mBio最新文献

{"title":"Perturbation of <i>Pseudomonas aeruginosa</i> peptidoglycan recycling by anti-folates and design of a dual-action inhibitor.","authors":"Luke N Yaeger, David Sychantha, Princeton Luong, Shahrokh Shekarriz, Océane Goncalves, Annamaria Dobrin, Michael R Ranieri, Ryan P Lamers, Hanjeong Harvey, George C diCenzo, Michael Surette, Jean-Phiippe Côté, Jakob Magolan, Lori L Burrows","doi":"10.1128/mbio.02984-24","DOIUrl":"10.1128/mbio.02984-24","url":null,"abstract":"<p><p>Peptidoglycan (PG) is an important bacterial macromolecule that confers cell shape and structural integrity, and is a key antibiotic target. Its synthesis and turnover are carefully coordinated with other cellular processes and pathways. Despite established connections between the biosynthesis of PG and the outer membrane, or PG and DNA replication, links between PG and folate metabolism remain comparatively unexplored. Folate is an essential cofactor for bacterial growth and is required for the synthesis of many important metabolites. Here we show that inhibition of folate synthesis in the important Gram-negative pathogen <i>Pseudomonas aeruginosa</i> has downstream effects on PG metabolism and integrity that can manifest as the formation of a subpopulation of round cells that can undergo explosive lysis. Folate inhibitors potentiated β-lactams by perturbation of PG recycling, reducing expression of the AmpC β-lactamase. Supporting this mechanism, folate inhibitors also synergized with fosfomycin, an inhibitor of MurA, the first committed step in PG synthesis that can be bypassed by PG recycling. These insights led to the design of a dual-active inhibitor that overcomes NDM-1 metallo-β lactamase-mediated meropenem resistance and synergizes with the folate inhibitor, trimethoprim. We show that folate and PG metabolism are intimately connected, and targeting this connection can overcome antibiotic resistance in Gram-negative pathogens.</p><p><strong>Importance: </strong>To combat the alarming global increase in superbugs amid the simultaneous scarcity of new drugs, we can create synergistic combinations of currently available antibiotics or chimeric molecules with dual activities, to minimize resistance. Here we show that older anti-folate drugs synergize with specific cell wall biosynthesis inhibitors to kill the priority pathogen, <i>Pseudomonas aeruginosa</i>. Anti-folate drugs caused a dose-dependent loss of rod cell shape followed by explosive lysis, and synergized with β-lactams that target D,D-carboxypeptidases required to tailor the cell wall. Anti-folates impaired cell wall recycling and subsequent downstream expression of the chromosomally encoded β-lactamase, AmpC, which normally destroys β-lactam antibiotics. Building on the anti-folate-like scaffold of a metallo-β-lactamase inhibitor, we created a new molecule, MLLB-2201, that potentiates β-lactams and anti-folates and restores meropenem activity against metallo-β-lactamase-expressing <i>Escherichia coli</i>. These strategies are useful ways to tackle the ongoing rise in dangerous bacterial pathogens.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0298424"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbe-derived betulinic acid alleviates sepsis-induced acute liver injury by inhibiting macrophage NLRP3 inflammasome in mice.","authors":"Xuheng Tang, Tairan Zeng, Wenyan Deng, Wanning Zhao, Yanan Liu, Qiaobing Huang, Yiyu Deng, Weidang Xie, Wei Huang","doi":"10.1128/mbio.03020-24","DOIUrl":"10.1128/mbio.03020-24","url":null,"abstract":"<p><p>Sepsis-induced acute liver injury (SALI) is a prevalent and life-threatening complication associated with sepsis. The gut microbiota plays a crucial role in the maintenance of health and the development of diseases. The impact of physical exercise on gut microbiota modulation has been well-documented. However, the potential impact of gut microbiome on exercise training-induced protection against SALI remains uncertain. Here, we discovered exercise training ameliorated SALI and systemic inflammation in septic mice. Notably, gut microbiota pre-depletion abolished the protective effects of exercise training in SALI mice. Fecal microbiota transplantation treatment revealed that exercise training-associated gut microbiota contributed to the beneficial effect of exercise training on SALI. Exercise training modulated the metabolism of <i>Ligilactobacillus</i> and enriched betulinic acid (BA) levels in mice. Functionally, BA treatment conferred protection against SALI by inhibiting the hepatic inflammatory response in mice. BA bound and inactivated hnRNPA2B1, thus suppressing NLRP3 inflammasome activation in macrophages. Collectively, this study reveals gut microbiota is involved in the protective effects of exercise training against SALI, and gut microbiota-derived BA inhibits the hepatic inflammatory response via the hnRNPA2B1-NLRP3 axis, providing a potential therapeutic strategy for SALI.