Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Tuberculosis (TB) in humans results from infection with members of the Mycobacterium tuberculosis complex (MTBC). The disease is endemic in many parts of the world. So is bovine tuberculosis (bTB) - a well-recognized zoonotic disease of bovine species (cattle and buffalo) also caused by infection with members of the MTBC. India has the world’s highest TB burden in humans, with more than 2M new cases and 400,000 TB-related deaths each year. India also hosts the largest bovine herd on the planet (~300M animals), and our recent studies suggest that more than 22M of those animals may suffer from bTB. Yet the risk of zoonotic TB (zTB) resulting from transmission of MTBC from bovines to humans in India and other high-TB burden settings is unknown. This is a major knowledge gap, and elimination of TB will be considerably more difficult if there is spillover from a domestic livestock reservoir to humans. This is of particular concern in countries such as India where the frequent consumption of unpasteurized milk and close contact with infected animals likely present additional elevated risks for zoonotic transmission. Because of this, the World Health Organization (WHO) and other supranational organizations have developed a "Roadmap for zoonotic TB" that calls for the establishment of a stronger evidence base to improve understanding of the burden and risk pathways of zTB to guide an effective response. To fill these knowledge gaps, we propose studies with the overall objective of estimating the risk associated with zTB in a high-TB-burden setting. We will accomplish this by applying rigorous quantitative risk assessment augmented by state-of-the-art whole-genome sequence (WGS)-based molecular epidemiology and multi-host transmission modeling. Performed at well-established study sites in Vellore and Tiruvallur districts in Tamil Nadu, India, our Specific Aims are to: 1) Estimate the risk of human TB associated with exposure to cattle, buffalo, or the consumption of raw milk in ~1,750 human cases and ~3,500 controls; 2) Apply WGS-based approaches to define the genetic diversity and molecular epidemiology and perform phylodynamic and phylogeographic analysis of MTBC lineages circulating in human TB cases, sympatric cattle and buffalo, and locally sourced raw milk; and 3) Perform multi-host transmission modeling to quantitatively assess zTB risk to humans and the potential benefits of control. These studies involve the application of innovative and powerful nested case-control epidemiological surveys with WGS-based genotyping and mathematical modeling. The results of our studies will inform and refine estimates of zTB risk, enable identification of transmission chains at a local scale, and transform our understanding of spillover and circulation of MTBC strains between human and bovine hosts. In the long-term, our findings will provide sustained positive impact through the development of evidence-based approaches to quantify and reduce risk of zTB in support of the global efforts to end TB.
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