Rationale: The purpose of this application is to strengthen the tuberculosis (TB) translational research capacity at UCSF/SFGH by developing a BSL-3 laboratory in which work with human TB can be safely carried out in tissue culture and in small animal models.  Such work will enable us to extend observations that we have made in molecular epidemiological studies of TB in San Francisco, permit new lab-based investigation in the context of existing, funded clinical studies in San Francisco and abroad, and facilitate additional studies in animal models of infection. Having such a facility will enable us to examine immunological responses to as well as the pathogenicity and virulence of clinical strains of M. tuberculosis (M.tb) isolated from patients in San Francisco and in other areas across the US and globally, and to study the impact of co-infections with M.tb and other pathogens (e.g., HIV). We have a superb multidisciplinary group of investigators working in the US as well as in Kenya, Tanzania, Zimbabwe, Uganda, and Vietnam in studies of the transmission and pathogenesis of TB. In a number of these studies, observations have been made that suggest differences among strains and interactions between specific strains and hosts of specific race/ethnicity. Examination of these findings in lab-based studies and/or in an animal model will, if confirmed, enable back translation to human studies and approaches to vaccine and drug development. The availability of a new BSL-3 will facilitate the work of investigators working across many disciplines and enable questions to be addressed that can only be examined in animal models. Given the international scope of existing research activities, this effort will also mesh with efforts at UCSF and SFGH to enhance global health. In recent efforts to recruit an investigator focused on TB immunology, the major limiting factor has been the lack of BSL-3 space. Thus, having such a facility is a critical element in filling a critical deficiency in our TB research program.

Plan: Although a BSL-3 laboratory exists in Building 100 at SFGH, this laboratory is heavily utilized, inadequately designed, and not amenable to the maintenance of M. tb infected animals. Other alternatives have been carefully explored but deemed not feasible for reasons of experimental protocol, safety, and/or cost. We propose to upgrade an existing BSL-2 laboratory in Building 3, a seismically sound building, to BSL-3 status. Based on input from the construction firm that built the existing space, the total cost of the build-out of the BSL3 is estimated to be $1.2M. There is widespread enthusiasm and broad support to create such a facility, as indicated by commitments that total $950,000 from a consortium of funders including the Department of Medicine, the Medical Service at SFGH, the SFGH Dean's Office, and the Ireland Fund, but there remains a $250,000 deficit. We are asking for $100,000 to help leverage these commitments. Given our success in raising the needed funds, we are confident that the additional $150,000 will be secured, even if it means obtaining a loan that would be paid back by users over time.

Criteria and Metrics for Success: The single metric will be the hiring of one independent TB immunology investigator by 2013. The Division of Experimental Medicine will commit the resources for at least one start-up package to hire faculty members focused on the immunology of human TB. Each package would include at least $1M in start-up funds and the provision of BSL1 and BSL2 space ensuring that, if the BSL-3 is built, the criterion of success will be met.

Approximate Cost and Justification: We are requesting $100,000, an amount that will be combined with additional resources that have already been committed (see above). These aggregated funds will be used to purchase or construct: 1) animal holding space with self-contained cage ventilated racks for mice or guinea pigs; 2) several biosafety cabinets for the safe handling of M.tb in tissue culture; 3) autoclave alcove to house the autoclave and the CO₂ gas manifold; 4) clean vestibule (entrance and exit); 5) dirty vestibule (entrance to both of the laboratories and the animal holding room); and 6) ultralow freezer for storage of bacterial stocks and infected tissues. The space will have the mechanical system required for a completely independent ventilation system.

Faculty who would use this facility: Hopewell, Havlir, Kato-Maeda, Catamanchi, Davis, Metcalfe, Nahid, Everett, Cox, McCune, Nixon