Global fungal-host interactome mapping identifies host targets of candidalysin.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.

A novel microRNA-182/Interleukin-8 regulatory axis controls osteolytic bone metastasis of lung cancer.

Bone metastasis is one of the main complications of lung cancer and most important factors that lead to poor life quality and low survival rate in lung cancer patients. However, the regulatory mechanisms underlying lung cancer bone metastasis are still poor understood. Here, we report that microRNA-182 (miR-182) plays a critical role in regulating osteoclastic metastasis of lung cancer cells. We found that miR-182 was significantly upregulated in both bone-metastatic human non-small cell lung cancer (NSCLC) cell line and tumor specimens. We further demonstrated that miR-182 markedly enhanced the ability of NSCLC cells for osteolytic bone metastasis in nude mice. Mechanistically, miR-182 promotes NSCLC cells to secrete Interleukin-8 (IL-8) and in turn facilitates osteoclastogenesis via activating STAT3 signaling in osteoclast progenitor cells. Importantly, systemically delivered IL-8 neutralizing antibody inhibits NSCLC bone metastasis in nude mice. Collectively, our findings identify the miR-182/IL-8/STAT3 axis as a key regulatory pathway in controlling lung cancer cell-induced osteolytic bone metastasis and suggest a promising therapeutic strategy that targets this regulatory axis to interrupt lung cancer bone metastasis.

Mycobiome Dysbiosis in Women with Intrauterine Adhesions.

The vaginal microbiota dysbiosis is closely associated with the development of reproductive diseases. However, the contribution of mycobiome to intrauterine adhesion (IUA) disease remains unknown. Harnessing 16S and ITS2 rDNA sequencing analysis, we investigate both bacterial and fungal microbiota compositions across 174 samples taken from both cervical canal (CC) and middle vagina (MV) sites of IUA patients. Overall, there is no significant difference in microbial diversity between healthy subjects (HS) and IUA patients. However, we observe the IUA-specific bacterial alterations such as increased Dialister and decreased Bifidobacterium and enriched fungal genera like increased Filobasidium and Exophiala. Moreover, site-specific fungal-bacterial correlation networks are discovered in both CC and MV samples of IUA patients. Mechanistic investigation shows that Candida parapsilosis, other than Candida albicans and Candida maltosa, prevents the exacerbation of inflammatory activities and fibrosis, and modulates bacterial microbiota during IUA progression in a rat model of IUA. Our study thus highlights the importance of mycobiota in IUA progression, which may facilitate the development of therapeutic target for IUA prevention. IMPORTANCE Intrauterine adhesion (IUA) often leads to hypomenorrhea, amenorrhea, repeat miscarriages, and infertility. It has been prevalent over the last few decades in up to 13% of women who experience pregnancy termination during the first trimester, and 30% of women undergo dilation and curettage after a late, spontaneous abortion. However, the pathogenesis of IUA remains unclear. Despite reports of microbiota dysbiosis during IUA progression, there is little information on the effect of fungal microbiota on the development of IUA. This study not only enhances our understanding of the mycobiome in IUA patients but also provides potential intervention strategies for prevention of IUA by targeting mycobiome.