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.

The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells.

Although polymorphic microbiomes have emerged as hallmarks of cancer, far less is known about the role of the intratumor mycobiome as living microorganisms in cancer progression. Here, using fungi-enriched DNA extraction and deep shotgun metagenomic sequencing, we have identified enriched tumor-resident Aspergillus sydowii in patients with lung adenocarcinoma (LUAD). By three different syngeneic lung cancer mice models, we find that A. sydowii promotes lung tumor progression via IL-1ß-mediated expansion and activation of MDSCs, resulting in suppressed activity of cytotoxic T lymphocyte cells and accumulation of PD-1+ CD8+ T cells. This is mediated by IL-1ß secretion via ß-glucan/Dectin-1/CARD9 pathway. Analysis of human samples confirms that enriched A. sydowii is associated with immunosuppression and poor patient outcome. Our findings suggest that intratumor mycobiome, albeit at low biomass, promotes lung cancer progression and could be targeted at the strain level to improve patients with LUAD outcome.

The Application of High-Throughput Technologies for the Study of Microbiome and Cancer.

Human gut microbiome research, especially gut microbiome, has been developing at a considerable pace over the last decades, driven by a rapid technological advancement. The emergence of high-throughput technologies, such as genomics, transcriptomics, and others, has afforded the generation of large volumes of data, and in relation to specific pathologies such as different cancer types. The current review identifies high-throughput technologies as they have been implemented in the study of microbiome and cancer. Four main thematic areas have emerged: the characterization of microbial diversity and composition, microbial functional analyses, biomarker prediction, and, lastly, potential therapeutic applications. The majority of studies identified focus on the microbiome diversity characterization, which is reaching technological maturity, while the remaining three thematic areas could be described as emerging.

Fingolimod Potentiates the Antifungal Activity of Amphotericin B.

Candida albicans (C. albicans) is an opportunistic human fungal pathogen that can cause severe infection in clinic. Its incidence and mortality rate has been increasing rapidly. Amphotericin B (AMB), the clinical golden standard antifungal agent, has severe side effects that limit its clinical application. Thus, lowering the concentration and increasing the efficacy of AMB in a combinatorial antifungal therapy have been pursued by both industry and academia. Here we identify that fingolimod (FTY720), an immunomodulatory drug used for oral treatment of relapsing-remitting multiple sclerosis, can potentiate the efficacy of AMB against C. albicans growth synergistically. Furthermore, we observe an antifungal efficacy of FTY720 in combination with AMB against diverse fungal pathogens. Intriguingly, cells treated with both drugs are hypersensitive to endothelial endocytosis and macrophage killing. This is later found to be due to the hyperaccumulation of reactive oxygen species and the corresponding increase in activities of superoxide dismutase and catalase in the cells that received combinatorial treatment. Therefore, the combination of AMB and FTY720 provides a promising antifungal strategy.

Microbiome dysbiosis in lung cancer: from composition to therapy.

The correlations between microbiota dysbiosis and cancer have gained extensive attention and been widely explored. As a leading cancer diagnosis worldwide, lung cancer poses a great threat to human health. The healthy human lungs are consistently exposed to external environment and harbor a specific pattern of microbiota, sharing many key pathological and physiological characteristics with the intestinal tract. Although previous findings uncovered the critical roles of microbiota in tumorigenesis and response to anticancer therapy, most of them were focused on the intestinal microbiota rather than lung microbiota. Notably, the considerable functions of microbiota in maintaining lung homeostasis should not be neglected as the microbiome dysbiosis may promote tumor development and progression through production of cytokines and toxins and multiple other pathways. Despite the fact that increasing studies have revealed the effect of microbiome on the induction of lung cancer and different disease status, the underlying mechanisms and potential therapeutic strategies remained unclear. Herein, we summarized the recent progresses about microbiome in lung cancer and further discussed the role of microbial communities in promoting lung cancer progression and the current status of therapeutic approaches targeting microbiome to alleviate and even cure lung cancer.

[Clinical observation of rapid massage at Shuidao (ST 28) to prevent postpartum urinary retention].

OBJECTIVE: To explore the clinical effect of rapid massage at Shuidao (ST 28) to prevent puerpera from postpartum urinary retention. METHODS: A total of 200 puerpera giving birth through vagina were enrolled and divided into an observation group and a control group according to the random number table method, 100 cases in each group. In the observation group, rapid massage at Shuidao (ST 28) was applied. In the control group,there was no intervention and urinated naturally. The traditional Chinese medicine syndrome scale was used to evaluate poor sense of urination, and record puerpera with or without postpartum urinary retention, the poor sense of first urination, the first time of urination, the amount of first urination and postpartum hemorrhage. RESULTS: The poor sense of first urination in the observation group was significantly lower than that in the control (P<0.001), the first time of urination in the observation group was significantly earlier than that in the control group (P<0.001), the amount of first urination in the observation group was significantly more than that in the control group (P<0.001), the observation group was superior to the control group to prevent postpartum urinary retention (P<0.05). CONCLUSION: Rapid massage at Shuidao (ST 28) can reduce the poor sense of first urination, significantly advance the time of spontaneous urination, significantly increase the amount of first urination and effectively prevent postpartum urinary retention.