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.

Multi-omics insights into the interplay between gut microbiota and colorectal cancer in the "microworld" age.

Colorectal cancer (CRC) is a multifactorial heterogeneous disease largely due to both genetic predisposition and environmental factors including the gut microbiota, a dynamic microbial ecosystem inhabiting the gastrointestinal tract. Elucidation of the molecular mechanisms by which the gut microbiota interacts with the host may contribute to the pathogenesis, diagnosis, and promotion of CRC. However, deciphering the influence of genetic variants and interactions with the gut microbial ecosystem is rather challenging. Despite recent advancements in single omics analysis, the application of multi-omics approaches to integrate multiple layers of information in the microbiome and host to introduce effective prevention, diagnosis, and treatment strategies is still in its infancy. Here, we integrate host- and microbe-based multi-omics studies, respectively, to provide a strategy to explore potential causal relationships between gut microbiota and colorectal cancer. Specifically, we summarize the recent multi-omics studies such as metagenomics combined with metabolomics and metagenomics combined with genomics. Meanwhile, the sample size and sample types commonly used in multi-omics research, as well as the methods of data analysis, were also generalized. We highlight multiple layers of information from multi-omics that need to be verified by different types of models. Together, this review provides new insights into the clinical diagnosis and treatment of colorectal cancer patients.