Cell reportsPub Date : 2025-05-06DOI: 10.1016/j.celrep.2025.115657
Charlotte Maserumule, Charlotte Passemar, Olivia S H Oh, Kriztina Hegyi, Karen Brown, Aaron Weimann, Adam Dinan, Sonia Davila, Catherine Klapholz, Josephine Bryant, Deepshikha Verma, Jacob Gadwa, Shivankari Krishnananthasivam, Kridakorn Vongtongsalee, Edward Kendall, Andres Trelles, Martin L Hibberd, Joaquín Sanz, Jorge Bertol, Lucia Vázquez-Iniesta, Kaliappan Andi, S Siva Kumar, Diane Ordway, Rafael Prados-Rosales, Paul A MacAry, R Andres Floto
{"title":"Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis.","authors":"Charlotte Maserumule, Charlotte Passemar, Olivia S H Oh, Kriztina Hegyi, Karen Brown, Aaron Weimann, Adam Dinan, Sonia Davila, Catherine Klapholz, Josephine Bryant, Deepshikha Verma, Jacob Gadwa, Shivankari Krishnananthasivam, Kridakorn Vongtongsalee, Edward Kendall, Andres Trelles, Martin L Hibberd, Joaquín Sanz, Jorge Bertol, Lucia Vázquez-Iniesta, Kaliappan Andi, S Siva Kumar, Diane Ordway, Rafael Prados-Rosales, Paul A MacAry, R Andres Floto","doi":"10.1016/j.celrep.2025.115657","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115657","url":null,"abstract":"<p><p>Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) remain poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify Toll-like receptor 8 (TLR8) as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances the killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant M1V, common in Far Eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signaling may, therefore, both regulate susceptibility to tuberculosis and provide novel drug targets.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115657"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-06DOI: 10.1016/j.celrep.2025.115658
Leora Duong, Yonghan Wu, Summer J Kasallis, Serena Abbondante, Paul J Hurst, Michaela E Marshall, Katherine McCarthy, Babu J N Reddy, Jean-Louis Bru, Kumar Perinbam, Eric Pearlman, Joseph P Patterson, Steven P Gross, Albert Siryaporn
{"title":"Bactericidal activity of mammalian histones is caused by large membrane pore formation.","authors":"Leora Duong, Yonghan Wu, Summer J Kasallis, Serena Abbondante, Paul J Hurst, Michaela E Marshall, Katherine McCarthy, Babu J N Reddy, Jean-Louis Bru, Kumar Perinbam, Eric Pearlman, Joseph P Patterson, Steven P Gross, Albert Siryaporn","doi":"10.1016/j.celrep.2025.115658","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115658","url":null,"abstract":"<p><p>Histones have an important role in eukaryotic innate immunity, wherein histones co-localize with antimicrobial peptides (AMPs). The mechanism of histone cooperation with AMPs and the extent to which histones form pores both remain a mystery. Here, we show that histones form large pores in bacterial membranes that lack lipopolysaccharide (LPS) and that their antimicrobial effect is significantly stronger than that of the clinical AMP polymyxin B. We find that histones and AMPs together produce potent antimicrobial synergy through the formation of 26 nm pores, whereby the pore-forming activity of AMPs on LPS-containing membranes enables histones to enter the periplasmic space and subsequently attack unprotected membranes to create pores. We provide a mechanistic explanation for the long-standing observations of histone antimicrobial activity and demonstrate how antimicrobial synergy arises. The ubiquity of histones and AMPs in innate immunity has significant implications for organismal defense and can be leveraged for novel antibiotic strategies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115658"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115650
Sophie A Howard, Rubén de Dios, Evgenia Maslova, Antonis Myridakis, Thomas H Miller, Ronan R McCarthy
{"title":"Pseudomonas aeruginosa clinical isolates can encode plastic-degrading enzymes that allow survival on plastic and augment biofilm formation.","authors":"Sophie A Howard, Rubén de Dios, Evgenia Maslova, Antonis Myridakis, Thomas H Miller, Ronan R McCarthy","doi":"10.1016/j.celrep.2025.115650","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115650","url":null,"abstract":"<p><p>Multiple bacteria encoding plastic-degrading enzymes have been isolated from the environment. Given the widespread use of plastic in healthcare, we hypothesized that bacterial clinical isolates may also degrade plastic. This could render plastic-containing medical devices susceptible to degradation and failure and potentially offer these pathogens a growth-sustaining substrate, enabling them to persist in the hospital-built environment. Here, we mined the genomes of prevalent pathogens and identified several species encoding enzymes with homology to known plastic-degrading enzymes. We identify a clinical isolate of Pseudomonas aeruginosa that encodes an enzyme that enables it to degrade a medically relevant plastic, polycaprolactone (PCL), by 78% in 7 days. Furthermore, this degradation enables the bacterium to utilize PCL as its sole carbon source. We also demonstrate that encoding plastic-degrading enzymes can enhance biofilm formation and pathogenicity. Given the central role of plastic in healthcare, screening nosocomial bacteria for plastic-degrading capacity should be an important future consideration.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":" ","pages":"115650"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115645
