| Abstrakt: |
ABSTRACTCytokine-mediated host defense against Candida glabratainfection was compared to that against C. albicans, using immunocompetent murine models of systemic candidiasis. The pathogenesis of infection was evaluated morphologically and by culture of target organs, while the kinetics of induction of cytokine mRNAs and corresponding proteins were determined in kidneys by real-time reverse transcription-PCR and cytokine-specific murine enzyme-linked immunosorbent assays, respectively. Systemic infection with C. glabrataresulted in a chronic, nonfatal infection with recovery of organisms from kidneys, while intravenous inoculation with C. albicansresulted in rapid mortality with logarithmic growth of organisms in kidneys and recovery of C. albicansfrom the spleen, liver, and lungs. Survival of C. glabrata-infected mice was associated with rapid induction of mRNAs and corresponding immunoreactive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and gamma interferon (IFN-γ) 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 induction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-α) or absent (i.e., IL-12 and IFN-γ) induction of immunoreactive proinflammatory cytokines. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to TNF-α, IL-12, or IFN-γ, and the effect on growth of C. glabratain kidneys was assessed. Neutralization of endogenous TNF-α resulted in a significant increase in C. glabrataorganisms compared to similarly infected mice administered an isotype-matched control MAb, while neutralization of endogenous IL-12 or IFN-γ had no significant effect on C. glabratareplication. These results demonstrate that in response to intravenous inoculation of C. glabrata, immunocompetent mice develop chronic nonfatal renal infections which are associated with rapid induction of the proinflammatory cytokines TNF-α, IL-12, and IFN-γ. Furthermore, TNF-α plays a key role in host defense against systemic candidiasis caused by either C. glabrataor C. albicans, as the absence of endogenous TNF-α activity was associated with enhanced tissue burden in both infection models. |
