The human fungal pathogen Candida albicans is constantly exposed to environmental challenges impacting the cell wall. Signaling pathways coordinate stress adaptation and are essential for commensalism and virulence. The transcription factors Sko1, Cas5, and Rlm1 control the response to cell wall stress caused by the antifungal drug caspofungin. Here, we expand the Sko1 and Rlm1 transcriptional circuit and demonstrate that Rlm1 activates Sko1 cell wall stress signaling. Caspofungin-induced transcription of SKO1 and several Sko1dependent cell wall integrity genes are attenuated in an rlm1Δ/Δ mutant strain when compared to the treated wild-type strain but not in a cas5Δ/Δ mutant strain. Genome-wide chromatin immunoprecipitation (ChIP-seq) results revealed numerous Sko1 and Rlm1 directly bound target genes in the presence of caspofungin that were undetected in previous gene expression studies. Notable targets include genes involved in cell wall integrity, osmolarity, and cellular aggregation, as well as several uncharacterized genes. Interestingly, we found that Rlm1 does not bind to the upstream intergenic region of SKO1 in the presence of caspofungin, indicating that Rlm1 indirectly controls caspofungin-induced SKO1 transcription. In addition, we discovered that caspofungin-induced SKO1 transcription occurs through selfactivation. Based on our ChIP-seq data, we also discovered an Rlm1 consensus motif unique to C. albicans. For Sko1, we found a consensus motif similar to the known Sko1 motif for Saccharomyces cerevisiae. Growth assays showed that SKO1 overexpression suppressed caspofungin hypersensitivity in an rlm1Δ/Δ mutant strain. In addition, overexpression of the glycerol phosphatase, RHR2, suppressed caspofungin hypersensitivity specifically in a sko1Δ/Δ mutant strain. Our findings link the Sko1 and Rlm1 signaling pathways, identify new biological roles for Sko1 and Rlm1, and highlight the complex dynamics underlying cell wall signaling.

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Integral membrane proteins from the ancient SPFH (stomatin, prohibitin, flotillin, HflK/HflC) protein superfamily are found in nearly all living organisms. Mammalian SPFH proteins are primarily associated with mitochondrial functions but also coordinate key processes such as ion transport, signaling, and mechanosensation. In addition, SPFH proteins are required for virulence in parasites. While mitochondrial functions of SPFH proteins are conserved in fungi, recent evidence has uncovered additional roles for SPFH proteins in filamentation and stress signaling. Inhibitors that target SPFH proteins have been successfully used in cancer and inflammation treatment. Thus, SPFH proteins may serve as a potential target for novel antifungal drug development. This review article surveys SPFH function in various fungal species with a special focus on the most common human fungal pathogen, Candida albicans.

Infection with parasites from the Entamoeba genus are significantly underreported causes of diarrheal disease that disproportionally impact tropical regions. There are several species of Entamoeba that infect humans to cause a range of symptoms from asymptomatic colonization of the intestinal tract to invasive disease with dissemination.

There are several Entamoeba species that colonize humans, but only Entamoeba histolytica causes severe disease. E. histolytica is transmitted through the fecal-oral route to colonize the intestinal tract of 50 million people worldwide. The current mouse model to study E. histolytica intestinal infection directly delivers the parasite into the surgically exposed cecum, which circumvents the natural route of infection and does not produce infectious cysts. To develop a fecal-oral mouse model, we screened our vivarium for a natural murine Entamoeba colonizer via a pan-Entamoeba PCR targeting the 18S ribosomal gene. We determined that C57BL/6 mice were chronically colonized by Entamoeba muris. This amoeba is closely related to E. histolytica, as determined by 18S sequencing and cross-reactivity with an E. histolytica-specific antibody. In contrast, outbred Swiss Webster (SW) mice were not chronically colonized by E. muris. We orally challenged SW mice with 1x105E. muris cysts and discovered they were susceptible to infection, with peak cyst shedding occurring between 5-7 days post-infection. Most infected SW mice did not lose weight significantly but trended toward decreased weight gain throughout the experiment when compared to mock-infected controls. Infected mice treated with paromomycin, an antibiotic used against non-invasive intestinal disease, do not become colonized by E. muris. Within the intestinal tract, E. muris localizes exclusively to the cecum and colon. Purified E. muris cysts treated with bovine bile in vitro excyst into mobile, pre-trophozoite stages. Overall, this work describes a novel fecal-oral mouse model for the important global pathogen E. histolytica.