Mycobacterial infection induces a specific human innate immune response

Abstract

The innate immune system provides the first response to infection and is now recognized to be partially pathogen-specific. Mycobacterium tuberculosis (MTB) is able to subvert the innate immune response and survive inside macrophages. Curiously, only 5-10% of otherwise healthy individuals infected with MTB develop active tuberculosis (TB). We do not yet understand the genetic basis underlying this individual-specific susceptibility. Moreover, we still do not know which properties of the innate immune response are specific to MTB infection. To identify immune responses that are specific to MTB, we infected macrophages with eight different bacteria, including different MTB strains and related mycobacteria, and studied their transcriptional response. We identified a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. This subset includes genes involved in phagosome maturation, superoxide production, response to vitamin D, macrophage chemotaxis, and sialic acid synthesis. We suggest that genetic variants that affect the function or regulation of these genes should be considered candidate loci for explaining TB susceptibility.The innate immune system provides the first line of defense against microbial pathogens. Broadly speaking, innate immune cells recognize foreign molecules through pattern recognition receptors (PRRs), e.g. Toll-like receptors (TLRs), which bind to highly-conserved pathogenic motifs known as pathogen-associated molecular patterns (PAMPs) 1,2 . In addition, innate immune cells recognize damage-associated molecular patterns (DAMPs) of host molecules released by infected cells 3 . The initial innate response involves the release of proinflammatory cytokines and lipids to recruit and activate other immune cells, phagocytosis of the pathogen, and apoptosis 4 . If the infection persists, the phagocytes stimulate the adaptive immune system by presenting antigens to activate T and B cells. In contrast to the highly specific adaptive immune response, the innate immune response has traditionally been viewed as a general response to infection.Yet, more recent work revealed that the innate immune system also produces a pathogen-specific response in addition to the general response [5][6][7][8] . Furthermore, this pathogen-specific innate response can in turn affect the specificity of the adaptive immune response by directing the differentiation of T cells into distinct subtypes 9 . That said, though we developed an appreciation for the importance of the specific innate immune response, we still do not know the extent to which the innate immune response differs between infections nor fully understand the consequences of specific innate immune responses for fighting pathogens. One of the first challenges is to distinguish the unique immune response to a specific pathogen from the large core more general response.The pathogen-specific innate immune response is determined, at least in part, by the specificity of the PRRs of the host immune cell. Each PRR binds to its s...

Genetic diversity of Mycobacterium bovis in Jalisco, Mexico: Tracing back sources of infection

“…Bacilli in this group are 99.9% genetically similar at the nucleotide level with identical 16S rRNA sequences (Boddinghaus et al, 1990;Sreevatsan et al, 1997) (O'Reilly and Daborn, 1995;Blischak et al, 2015). The proportion of cases due to M. bovis in humans in the last two decades has been variable, ranging from 0.5 to 13% depending on the study population, and it is estimated that nearly 10 million people are affected by tuberculosis worldwide every year (Müller et al, 2013;Olea-Popelka et al, 2017;PereaRazo et al, 2017).…”