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.
Highlights
IntroductionThese questions are central to the study of microbial pathogenesis, and they have been addressed by diverse approaches [1,2,3,4]
Which genes does a pathogen express during infection? Which regulatory pathways govern expression of those genes in vivo? These questions are central to the study of microbial pathogenesis, and they have been addressed by diverse approaches [1,2,3,4]
Our findings reveal that there are distinct early and late phases of infection, and identify new genes that govern the early zinc acquisition response necessary for proliferation in vivo—and required for infection
Summary
These questions are central to the study of microbial pathogenesis, and they have been addressed by diverse approaches [1,2,3,4]. Despite those efforts, we have a limited understanding of gene expression dynamics during infection of humans or animals by most pathogens. We have used an exquisitely sensitive technology to elucidate gene regulation during tissue invasion by the fungal pathogen Candida albicans. By 24 hr, the fungal burden increases by a factor of 100, and leukocyte infiltration begins. By 48 hr, the fungal burden increases by another factor of 10, and leukocyte infiltration is extensive [7]
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