ORCID
https://orcid.org/0000-0002-9276-1469
Date of Award
8-7-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Tuberculosis (TB) is a global health threat, with 10 million people developing active TB disease and a million deaths attributed to TB annually. Emergence of drug resistance in Mycobacterium tuberculosis (Mtb), the causative agent of TB, has led to half a million cases of drug resistant (DR) TB annually. Further, clinical reports suggest dysregulation and suppression of immune responses in DR TB patients as compared with DS TB patients. However, we do not understand how acquisition of drug resistance-conferring mutations can drive broad and systemic differences in immune responses of DR TB patients. We found that rpoB-H445Y a specific DR mutation, can alter macrophage cytokine and metabolic responses to Mtb infection to drive heightened type I interferon (IFN) production in vitro and bypass interleukin-1 (IL-1) signaling for protection in vivo. Using a variety of mouse models, we now study the role of type I IFN signaling during DR Mtb infection in the lung. Unlike during drug sensitive (DS) Mtb infection, type I IFN signaling drives suppressed myeloid and T cell responses during DR Mtb infection, promoting chronic DR Mtb survival. We also found additional immunosuppressive effects during DR Mtb infection in the bone marrow with limited expansion of hematopoietic stem cells and a bias towards granulopoiesis. However, type I IFN also plays a protective role in LysM-expressing cells and contributed to the IL-1 independent protection seen during DR Mtb infection. These findings further our understanding of how drug resistance-conferring mutations contribute to altered pathogenesis in DR TB patients and suggest alternative targets for host-directed therapeutics to treat DR TB.
Language
English (en)
Chair and Committee
Shabaana Khader
Committee Members
Jennifer Philips
Recommended Citation
Bobba, Suhas, "Roles of Type I Interferon Signaling in Drug Resistant Mycobacterium tuberculosis Infection" (2023). Arts & Sciences Electronic Theses and Dissertations. 3125.
https://openscholarship.wustl.edu/art_sci_etds/3125