Characterization of a novel mouse model and vaccines for pulmonary pathogens

Abstract

Lower respiratory tract (LRT) infections are an important cause of morbidity and mortality worldwide, especially in developing countries. There are many causes of LRT infections, including numerous viral and bacterial etiologies. The research presented in this thesis focuses on two important pathogens that infect the lung: (1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease 2019 (COVID-19) pandemic, and (2) Mycobacterium tuberculosis, which causes tuberculosis (TB). Viruses are the most common cause of LRT infections, so this thesis begins with a comprehensive review of the animal models and comparative pathology of three main etiologies of viral pneumonia, including SARS-CoV-2. There are several established transgenic mouse models for COVID-19, but due to differences in receptor distribution and expression levels, these models generally result in non-physiologic disease. To address this, the first research study describes the development and characterization of a new gene replacement mouse model (ACE2-GR) for COVID-19. Mice were productively infected with SARS-CoV-2, displayed no symptoms, and developed mild viral pneumonia prior to recovery. These findings establish ACE2-GR mice as a physiologically relevant model for mild disease. The second research study characterizes a novel viral-vectored TB vaccine in mice, as there is currently no effective vaccine for this disease. The multivalent Pichinde virus (PICV)-vectored TB vaccines elicited strong, functional T cell responses that reduced the bacterial burden in mice. This study supports the continued development of TB vaccines using the PICV vector. Collectively, the research presented in this thesis establishes the groundwork for future studies to investigate disease pathogenesis and discover new vaccines and therapeutics for high-impact pulmonary pathogens.