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.
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.
| 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 |
| Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10 |
| Roh-Johnson, Minna; Shah, Arish N; Stonick, Jason A et al. (2017) Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo. Dev Cell 43:549-562.e6 |
| Pagán, Antonio J; Ramakrishnan, Lalita (2017) TORmented macrophages spontaneously form granulomas. Nat Immunol 18:252-253 |
| Madigan, Cressida A; Cameron, James; Ramakrishnan, Lalita (2017) A Zebrafish Model of Mycobacterium leprae Granulomatous Infection. J Infect Dis 216:776-779 |
| Cambier, C J; O'Leary, Seónadh M; O'Sullivan, Mary P et al. (2017) Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages. Immunity 47:552-565.e4 |
| Conrad, William H; Osman, Morwan M; Shanahan, Jonathan K et al. (2017) Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions. Proc Natl Acad Sci U S A 114:1371-1376 |
| Levitte, Steven; Adams, Kristin N; Berg, Russell D et al. (2016) Mycobacterial Acid Tolerance Enables Phagolysosomal Survival and Establishment of Tuberculous Infection In Vivo. Cell Host Microbe 20:250-8 |
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