UC Berkeley

Mycobacterium tuberculosis (Mtb) is the etiological agent of the disease tuberculosis (TB), and is the leading cause of death worldwide from a single pathogen1. Exposure to Mtb in immunocompetent humans results in diverse outcomes, varying from active, transmissible disease to asymptomatic infection that cannot spread to others. Host genetics, amongst other factors, are thought to contribute to the divergent outcomes upon Mtb infection. Improved understanding of the host immune responses against Mtb—how is the pathogen detected, what immune responses are induced, and which responses are protective—would better inform future development of vaccines, therapeutics and diagnostics.

To study the effect of host genetics on susceptibility to Mtb infection, I used a previously published congenic mouse (B6.Sst1S) that carries the susceptible allele of the Super susceptibility to tuberculosis 1 (Sst1) locus on the C57BL/6 (B6) background 2,3. Compared to B6 mice, B6.Sst1S mice are significantly more susceptible to Mtb infection, though the mechanisms of this susceptibility are not well understood. A previous study proposed Ipr1 (also known as Sp110) as the causative gene within the Sst1 locus2, though this has never been thoroughly verified. In this dissertation I first investigate the mechanisms of susceptibility in the B6.Sst1S mice, and demonstrate that the susceptibility is driven by type I interferon (IFN) signaling (Chapter 2). I further show that type I IFN signaling upregulates interleukin-1 receptor antagonist (IL-1Ra), which blocks signaling of interleukin-1 (IL-1), a vital antibacterial cytokine. Inhibition of IL-1Ra by genetic deletion or neutralization with a blocking antibody protected B6.Sst1S mice, suggesting that IL-1Ra is a potential target for host-directed therapy.

I then examine the genetic determinants of the Sst1 locus, where I observe that contradictory to previous report2, Sp110–/– mice were not susceptible to Mtb infections (Chapter 3). I demonstrate that a homolog of Sp110, Sp140 is also a possible candidate gene, and generated Sp140–/– mice that were similarly susceptible to infections by Mtb and other intracellular bacteria as B6.Sst1S mice. My work suggests that Sp140 is the dominant causal gene within the Sst1 locus, and is a novel negative regulator of type I IFN signaling during bacterial infections.

The findings presented in this dissertation highlight the complexities of immune regulation during Mtb infection in vivo, as well as the many questions that remain open. In Chapter 4, I discuss some ideas on future directions and potential experiments that may help illuminate some of these outstanding questions.