Jane Y Song, Fabien Wehbe, Aaron K Wong, Ben M Hall, Jason A Vander Heiden, Hans D Brightbill, Joseph R Arron, David A Garfield, Anwesha Dey, Jason R Rock
{"title":"YAP/TAZ activity in PDGFRα-expressing alveolar fibroblasts modulates AT2 proliferation through Wnt4.","authors":"Jane Y Song, Fabien Wehbe, Aaron K Wong, Ben M Hall, Jason A Vander Heiden, Hans D Brightbill, Joseph R Arron, David A Garfield, Anwesha Dey, Jason R Rock","doi":"10.1016/j.celrep.2025.115645","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115645","url":null,"abstract":"<p><p>The Hippo pathway, mediated by its transcriptional effectors Yes-associated protein 1 (YAP) and WW-domain-containing transcription regulator 1 (TAZ), is crucial in maintaining lung homeostasis and facilitating injury repair. While its roles in epithelial cells are well established, its regulatory effects on lung fibroblasts remain less understood. We engineered a mouse model for the inducible knockdown of YAP/TAZ and showed that fibroblast-specific knockdown enhances PDGFRα+ alveolar fibroblasts' support for alveolar-epithelial-stem-cell-derived organoids in vitro. Single-cell profiling revealed changes in fibroblast subpopulations, including the emergence of a Wnt4+ enriched subpopulation. Epigenomic analyses revealed shifts in transcription factor motif enrichment in both fibroblasts and epithelial cells due to fibroblast YAP/TAZ suppression. Further computational and in vivo analyses confirmed increased Wnt signaling and Wnt4 expression in PDGFRα-lineage+ fibroblasts, which enhanced SPC+ alveolar type 2 (AT2) cell proliferation. These findings highlight a mechanistic role of YAP/TAZ in PDGFRα+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115645"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115663
Narmada Sambaturu, Emily J Fray, Vivek Hariharan, Fengting Wu, Carolin Zitzmann, Francesco R Simonetti, Dan H Barouch, Janet D Siliciano, Robert F Siliciano, Ruy M Ribeiro, Alan S Perelson, Carmen Molina-París, Thomas Leitner
{"title":"SIV proviruses seeded later in infection are harbored in short-lived CD4<sup>+</sup> T cells.","authors":"Narmada Sambaturu, Emily J Fray, Vivek Hariharan, Fengting Wu, Carolin Zitzmann, Francesco R Simonetti, Dan H Barouch, Janet D Siliciano, Robert F Siliciano, Ruy M Ribeiro, Alan S Perelson, Carmen Molina-París, Thomas Leitner","doi":"10.1016/j.celrep.2025.115663","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115663","url":null,"abstract":"<p><p>The human immunodeficiency virus (HIV) can persist in a latent form as integrated DNA (provirus) in resting CD4<sup>+</sup> T cells unaffected by antiretroviral therapy. Despite being a major obstacle for eradication efforts, it remains unclear which infected cells survive, persist, and ultimately enter the long-lived reservoir. Here, we determine the genetic divergence and integration times of simian immunodeficiency virus (SIV) envelope sequences collected from infected macaques. We show that the proviral divergence and the phylogenetically estimated integration times display a biphasic decline over time. Investigating the dynamics of the mutational distributions, we show that SIV genomes in short-lived cells are, on average, more diverged, while long-lived cells contain less diverged virus. The change in the mutational distributions over time explains the observed biphasic decline in the divergence of the proviruses. This suggests that long-lived cells harbor viruses deposited earlier in infection, while short-lived cells predominantly harbor more recent viruses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115663"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115613
Antonio G Dias, Elias M Duarte, Jose Victor Zambrana, Jaime A Cardona-Ospina, Sandra Bos, Vicky Roy, Julia Huffaker, Guillermina Kuan, Angel Balmaseda, Galit Alter, Eva Harris
{"title":"Anti-dengue virus antibodies that elicit complement-mediated lysis of Zika virion correlate with protection from severe dengue disease.","authors":"Antonio G Dias, Elias M Duarte, Jose Victor Zambrana, Jaime A Cardona-Ospina, Sandra Bos, Vicky Roy, Julia Huffaker, Guillermina Kuan, Angel Balmaseda, Galit Alter, Eva Harris","doi":"10.1016/j.celrep.2025.115613","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115613","url":null,"abstract":"<p><p>Antibodies from primary dengue (DENV1-4) or Zika (ZIKV) virus infections can influence subsequent heterotypic infections, but their protective characteristics are not well defined. We analyzed pre-infection plasma samples from children in our Nicaraguan cohort study who later developed either dengue fever (DF; n = 31) or dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS; n = 33) upon secondary heterotypic DENV infection. Various antibody properties, notably antibody-dependent complement deposition, correlated with protection against DHF/DSS. Interestingly, this association was strongest when using recombinant ZIKV antigens despite participants being ZIKV naive. Additionally, complement-mediated virion lysis (virolysis) with ZIKV virions was strongly associated with protection, a finding replicated in an independent sample set. ZIKV virolysis emerged as the only antibody property linked to reduced risk of DHF/DSS and severe symptoms such as thrombocytopenia and plasma leakage. These results suggest that ZIKV-cross-reactive anti-DENV antibodies that mediate complement-dependent virolysis may lower the risk of severe disease, informing the development of effective dengue vaccines and therapeutics.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115613"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115649
