Investigating the Effects of Mycobacterium tuberculosis Bacterial Heterogeneity on Innate Immune Cell Tropism

Abstract

Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Tuberculosis is the leading cause of death by a single infectious agent worldwide despite the use of a live attenuated vaccine and treatment antibiotics. Mtb spreads from person to person by aerosolized particles primarily through inhalation, where it encounters cells of the innate immune system. Previous research has found that TB patients harbor a diverse population of Mtb, and further evidence suggests that the bacterial population measurably evolved in response to selective pressures driven by environments within hosts. Yet, there is limited research on how these heterogenous populations respond to different kinds of immune cells. The aim of this research is to investigate differences in cell tropism through phagocytic uptake – a ubiquitous function of many innate immune cells- when infected by heterogenic clinical isolates of Mycobacterium tuberculosis. Here, several innate immune cells (monocytes, neutrophils, macrophages, and dendritic cells) from healthy, TB-naïve human donors were infected for four hours with a unique molecularly barcoded library of Mtb clinical isolates from Vietnam. It was found that uptake by cells altered relative abundance of strains compared to background growth in media. Interestingly, there were several strains within sub-lineages and clades that may be driving phagocytic uptake within cell types, such as monocytes and neutrophils, suggesting cell tropism that is unique to individual strains. Together, these data suggest that bacteria heterogeneity plays an important role in phagocytic uptake in human innate immune cells.