RESPONSES OF HUMAN LEUKOCYTES TO LIPOARABINOMANNAN

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DESCRIPTION (Adapted from applicant's abstract and specific aims): Tuberculosis is responsible for more human deaths worldwide each year than any other single infectious disease. Current understanding of the pathogenesis of tuberculosis suggests that innate host defenses determine whether mycobacterial infection results in active disease or whether the infection is successfully contained. Host responses designed to limit mycobacterial growth include the activation of leukocytes and the formulation of granulomas. Effective granuloma formation is critical for the control of tuberculosis, and begins with the migration of peripheral leukocytes to the lung. While the production of chemoattractant cytokines by infected alveolar macrophages is likely to stimulate leukocyte recruitment, the effect of specific mycobacterial products on this response has yet to be determined. This application hypothesizes that the release of the mycobacterial cell wall glycophospholipid lipoarabinomannan (LAM) from infected alveolar macrophages serves to recruit peripheral T cells to the site of infection, and subsequently suppress the activation of these migrating T cells. The specific aims are: 1) to characterize the function and phenotype of leukocytes which migrate to LAM; 2) to define a mechanistic basis for the chemotactic response of leukocytes to LAM; and 3) to determine the molecular basis for suppression of leukocyte activation by LAM.