Pulmonary tuberculosis remains a serious world-wide problem. Mycobacterium tuberculosis (MTB) causes pulmonary infection by first being inhaled into the alveolar spaces where it attaches and enters alveolar macrophages (AM) to survive and replicate. The ability of MTB to use AM as a """"""""safe habitat"""""""" is central to its survival during the earliest stages of infection. Studies from this laboratory indicate that bronchoalveolar lavage (BAL) fluid from HIV subjects contains a factor that promotes attachment of MTB to AM. This factor was shown to be surfactant protein A (SP-A). Preliminary data indicate that SP-D is also elevated in the HIV BAL fluid and can also promote MTB attachment to AM. Interestingly, two conditions associated with a marked elevation of SP-A and SP-D include HIV disease and silicosis; both conditions are associated with an increased risk for tuberculosis. Thus, the hypothesis is: SP-A/SP-D mediates attachment of MTB to AM in HIV-infected subjects facilitating MTB growth and survival in the alveolar spaces.
The Specific Aims of this proposal include: 1 Determine molecular site(s) and characteristics of SP-A/SP-D binding to MTB; 2. Determine if: a)SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 3.) Determine if: a) SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D- mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 4) Determine how human BAL fluid from normal and HIV-infected individuals influences MTB attachment to AM, the AM cytotoxic response and growth of MTB inside AM. If successful, these studies will result in the development of fundamentally new approaches to the study of pulmonary tuberculosis in HIV subjects. The opportunity to determine the specific site of SP-A or SP-D binding to MTB may provide insights that suggest novel therapeutic strategies in the future.
