Regulation of Macrophage Innate Immunity During Intracellular Bacterial Infection
Abstract
The innate immune system is a rapid response system that functions to prevent, recognize and limit infection by responding to danger signals such as those associated with bacterial pathogens. Macrophages, a type of innate immune cell, possess numerous means of detecting pathogens at multiple points, including at the cell surface and within the macrophage cytosol. For a pathogenic bacterial species to survive, it must evolve ways to escape host detection and elimination. Successful intracellular bacterial pathogens are unique in that they are not only capable of overcoming host immune surveillance but have evolved mechanisms to survive and replicate within the very cells meant to neutralize them. The ability of innate immune cells such as macrophages to overcome these bacterial survival mechanisms and respond efficaciously to infection are dependent on an elegant system of checks and balances between sensors and regulators. Understanding how bacteria are sensed by the host and how host immunity is regulated is imperative for developing ways to promote positive patient outcomes. Here we use three intracellular bacterial pathogens to interrogate this system. First, we explore how macrophages recognize intracellular bacteria and how bacteria can manipulate and exploit the immune system. To begin, we show that Rhodococcus equi is recognized by cytosolic DNA sensors. Upon triggering this cytosolic DNA sensing pathway, R. equi elicits an antiviral type I interferon (IFN) immune response. We next interrogate innate immune regulation and show that loss of a novel innate immune regulator, leucine rich repeat kinase 2 (LRRK2) results in dysregulation of innate immunity in uninfected macrophages. This immune defect is associated with an elevated baseline type I IFN signature and impaired response to infection ex vivo. Furthermore, we use a Lrrk2^-/- mouse model to demonstrate an abnormal host response during infection by either Mycobacterium tuberculosis or Listeria monocytogenes. Finally, we show that the Parkinson’s disease (PD) associated Lrrk2^G2019S mutation contributes to M. tuberculosis pathogenesis in vivo whereby mice harboring the Lrrk2^G2019S mutation exhibit overwhelmingly severe lung pathology.
Citation
Vail, Krystal J. (2021). Regulation of Macrophage Innate Immunity During Intracellular Bacterial Infection. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /195750.