Tanmay Arekar, Divya Katikaneni, Sadat Kasem, Dhruv Desai, Thrisha Acharya, Augustina Cole, Nazli Khodayari, Sophie Vaulont, Bernhard Hube, Elizabeta Nemeth, Alexander Drakesmith, Michail S Lionakis, Borna Mehrad, Yogesh Scindia
{"title":"Essential role of hepcidin in host resistance to disseminated candidiasis.","authors":"Tanmay Arekar, Divya Katikaneni, Sadat Kasem, Dhruv Desai, Thrisha Acharya, Augustina Cole, Nazli Khodayari, Sophie Vaulont, Bernhard Hube, Elizabeta Nemeth, Alexander Drakesmith, Michail S Lionakis, Borna Mehrad, Yogesh Scindia","doi":"10.1016/j.celrep.2025.115649","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115649","url":null,"abstract":"<p><p>Candida albicans is a leading cause of life-threatening invasive infection despite antifungal therapy. Patients with chronic liver disease are at increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is an attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3-β-glucan, which exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcome of infection. Thus, we identify hepcidin deficiency as a host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115649"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The complete reference genome of Tartary buckwheat and its mutation library provide important resources for genetic studies and breeding.","authors":"Hongyou Li, Qiuyu Lv, Taoxiong Shi, Yaling Jian, Bin Ran, Yuanzhi Cheng, Lei Wang, Jing Zhang, Juan Huang, Jiao Deng, Liwei Zhu, Qijiao Chen, Fang Cai, Ruiyuan Li, Qi Wu, Yizhong Zhang, Yuliang Zhang, Zhang Zhang, Feng Yu, Qingfu Chen","doi":"10.1016/j.celrep.2025.115621","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115621","url":null,"abstract":"<p><p>Tartary buckwheat (TB), Fagopyrum tataricum, is an important medicinal and edible crop with a worldwide distribution. However, reference genomes with gaps and mutant population scarcity have hindered functional genomics and genetic improvement of TB. Here, we present a telomere-to-telomere (T2T) gap-free genome assembly of the elite TB inbred line Guiku1 and its ethyl-methyl-sulfonate (EMS)-induced phenotypically rich mutation library. The Guiku1 gap-free genome spans 453.83 Mb, containing 43,441 predicted protein-coding genes. The mutation library includes 751 mutants with stably heritable phenotypes. Whole-genome resequencing of 320 mutants identified 105,682 single-nucleotide polymorphisms (SNPs) and 21,461 insertions/deletions (indels), affecting the protein-coding sequences of 25,986 genes. Genes responsible for the pink stem and petiole mutant trait and flavonoid content variation were identified using forward- and reverse-genetics approaches, respectively. Collectively, the T2T gap-free genome of Guiku1 and its EMS mutation library provide important resources for functional genomics studies and the genetic improvement of TB.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115621"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-05-05DOI: 10.1016/j.celrep.2025.115648
Cheng-Yen Chen, Naweed I Naqvi
{"title":"Endophytic mycobiont provides growth benefits via a phenylpropanoid-auxin axis in host plants.","authors":"Cheng-Yen Chen, Naweed I Naqvi","doi":"10.1016/j.celrep.2025.115648","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115648","url":null,"abstract":"<p><p>Beneficial association with symbiotic fungi helps improve growth and fitness in most land plants and shows great potential as biofertilizers in precision agriculture. Here, we demonstrated that a root fungal endophyte, Tinctoporellus species isolate AR8, enabled yield improvement in Brassicaceae leafy green choy sum (Brassica rapa var. parachinensis). Mechanistically, AR8 colonized the root cortex/endosphere and channeled the metabolic flux to phenylpropanoids and requisite secondary metabolites to promote plant growth. AR8-assisted biosynthesis of auxin improved root growth and provided an intrinsic source for long-distance signaling that enhanced shoot biomass. Chemical complementation with exogenous p-coumaric acid restored auxin signaling and enhanced growth in AR8-inoculated pal1 mutant plants, thus implicating such a phenylpropanoid-auxin nexus as a pivotal regulator of symbiotic plant growth. Comparative metabolomics established hydroxycinnamic acid and p-coumaric acid as major plant-growth-promoting hubs that bridge the phenylpropanoid pathway and auxin signaling in the cross-kingdom AR8 symbiotic interaction model.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115648"},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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