Tuberculosis (TB), which in humans is caused by Mycobacterium tuberculosis, is one of the leading causes of death from infectious diseases worldwide. There are more TB cases now than at any other time in history and this is largely attributed to the HIV epidemic. Factors that make it difficult to thwart the TB epidemic include the lack of an effective vaccine and the requirement for long multidrug treatment regimens to obtain cures. The latter has led to the selection and spread of extensively drug resistance strains that make TB the lethal disease it was in the pre-antibiotic era. TB results from complex interactions between mycobacteria and their vertebrate hosts. Upon infection by pathogenic mycobacteria, macrophages are recruited to the infection site where they phagocytose the bacteria. However, instead of eradicating the bacteria, macrophages migrate into deeper tissues serving to disseminate the infection. Additional uninfected macrophages are then recruited, and aggregate into the hallmark pathological structure of TB, the granuloma. Long thought to be a host beneficial structure that walls off the infection, we have found that the granuloma, at least in its early stages, serves as a vehicle for bacterial expansion and dissemination. To understand the process of granuloma development, we study Mycobacterium marinum, a close genetic relative of M. tuberculosis, in its natural host, the zebrafish. Zebrafish are genetically tractabl vertebrates with a similar complex immune system to that of mammals and are transparent in the early weeks of development. These features allow a detailed, serial, live-monitoring of infection in animals that have been genetically manipulated. The long term objective of this proposal is to better understand the host-pathogen interactions that occur during granuloma development, with the goal of identifying targets for potential host-directed therapeutics. In this proposal specifically, we will use a variety of molecular and genetic techniques to probe pathways of cell death and recruitment during granuloma development, and to identify pharmacological agents that intercept this process to the benefit of the host.

Public Health Relevance

Tuberculosis is a leading cause of death with more cases now than at any previous time. TB has been difficult to eradicate due to a requirement for long treatment regimens, which lead to non-compliance, and the development of antibiotic resistance. This proposal will identify strategies and molecules that are exploited by the bacteria to produce disease, so as to direct new classes of host-targeting drugs to treat TB. It will also identify host markers of susceptibility that will aid in the development of more efficacious, personalized treatment regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI054503-10
Application #
8290839
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Leitner, Wolfgang W
Project Start
2003-04-15
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$386,041
Indirect Cost
$136,041
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
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
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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