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A broad-spectrum anti-fungal effector dictates bacterial-fungal interkingdom interactions.

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Název: A broad-spectrum anti-fungal effector dictates bacterial-fungal interkingdom interactions.
Autoři: Yan, Shuangquan, Zou, Yun, Wu, Tingting, Kan, Yumin, Luo, Han, Pei, Tong-Tong, Liang, Xiaoye, An, Ying, Meng, Pengfei, Song, Yi, Qin, Wen-Ming, Chen, Changbin, Dong, Tao
Zdroj: PLoS Pathogens; 10/27/2025, Vol. 21 Issue 10, p1-25, 25p
Témata: ANTIFUNGAL agents, DRUG resistance, CRYPTOCOCCUS neoformans, THERAPEUTICS, ANTIBIOSIS, CANDIDA, ANTAGONISTIC fungi
Abstrakt: Bacteria–fungi interactions play crucial roles in shaping microbial communities across diverse environmental and host-associated niches. While their antagonism through diffusible metabolites is a well-known ecological phenomenon, delivery of bacterial effectors into the nucleus of fungal cells remains rare, and the mechanisms are poorly understood. Here, we identify and characterize a potent anti-fungal nuclease effector, TseN, delivered by the type VI secretion system (T6SS) of Acidovorax citrulli. TseN possesses a nuclear localization signal and inhibits multiple fungal species, including emerging human pathogens Candida auris and Cryptococcus neoformans. Structural and biochemical analyses show that TseN possesses a unique C-terminal DNase domain that defines a new effector class, with its activity neutralized by a cognate immunity protein TsiN. The delivery of TseN requires the upstream-encoded VgrG5, a chaperone Aave_2128, and PAAR5. Transcriptome profiling of co-cultured bacterial-fungal cells demonstrates that the T6SS attack triggers extensive reprogramming in fungal cells, affecting DNA repair, stress response, and filamentation pathways. These responses not only compromise fungal survival but also modulate fungal drug resistance, as evidenced by the synergistic enhancement of azole efficacy against drug-resistant Candida albicans. Importantly, in vivo experiments confirm that the T6SS, via TseN, can significantly reduce fungal burden on murine skin. Phylogenetic analysis shows TseN homologs are present in a large number of bacterial species. Collectively, our findings highlight a previously underappreciated interkingdom antagonism modulated by a novel effector. The broad-spectrum anti-fungal activities of TseN and its homologs may be explored for therapeutic strategies targeting fungal pathogens in both clinical and environmental settings. Author summary: Multidrug-resistant fungal pathogens are an escalating global health concern, yet current options for treatment and for reducing environmental transmission remain limited. In nature, bacteria and fungi frequently compete for resources, providing an important source of new antifungal strategies. Here, we show that the plant-associated bacterium Acidovorax citrulli uses a needle-like type VI secretion system (T6SS) to inject a DNase effector, TseN, directly into fungal cells. Once delivered, TseN employs its nucleolar localization sequence to enter the fungal nucleus and damage DNA, thereby suppressing growth across diverse fungal species, including drug-resistant human pathogens. In mouse infection models, TseN-mediated activity reduced fungal burden in skin infections. The widespread distribution of TseN homologs suggests this represents a conserved mechanism of bacterial antagonism against fungi. These findings highlight new opportunities to develop innovative strategies to combat fungal infections in humans, animals, and plants. [ABSTRACT FROM AUTHOR]
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Databáze: Complementary Index
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Abstrakt:Bacteria–fungi interactions play crucial roles in shaping microbial communities across diverse environmental and host-associated niches. While their antagonism through diffusible metabolites is a well-known ecological phenomenon, delivery of bacterial effectors into the nucleus of fungal cells remains rare, and the mechanisms are poorly understood. Here, we identify and characterize a potent anti-fungal nuclease effector, TseN, delivered by the type VI secretion system (T6SS) of Acidovorax citrulli. TseN possesses a nuclear localization signal and inhibits multiple fungal species, including emerging human pathogens Candida auris and Cryptococcus neoformans. Structural and biochemical analyses show that TseN possesses a unique C-terminal DNase domain that defines a new effector class, with its activity neutralized by a cognate immunity protein TsiN. The delivery of TseN requires the upstream-encoded VgrG5, a chaperone Aave_2128, and PAAR5. Transcriptome profiling of co-cultured bacterial-fungal cells demonstrates that the T6SS attack triggers extensive reprogramming in fungal cells, affecting DNA repair, stress response, and filamentation pathways. These responses not only compromise fungal survival but also modulate fungal drug resistance, as evidenced by the synergistic enhancement of azole efficacy against drug-resistant Candida albicans. Importantly, in vivo experiments confirm that the T6SS, via TseN, can significantly reduce fungal burden on murine skin. Phylogenetic analysis shows TseN homologs are present in a large number of bacterial species. Collectively, our findings highlight a previously underappreciated interkingdom antagonism modulated by a novel effector. The broad-spectrum anti-fungal activities of TseN and its homologs may be explored for therapeutic strategies targeting fungal pathogens in both clinical and environmental settings. Author summary: Multidrug-resistant fungal pathogens are an escalating global health concern, yet current options for treatment and for reducing environmental transmission remain limited. In nature, bacteria and fungi frequently compete for resources, providing an important source of new antifungal strategies. Here, we show that the plant-associated bacterium Acidovorax citrulli uses a needle-like type VI secretion system (T6SS) to inject a DNase effector, TseN, directly into fungal cells. Once delivered, TseN employs its nucleolar localization sequence to enter the fungal nucleus and damage DNA, thereby suppressing growth across diverse fungal species, including drug-resistant human pathogens. In mouse infection models, TseN-mediated activity reduced fungal burden in skin infections. The widespread distribution of TseN homologs suggests this represents a conserved mechanism of bacterial antagonism against fungi. These findings highlight new opportunities to develop innovative strategies to combat fungal infections in humans, animals, and plants. [ABSTRACT FROM AUTHOR]
ISSN:15537366
DOI:10.1371/journal.ppat.1013598