Infections due to C. neoformans occur preferentially in patients with impaired cell-mediated immunity (CMI), especially those with AIDS. The central hypothesis of this proposal is that the mononuclear phagocyte (MNP) plays a critical role in the immunology of cryptococcosis by acting both as an effector cell controlling fungal proliferation and as a cytokine-producing affecter cell modulating the inflammatory response. The three specific aims focus on defining unique aspects of how mononuclear phagocytes (MNP) contribute to CMI against cryptococcosis, and how infection with human immunodeficiency virus (HIV) modulates this response.
Aim 1 is to define the effects of suppressive (TGF-beta, IL-4, IL-10) and activating (IFN-g, TNFa, M-CSF, GM-CSF) cytokines on MNP responses to C. neoformans. Responses to be examined include binding, phagocytosis, growth inhibition, killing, oxidant generation and, in conjunction with aim 2, cytokine production. The mechanisms responsible for the cytokine-induced alterations will be investigated.
Aim 2 is to examine cytokine gene expression and release by MNP stimulated with C. neoformans. Studies will focus on the proinflammatory cytokines TNFa, IL-1, IL-6, IL-8 and IL-12. Cellular mechanisms of cytokine induction will be studied by examining the role of phagocytic receptors and transcriptional factors.
Aim 3 is to examine the effects of co-infection of MNP with HIV and C. neoformans. These experiments seek to test two basic hypotheses regarding HIV and cryptococcosis: (i) Challenge of HIV-infected MNP with C. neoformans induces viral replication. If this hypothesis proves true, it would imply that by inducing HIV, cryptococcosis could accelerate the progression of AIDS. The role of the transcriptional factor NF-KB in HIV induction will be determined. (ii) Effector and affecter responses in HIV-infected MNP are impaired compared with uninfected MNP. Where HIV- related impairments are found, the mechanisms responsible will be explored. For each of the aims, the effect of cryptococcal capsule will be explored by comparing isolates with differing capsule size including a capsular mutants. The effect of opsonins will be defined by comparing responses to selectively opsonized fungi. Completion of these studies will contribute important new information to our basic understanding of the immunology of cryptococcosis, and may provide a rational basis for novel approaches to combating cryptococcosis and slowing the progression of AIDS.
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