxide and TNF that are critical for Mtb control, ‘sensors’ like PRRs are less critical for the outcome of Mtb infection. This is potentially due to redundancy of the numerous PRRs in the innate arsenal, such that Mtb rarely goes unnoticed. Genetic association studies investigating PRRs during Mtb infection should therefore be designed to investigate endophenotypes of infection – such as immunological or clinical variation – rather than just TB disease, if we hope to understand the molecular interface between innate immunity and Mtb.
Highlights
Tuberculosis (TB) was the number one cause of death due to a single infectious agent, Mycobacterium tuberculosis (Mtb), in the year 2019 according to the while treatment has saved million (WHO)
One example where Mtb has potentially exerted a purifying selection on humans is that of the TYK2 P1104A variant, which was calculated to have decreased in western Europeans concomitant with endemic TB over the last two millennia [6, 7]
Below, we briefly review the molecular functionality of the Pattern recognition receptor (PRR) which have been demonstrated to mediate an immune response to mycobacteria
Summary
Tuberculosis (TB) was the number one cause of death due to a single infectious agent, Mycobacterium tuberculosis (Mtb), in the year 2019 according to the WHO. Mif-KO mice have impaired survival and immunity compared to WT during aerosol infection with Mtb HN878 strain, while bacterial killing and cytokine production were nearly restored when Mif-KO cells were complemented with Dectin-1 (overexpressed) These results suggest the MIF defect mostly manifests in defective Dectin-1 signalling [60]. Numerous KO mouse studies of Mtb infection have been performed over the years with hypotheses of defective immunity in the animal that should manifest as decreased survival, increased bacterial burden and/or detectable differences in the immune response (e.g. bronchoalveolar lavage cytokines or T-cell defects). MCL might play a role early in infection to control the immune response, but not so much for bacterial control Another lone report showed Dectin-1 (Clec7a)-KO mice did not have changed mortality after infection with Mtb, and had slightly lower bacterial burdens compared to WT at 2 and 4 months post infection [144].
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