Hide and Seek: How mycobacteria evade and manipulate cellular immune responses

Abstract

Mycobacterium tuberculosis, the causative pathogen of human tuberculosis, is one of the most deadly infectious diseases to inflict man, having killed one-quarter of the population of Europe during the 19th century. The evolutionary success of this pathogen is dependent on its ability to cause disease in order to transmit. Disease symptoms are driven by the bacteria's ability to orchestrate the formation of immune cell aggregates, known as granulomas. Using the zebrafish model of mycobacterial infection, I have taken advantage of the optical transparency of the zebrafish larvae to intricately detail the cellular responses mediating granuloma development. I have identified both host-evasion and host-manipulation strategies used by mycobacteria to cause disease. Mycobacteria avoid detection by immune pattern recognition receptors that identify both pathogens and commensals. This evasion strategy fails in the presence of other bacteria and therefore provides an explanation for the longstanding observation that M. tuberculosis must initiate infection in the relatively sterile lower lung, as opposed to the upper airways, which are replete with commensals. Mycobacteria also manipulate the immune response by driving the expression of host chemokines to recruit bacterial permissive cells, which they must infect in order to cause disease. A finding that provides a mechanistic understanding for human studies where overexpression of these same chemokines were associated with developing active tuberculosis. Finally, my work identified a tissue resident macrophage population as being able to clear infection in unimmunized hosts, an epidemiologically documented process that is rarely represented in animal models. These data strengthen our understanding of mycobacterial pathogenesis and will help to guide future therapeutic and vaccine efforts.