Comparison of pathogenesis and host immune responses to Candida glabrata and Candida albicans in systemically infected immunocompetent mice

Cytokine-mediated host defense against Candida glabrata infection was compa red to that against C. albicans, using immunocompetent murine models of sys temic candidiasis. The pathogenesis of infection was evaluated morphologica lly and by culture of target organs, while the kinetics of induction of cyt okine mRNAs and corresponding proteins were determined in kidneys by real-t ime reverse transcription-PCR and cytokine-specific murine enzyme-linked im munosorbent assays, respectively. Systemic infection with C. glabrata resul ted in a chronic, nonfatal infection with recovery of organisms from kidney s, while intravenous inoculation with C. albicans resulted in rapid mortali ty with logarithmic growth of organisms in kidneys and recovery of C. albic ans from the spleen, liver, and lungs. Survival of C. glabrata-infected mic e was associated with rapid induction of mRNAs and corresponding immunoreac tive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12), and gamma interferon (IFN-gamma) and the lack of induction of protein for the anti-inflammatory cytokine IL-10. In contrast, mortality in C. albicans-infected mice was associated with ind uction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-a lpha) or absent (i.e., IL-12 and IFN-gamma) induction of immunoreactive pro inflammatory cytokines. Mice were subsequently treated with cytokine-specif ic neutralizing monoclonal antibodies (MAbs) to TNF-alpha, IL-12, or IFN-ga mma, and the effect on growth of C. glabrata in kidneys was assessed. Neutr alization of endogenous TNF-alpha resulted in a significant increase in C. glabrata organisms compared to similarly infected mice administered an isot ype-matched control MAb, while neutralization of endogenous IL-12 or IFN-ga mma had no significant effect on C. glabrata replication. These results dem onstrate that in response to intravenous inoculation of C. glabrata, immuno competent mice develop chronic nonfatal renal infections which are associat ed with rapid induction of the proinflammatory cytokines TNF-alpha, IL-12, and IFN-gamma. Furthermore, TNF-alpha plays a key role in host defense agai nst systemic candidiasis caused by either C. glabrata or C. albicans, as th e absence of endogenous TNF-alpha activity was associated with enhanced tis sue burden in both infection models.