We have used the zebrafish model to detail the host-pathogen interface in tuberculosis, and our discoveries have led to a more nuanced understanding of the role of inflammation, macrophages and granulomas in infection. In so doing, we have also achieved a better understanding of fundamental host processes particularly those involving macrophages and inflammation. In this next phase of the grant, we will continue to characterize the role of newly-identified host factors that alter mycobacterial infection. Some of these were already identified but not fully characterized in the last funding period, and others will be identified in the zebrafish mutant screen that we are continuing now, using the comprehensive sequenced zebrafish mutant library that has been created by the Sanger Institute and made available to us. Comprehensive transcriptomics will also be carried out for us at the Sanger Institute with full bioinformatics support, leaving us to focus on the phenotypic characterization of the mutants with altered susceptibility. With advances in microscopic imaging capability that are continuously occurring in our laboratory, and the use of pharmacological approaches for additional pathway dissection and drug identification, we hope to have an accelerated pace of discovery during this next phase.

Public Health Relevance

Tuberculosis is a leading cause of death worldwide and a growing global health concern. TB has been difficult to eradicate due to a combination of factors, including the development of antibiotic resistance. Our research proposes to identify strategies and molecules that can direct development of new classes of host-targeting drugs to treat TB.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Singleton, Kentner L
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University of Cambridge
United Kingdom
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Hernandez, Rafael E; Galitan, Louie; Cameron, James et al. (2018) Delay of Initial Feeding of Zebrafish Larvae Until 8 Days Postfertilization Has No Impact on Survival or Growth Through the Juvenile Stage. Zebrafish 15:515-518
Takaki, Kevin; Ramakrishnan, Lalita; Basu, Soumyava (2018) A zebrafish model for ocular tuberculosis. PLoS One 13:e0194982
Pagán, Antonio J; Ramakrishnan, Lalita (2018) The Formation and Function of Granulomas. Annu Rev Immunol 36:639-665
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