Abstract
The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be deadly, only 5-10% of individuals infected with MTB develop active disease. The risk for disease susceptibility is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacteria, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. Although the ensued gene regulatory responses were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB.
Author Summary Tuberculosis (TB) is a deadly disease responsible for millions of deaths annually. It is caused by infection with Mycobacterium tuberculosis (MTB), an ancient human pathogen. Approximately a third of the world’s population is infected with MTB, yet only an estimated 5-10% of individuals will develop an active form of the disease. While this variation in TB susceptibility has been demonstrated to be heritable, we still know little about its underlying genetic basis. The genetic variation that affects TB susceptibility likely involves the innate immune system, which is our first line of defense against invading pathogens, because infection with MTB does not prevent future infections. However, we do not fully understand how the innate immune system differs in its response to MTB versus other bacteria. To investigate this further, we infected macrophages with MTB, related mycobacteria, and other bacteria, and measured how their gene expression levels changed in response. We identified a subset of genes that respond preferentially to infection with mycobacterial species. These genes provide insight into the interactions between MTB and the innate immune system and are candidate loci for explaining inter-individual susceptibility to TB.
