Protective immunity to Histoplasma capsulatum requires the interaction of T cells with macrophages and dendritic cells. The human immune response to this fungus is effective at limiting infection, but not at sterilizing tissues. Once infected, the yeast may remain dormant for years within granulomas or other niches. When the integrity of the human immune system is breached, either by other infections such as human immunodeficiency virus or by pharmacologic agents that suppress immunity, the organism may escape the confines of the granuloma and replicate. This form is known as reactivation histoplasmosis and may be associated with life-threatening progressive infection if not promptly diagnosed and treated. The mechanisms that permit the organism to evade confinement are unknown. We have developed a murine model of reactivation histoplasmosis that will enable us to understand the perturbations in immunity that create a favorable environment for the organism to escape host defense mechanisms. C57BL/6 mice are infected with a nonlethal inoculum of yeast and at 42 days postinfection, when organisms are no longer detected by routine culture methods, mice are depleted of CD4+ and CD8+ cells. The loss of these cells, but not the individual subpopulation alone, is accompanied by a growth of the organism from both lungs and spleens. The infection becomes persistent over the next 46 days. We also have shown that the absence of B cells enhances the severity of reactivation. Unlike B cell sufficient mice, depletion of CD4+ cells in B cell knockout mice induces reactivation. Thus, the development of this model has permitted us to begin to explore the immunologic defects that are associated with this extremely important form of histoplasmosis. In the following proposal we will address two aims: 1) To determine the immunological mechanisms that modulate reactivation. Specific projects include: a) To determine the molecular constituents produced by CD4+ and/or CD8+ cells from lungs and spleens that prevent reactivation, b) To elucidate the immunologic elements that prevent reactivation from becoming progressive, c) To determine the contribution of B cells to reactivation, d) To examine the interaction between B cells and CD8 + cells, and e) To determine if the absence of transporter associated with antigen processing alters reactivation in mice.
Specific Aim 2) To determine the influence of Th 1 and 2 immunity on reactivation. Specific projects include: a) To determine if a preexisting bias in Th 2 immunity increases severity of reactivation, b) To determine if mice with an induced Th 2 response manifest enhanced severity of reactivation, c) To determine if age influences reactivation, d) To determine if a preexisting bias in Th 1 immunity modulates reactivation, e) To determine if the absence of B ceils alters reactivation in mice with a preexisting bias in Th 1or 2 immunity, and f) To determine the influence of corticosteroids on the reactivation process. Knowledge gained will advance our ability to prevent and/or treat this form of histoplasmosis.
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