Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), possesses an arsenal of virulence factors to evade host immunity. Not only is Mtb able to evade innate immunity, but adaptive immunity also often fails to adequately control Mtb infection. A mechanistic understanding of how Mtb establishes infection and evades immunity is critical to the development of a protective vaccine and novel therapeutics. The Mtb protein CpsA protects Mtb against the host NADPH oxidase and LC3-asociated phagocytosis of the innate immune system. Consequently, a ΔcpsA mutant is initially attenuated in vivo but eventually reaches the same bacterial burden in the lungs as wild type (WT) Mtb. Using flow cytometry, we found that CpsA promotes dissemination of Mtb from alveolar macrophages and the airways into recruited myeloid cells in the lung interstitium, which promotes priming of naïve T cells. Because it elicits a delayed adaptive immune response, the ΔcpsA mutant experiences a more permissive environment, allowing it to ultimately achieve the same bacterial burden as WT Mtb. Our studies reveal that a more effective innate immune response against Mtb can be undermined by a corresponding delay in the adaptive immune response. CD4+ T cells are crucial for protective immunity to Mtb. A direct cognate interaction between CD4+ T cells and infected macrophages is important for control of Mtb; however, the mechanism has been elusive. We found that in Mtb-infected mice and macaques, SLAMF1 expression was induced in diverse myeloid cells specifically by the combination of Mtb infection and T cells and depended, in part, on autophagy. Moreover, when we infected Slamf1-/- mice, we found they had higher Mtb burdens, dysregulated inflammatory responses, and more rapid disease progression than wild type mice. In macaques, macrophage SLAMFI expression was highest in protective granulomas and after highly-protective intravenous BCG vaccination. Together, these data demonstrate that SLAMF1 is a T cell contact-dependent factor in macrophages that contributes to host protection from TB. Overall, these findings provide insight into the protective immune response to Mtb and the virulence strategies of Mtb that must be overcome by an effective vaccine.

Committee Chair

Jennifer Philips

Committee Members

Celeste Morley; Christina Stallings; David Sibley; Mary Dinauer

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-21-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-7987-6360

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