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<p>In the past 200 years, tuberculosis (TB) has caused more deaths than any other
infectious disease and currently infects more people than it has at any other time
in human history. Mycobacterium tuberculosis (Mtb), the etiological agent of TB, is
an obligate human pathogen that has evolved through the millennia to become the archetypal
human-adapted pathogen. This work focuses on the evolutionary framework by which Mtb
emerged as a specialized human pathogen, and applying this perspective to outbreak
strains and the strategies Mtb deploys to manipulate its host environment.</p><p>There
are seven major lineages that define the human-adapted species of Mtb. Beijing lineage
strains, also known as Lineage 2 strains, have emerged as important drivers of global
Mtb burden due to the elevated rates of drug-resistance, rapid disease progression,
and increased transmission characteristics they display. Beijing lineage strains are
endemic to East Asia, but have recently expanded globally. In Chapter 2, we investigate
circulating Beijing strains in Guatemala, a country with limited data regarding the
molecular epidemiology of Mtb and few reported cases of disease caused by Beijing
strains. We report the first whole genome sequencing of Central American Beijing-lineage
strains of Mtb. We find that multiple Beijing-lineage strains, derived from independent
founding events, are currently circulating in Guatemala, but overall still represent
a relatively small proportion of disease burden. Finally, we identify a specific Beijing-lineage
outbreak centered on a poor neighborhood in Guatemala City.</p><p>Pairing whole genome
sequencing with outbreak strains displaying unusual disease phenotypes provides compelling
insight into the genetic changes underlying the corresponding disease presentation.
Mtb most commonly causes lung disease, but can also disseminate to other tissue sites.
We identified an outbreak strain of Mtb that presented clinically with unusually high
rates of extrapulmonary and bone disease in seemingly immunocompetent individuals.
We find that the outbreak was caused by an ancient strain of Mtb that, like other
ancestral strains and animal-adapted mycobacterial pathogens, carries a full-length
version of the Type VII secreted effector EsxM. Here we show that EsxM is required
for the full disseminative properties of mycobacterium-infected macrophages and is
sufficient to directly enhance macrophage motility. Moreover, we find that EsxM has
been inactivated in all modern strains of Mtb, suggesting a potential selective advantage
to limiting dissemination as Mtb adopted and adapted to its modern pulmonary niche.</p><p>Pathogenic
mycobacteria have long been known to utilize an array of effectors to manipulate their
host environment. Mycobacterial infection initiates the assembly of granulomas, which
are discrete host structures composed of tightly associated immune cell aggregates.
Macrophages within the granuloma have been described as "epithelioid" due to the morphological
transformation they undergo as they interdigitate with their neighboring cells. The
epithelial transformation macrophages undergo is central to the formation of the granuloma,
yet this transformation has not been well characterized at the molecular level during
mycobacterial infection. Our laboratory has utilized the zebrafish to dissect the
epithelial transformation of macrophages during mycobacterial infection. In Chapter
4, I outline the transcriptional reprogramming that occurs in granuloma macrophages
that underlies this transformation. We find that granulomas exhibit distinct transcriptional
profiles from macrophages, and, surprisingly, that immune cells deploy developmental
programs to construct the granuloma.</p>
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