Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

Abstract

Human genetic control is thought to affect a considerable part of the outcome of infection withMycobacterium 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 toMtbinfection, 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 andMtbwhich suggests the potential for co-evolution. In this review, we explore the roles ascribed to PRRs duringMtbinfection and ask whether such a longstanding and intimate interface between our immune system and this pathogen plays a critical role in determining the outcome ofMtbinfection. The scientific evidence to date suggests that PRR variation is clearly implicated in altered immunity toMtbbut 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 forMtbcontrol, ‘sensors’ like PRRs are less critical for the outcome ofMtbinfection. This is potentially due to redundancy of the numerous PRRs in the innate arsenal, such thatMtbrarely goes unnoticed. Genetic association studies investigating PRRs duringMtbinfection 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 andMtb.