Activation and Alliance of Regulatory Pathways in C. albicans during Mammalian Infection

Abstract

Gene expression dynamics have provided foundational insight into almost all biological processes. Here, we analyze expression of environmentally responsive genes and transcription factor genes to infer signals and pathways that drive pathogen gene regulation during invasive Candida albicans infection of a mammalian host. Environmentally responsive gene expression shows that there are early and late phases of infection. The early phase includes induction of zinc and iron limitation genes, genes that respond to transcription factor Rim101, and genes characteristic of invasive hyphal cells. The late phase includes responses related to phagocytosis by macrophages. Transcription factor gene expression also reflects early and late phases. Transcription factor genes that are required for virulence or proliferation in vivo are enriched among highly expressed transcription factor genes. Mutants defective in six transcription factor genes, three previously studied in detail (Rim101, Efg1, Zap1) and three less extensively studied (Rob1, Rpn4, Sut1), are profiled during infection. Most of these mutants have distinct gene expression profiles during infection as compared to in vitro growth. Infection profiles suggest that Sut1 acts in the same pathway as Zap1, and we verify that functional relationship with the finding that overexpression of either ZAP1 or the Zap1-dependent zinc transporter gene ZRT2 restores pathogenicity to a sut1 mutant. Perturbation with the cell wall inhibitor caspofungin also has distinct gene expression impact in vivo and in vitro. Unexpectedly, caspofungin induces many of the same genes that are repressed early during infection, a phenomenon that we suggest may contribute to drug efficacy. The pathogen response circuitry is tailored uniquely during infection, with many relevant regulatory relationships that are not evident during growth in vitro. Our findings support the principle that virulence is a property that is manifested only in the distinct environment in which host–pathogen interaction occurs.

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

“…Our studies reveal two faces of host Cu during infection with C. albicans: while serum Cu elevates, Cu can become limiting at the major site of infection in the kidney. As one possibility, the host may intentionally restrict Cu as part of an innate nutritional immunity response, similar to host withholding of Fe, Mn, and Zn for invading microbes (3)(4)(5)(6)(7)(8)(9)(10). Recent studies by Brown and colleagues have shown that during C. albicans infection of the kidney, Fe moves away from sites of fungal lesions in the cortex to the medulla as an apparent mechanism for Fe withholding (9).…”

“…As part of the innate immune response, the host deliberately withholds metals, such as Fe, Zn, and Mn, from invading microbes in a process known as "nutritional immunity" (3)(4)(5). Like other infectious agents, C. albicans is equipped to handle restrictions placed on these micronutrients and can activate diverse pathways for scavenging host sources of Fe and Zn (6)(7)(8)(9)(10).…”

Plasticity of Candida albicans Biofilms

“…Profiling can be performed by assessing genome-wide transcription by using microarrays (195,200,(244)(245)(246)(247)(248), NanoString nCounter technology (249,250), and RNA sequencing (RNA-Seq) (197,200) or by using quantitative reverse transcription-PCR (RT-PCR) or Northern blot analysis of a smaller, select group of genes (251). Such comparisons are often made between biofilm preparations and planktonic cultures.…”

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

“…Distinct features of the infection environment have been revealed by diverse approaches that include histological analysis [23,24], imaging mass spectrometry [25], and transcriptional profiling [26]. We have previously used transcriptional profiling to understand the genetic control of pathogenicity in infected tissue [8,27,28]. We have found that many mutants that are defective in proliferation during infection present alterations of gene expression that can reveal the role of the mutated gene in pathogenicity.…”