Out of control – Ablation of the C. albicans Histone Chaperone HIR Drives Fungal Hypervirulence — ASN Events

Out of control – Ablation of the C. albicans Histone Chaperone HIR Drives Fungal Hypervirulence (#138)

Karl Kuchler 1 , Sabrina Jenull , Florian Zwolanek , Michael Riedelberger , Michael Tscherner
  1. Medical University Vienna, Vienna, Austria

Fungal pathogens are considered hidden killers of mankind, as invasive fungal infections claim around 1,5 million lifes per year. Thus, fungal infections constitute a medical problem of epic proportions. Candida albicans is an extraordinary example of how a commensal pathogen can sense and integrate host immune signals to allow for rapid adaptation and survival within distinct host niches. Subtle transcriptional changes can be linked to altered chromatin organization, which profoundly affects morphogenetic cell fate decisions as observed during the C. albicans yeast-to-hyphae transition. Morphogenesis is dynamic and triggered by various host signals, involving both transient transcriptional modulation and chromatin re-modeling. We have shown that the HIR histone chaperone complex subunit facilitates replication-independent histone deposition onto chromatin but also acts as a transcriptional co-regulator of morphogenesis genes. Indeed, ablation of Hir1 decreases the sensitivity to morphogenetic signals, resulting in impaired hyphal formation. HIR1-deficient cells show markedly decreased transcriptional amplitudes of both repressing and activating genes during hyphal initiation, and a deregulated expression of extracellular proteolytic activities, suggesting that Hir1 modulates the fine-tuning of transcriptional responses during filamentation. Here, we delineate the in vivo host immune response to C. albicans hir1Δ/Δ cells. Strikingly, hir1Δ/Δ cells display a dramatic hypervirulence phenotype in a mouse model of invasive candidiasis when compared to wild type cells. Hypervirulence of hir1Δ/Δ is accompanied by dramatic increases in kidney cfu burdens, indicating that hir1Δ/Δ cells show a fitness gain and increased growth rates in vivo, resulting in their impaired clearance when compared to wild type cells. Most unexpectedly, neutrophils, but not monocytes or macrophages, are no longer recruited to kidneys harboring hir1Δ/Δ cells. Neutrophils appear “blind” towards pathogenic signals originating from hir1Δ/Δ cells, all in all allowing for their outgrowth in vivo. We propose that hir1Δ/Δ cells alter fungal immune surveillance by either selectively impairing recruitment or activation of neutrophils that are otherwise essential for pathogen clearance. Taken together, our data suggest Hir1-mediated alterations in fungal chromatin drives immune evasion, since it reduces inflammatory responses below threshold levels otherwise required for clearance.

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