Tuberculosis (TB) is a deadly disease that has afflicted humankind throughout history and pre-history before becoming endemic in many parts of the world by the end of the 19th century. Following the discovery of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis by Robert Koch in 1882 TB began to be brought under control by a combination of the novel treatment methods (e.g. the sanatorium movement), increasing public health measures, the invention of a partially effective vaccine and, in the mid-20th century, the discovery of effective drugs and drug treatment regimens.
TB incidence has declined throughout the 20th century but remains the leading cause of death due to infectious disease worldwide causing about 1.5 million deaths per year. The failure to develop a fully effective vaccine and the emergence of multiply-, extensively-, and totally drug resistant strains are barriers to more effective TB control and highlight the need to develop novel treatment modalities based on a deeper understanding of Mtb’s unique physiology and intracellular niche.
Chapter 1 of this thesis explores Mtb’s use of the carbohydrate trehalose that Mtb, nearly uniquely among bacteria, utilizes for a variety of essential metabolic and structural purposes. The osmotic stress model demonstrates that Mtb regulates and controls its large pool of free trehalose. The results presented here suggest that a deeper understanding of the loci and methods of trehalose regulation and control may open avenues to undermine the fitness of mycobacterial pathogens in vivo and, ultimately, during human disease. In Chapter 2, a class of compounds called cationic amphiphilic drugs (CADs) are investigated for their ability to restrict the growth of intracellular Mtb.
In 2020 the novel human disease COVID-19 caused by the virus SARS-CoV-2 emerged to displace TB as the leading cause of infectious disease deaths worldwide. In January 2021, two novel strains of SARS-CoV-2 (B.1.427 and B.1.149) emerged in California and were jointly designated as variants of concern (epsilon) by the World Health Organization. Chapter 3 presents the use of the Syrian hamster model to characterize the virulence, transmissibility, and susceptibility to pre-existing immunity of these variants in vivo relative to an earlier strain (B.1 [D614G]). In hamsters, epsilon was found to cause more severe disease and higher viral RNA levels in oropharyngeal swabs compared to B.1. These findings are consistent with human clinical and epidemiological data and help explain the emergence and rapid spread of this variant in early 2021.
