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.

Dietary fatty acids and risk for Alzheimer's disease, dementia, and mild cognitive impairment: A prospective cohort meta-analysis.

The association between dietary fatty acid intake and Alzheimer's disease (AD), dementia, and mild cognitive impairment (MCI) risk is inconsistent. This meta-analysis examined the effect of dietary fatty acid intake in prospective cohort studies including patients with AD, dementia, and MCI. PubMed, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database were systematically searched through September 2020. The random-effects model was used to combine the highest and lowest categories of multivariable adjusted relative risk (RR). Prospective cohort studies that included associations between dietary fatty acid intake and the risk for AD, dementia, or MCI were included. Fourteen studies were included, comprising 54 177 participants: 1696 patients with AD, 1118 patients with dementia, and 2889 with MCI. The pooled RR showed a significant association only between ω-3 polyunsaturated fatty acid (PUFA) intake and MCI risk (RR, 0.86; 95% CI, 0.75-0.98), with no heterogeneity between studies (I2 = 0%). The intake of total fatty acids, saturated fatty acids (SFAs), cholesterol, monounsaturated fatty acids (MUFAs), PUFAs, ω-3 PUFAs, ω-6 PUFAs, docosahexaenoic acids (DHAs), and eicosapentaenoic acids (EPAs) was not significantly associated with AD risk. The intake of total fatty acids, SFAs, MUFAs, PUFAs, and ω-3 PUFAs was not significantly associated with dementia risk. This meta-analysis provided evidence that ω-3 PUFA intake may be negatively associated with MCI risk.