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Massive induction of innate immune response to Candida albicans in the kidney in a murine intravenous challenge model.

ABSTRACT: In the experimental Candida albicans intravenous challenge model, the kidney is one of the main organs involved in disease. In progressive infection, fungal burdens are found to increase over time, with rapid increases occurring from 24 h postinfection. Renal transcriptional responses were analyzed at this time in the kidneys of mice infected by either a virulent or an attenuated C. albicans strain, allowing comparison of host responses in progressive and nonprogressive infection. The results of this study demonstrate that both infections share a common transcriptional response, consisting of functions associated with the acute-phase reaction. In addition, challenge with the virulent strain led to a massively increased expression of cytokine genes, other innate response genes and genes suggestive of initiation of the adaptive immune response. This immune response to C. albicans infection, which occurs only in progressive infection, may contribute to development of sepsis and, ultimately, host death.

SUBMITTER: MacCallum DM

PROVIDER: S-EPMC2784217 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Massive induction of innate immune response to Candida albicans in the kidney in a murine intravenous challenge model.

MacCallum Donna M DM

FEMS yeast research 20091001 7

In the experimental Candida albicans intravenous challenge model, the kidney is one of the main organs involved in disease. In progressive infection, fungal burdens are found to increase over time, with rapid increases occurring from 24 h postinfection. Renal transcriptional responses were analyzed at this time in the kidneys of mice infected by either a virulent or an attenuated C. albicans strain, allowing comparison of host responses in progressive and nonprogressive infection. The results of ...[more]

PMID: 19845042

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Project description:Candida albicans bloodstream infection is increasingly frequent and can result in disseminated candidiasis associated with high mortality rates. To analyze the innate immune response against C. albicans, fungal cells were added to human whole-blood samples. After inoculation, C. albicans started to filament and predominantly associate with neutrophils, whereas only a minority of fungal cells became attached to monocytes. While many parameters of host-pathogen interaction were accessible to direct experimental quantification in the whole-blood infection assay, others were not. To overcome these limitations, we generated a virtual infection model that allowed detailed and quantitative predictions on the dynamics of host-pathogen interaction. Experimental time-resolved data were simulated using a state-based modeling approach combined with the Monte Carlo method of simulated annealing to obtain quantitative predictions on a priori unknown transition rates and to identify the main axis of antifungal immunity. Results clearly demonstrated a predominant role of neutrophils, mediated by phagocytosis and intracellular killing as well as the release of antifungal effector molecules upon activation, resulting in extracellular fungicidal activity. Both mechanisms together account for almost [Formula: see text] of C. albicans killing, clearly proving that beside being present in larger numbers than other leukocytes, neutrophils functionally dominate the immune response against C. albicans in human blood. A fraction of C. albicans cells escaped phagocytosis and remained extracellular and viable for up to four hours. This immune escape was independent of filamentation and fungal activity and not linked to exhaustion or inactivation of innate immune cells. The occurrence of C. albicans cells being resistant against phagocytosis may account for the high proportion of dissemination in C. albicans bloodstream infection. Taken together, iterative experiment-model-experiment cycles allowed quantitative analyses of the interplay between host and pathogen in a complex environment like human blood.

Dataset Information

Massive induction of innate immune response to Candida albicans in the kidney in a murine intravenous challenge model.

Publications

Massive induction of innate immune response to Candida albicans in the kidney in a murine intravenous challenge model.

Similar Datasets

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