Our aim is to utilize a Cryptococcus neoformans model in mice in order to study the pathogenesis and potential methods for control of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS). In the majority of patients with AIDS, the respiratory tract is the probable portal of entry for the opportunistic infectious agent, and/or pulmonary disease is the most devastating manifestation of the infection. Our cryptococcal model will utilize the intratracheal route of inoculation in contrast to the frequent use of the intraperitoneal and intravenous routes of inoculation for this organism. We will determine which lung defenses are crucial in controlling the infection with particular emphasis on the nonimmune mechanisms. Since patients with AIDS are T cell deficient, our strategy will be to study mechanisms for early lung clearance of C. neoformans before T cell immunity can become involved. Thus, we will assess the relative importance of lung macrophages (Mo) and natural killer cells (NK) in the early lung clearance of intratracheally inoculated C. neoformans. We will enumerate pulmonary Mo and NK before C. neoformans inoculation and at various times thereafter. In addition, the role of NK in early lung clearance will be assessed by pretreatment of animals to remove NK. We will also attempt to enhance Mo and NK activity in the lung with the agents Proprionibacterium acnes, muramyl dipeptide and alpha and gamma interferon in order to accelerate early clearance. If these local therapeutic maneuvers are successful, we will determine whether we can modify the protocols to enhance Mo and NK activity systemically in order to rescue infected, immunosuppressed animals from cryptococcal infections.
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