Novel therapeutic and prophylactic approaches to combat clinically relevant respiratory viral and bacterial pathogens that cause high morbidity and mortality

Tuberculosis (TB, caused by Mycobacterium tuberculosis, Mtb) causes significant mortality and morbidity, particularly in instances of coinfection with human immunodeficiency virus (HIV). Bone marrow-liver-thymus-lung (BLT-L) mice are susceptible to HIV and mycobacteria. I infected BLT-L mice with Bacillus Calmette-Guérin (BCG, an attenuated vaccine strain of mycobacteria) and HIV and characterized T cell activation, T memory cell frequency, and CCR5 and CXCR4 expression after coinfection. Next, I tested the efficacy of a novel long-acting formulation of rifabutin (LA-RFB) for prevention and treatment of TB. Treatment of drug susceptible Mtb is challenging due to the extended duration. Antibiotic resistant strains are increasingly prevalent, and often occur due to lack of treatment adherence. LA formulations could increase adherence, improve treatment outcomes, and reduce drug resistance. The optimized formulation described here delivers rifabutin for 16 weeks above the minimum inhibitory concentration and exhibits high tissue penetration. A single dose prevents acquisition of Mtb, clears acute Mtb infection in the lung, prevents bacterial dissemination to distal organs, and eliminates pathology in the lung. Finally, I describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. I present two animal models for SARS-CoV-2 infection, lung only mice (LoM) and BLT-L mice. Epithelial cells within the human lung implants in LoM and BLT-L mice express angiotensin converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2 infection. Thus, epithelial cells are the primary target for SARS-CoV-2 infection. Next, I describe treatment with EIDD-2801, which significantly reduces the prevalence of replication competent virus in LoM. Finally, I describe downstream sequelae of infection, including a significant macrophage response and the induction of a pro-fibrotic environment. Importantly, downstream sequelae are reduced by treatment with EIDD-2801 but persist in BLT-L, which clear infection naturally. Herein, I describe novel therapeutic and prophylactic approaches to two respiratory pathogens, Mtb and SARS-CoV-2. Furthermore, the novel approaches and discoveries described in this dissertation establish multiple future directions, including modeling mucosal acquisition of HIV after BCG vaccination, the development of further LA formulations containing multiple anti-TB drugs, and assessment of the impact of SARS-CoV-2 strain variability on downstream sequelae.