</p><p><strong>Importance: </strong>Sepsis is characterized by a dysregulated immune response to an infection that leads to multiple organ dysfunction. The occurrence of acute liver injury is frequently observed during the initial stage of sepsis and is directly linked to mortality in the intensive care unit. The preventive effect of physical exercise on SALI is well recognized, yet the underlying mechanism remains poorly elucidated. Exercise training alters the gut microbiome in mice, increasing the abundance of Ligilactobacillus and promoting the generation of BA. Additionally, BA supplementation can suppress the NLRP3 inflammasome activation in macrophages by directly binding to hnRNPA2B1, thereby mitigating SALI. These results highlight the beneficial role of gut microbiota-derived BA in inhibiting the hepatic inflammatory response, which represents a crucial stride toward implementing microbiome-based therapeutic strategies for the clinical management of sepsis.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0302024"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MeJA inhibits fungal growth and DON toxin production by interfering with the cAMP-PKA signaling pathway in the wheat scab fungus <i>Fusarium graminearum</i>.","authors":"Kaili Duan, Shaozhe Qin, Fangling Cui, Liangyuan Zhao, Yongqing Huang, Jin-Rong Xu, Guanghui Wang","doi":"10.1128/mbio.03151-24","DOIUrl":"10.1128/mbio.03151-24","url":null,"abstract":"<p><p>Deoxynivalenol (DON), a mycotoxin primarily produced by <i>Fusarium</i> species, is commonly found in cereal grains and poses risks to human and animal health, as well as global grain trade. This study demonstrates that methyl jasmonate (MeJA), a natural plant hormone, inhibits the growth and conidiation of <i>Fusarium graminearum</i>. Importantly, MeJA significantly reduces DON production by suppressing <i>TRI</i> gene expression and toxisome formation. To explore the molecular mechanism, we identified MeJA-tolerant mutants, including a transcription factor <i>MRT1</i> and cAMP-PKA pathway-related genes (<i>FgGPA1</i> and <i>FgSNT1</i>). MeJA treatment reduced PKA activity and intracellular cAMP levels in <i>F. graminearum</i>, suggesting it targets the cAMP-PKA pathway. Notably, the MeJA-resistant mutant <i>FgGPA1</i>^R178H enhanced fungal growth, DON production, and cAMP levels in the presence of MeJA. Exogenous cAMP alleviated MeJA's inhibitory effects on DON production, further supporting this pathway's involvement. Interestingly, MeJA had no effect on all three MAP kinase pathways (Mgv1, Gpmk1, and FgHog1). Truncated and phospho-mimicking mutations in Mrt1 or FgSnt1 conferred MeJA resistance, suggesting they may act downstream of the cAMP-PKA pathway. In conclusion, MeJA presents a promising approach to control <i>F. graminearum</i> growth and DON production.IMPORTANCEDeoxynivalenol (DON) poses significant risks to both human and animal health and severely disrupts the global grain trade due to its prevalence as a common contaminant in wheat grains. With rising public concern over food safety, finding effective and sustainable methods to reduce DON contamination becomes increasingly urgent. In our study, we found that methyl jasmonate (MeJA), a natural plant hormone, can effectively inhibit the vegetative growth of <i>F. graminearum</i> and significantly reduce its DON toxin production. To explore the underlying molecular mechanism, we identified the mutations in MeJA-tolerant mutants and revealed that MeJA effectively exerts its antifungal activities by inhibiting the cAMP-PKA signaling pathway in <i>F. graminearum</i>. Our work provides a promising natural solution to reduce DON toxin contamination in cereal grains, enhancing food safety while decreasing the reliance on chemical fungicides and their associated environmental impact.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0315124"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mGem: A quarter century with the Pirofski-Casadevall damage response framework-a dynamic construct for understanding microbial pathogenesis.","authors":"Joshua D Nosanchuk","doi":"10.1128/mbio.02945-24","DOIUrl":"10.1128/mbio.02945-24","url":null,"abstract":"<p><p>A quarter of a century ago, Liise-anne Pirofski and Arturo Casadevall shared their concepts of microbial pathogenesis through the lens of a damage-response framework (DRF), which characterizes disease by assessing the dynamic interactions between the host and pathogen as reflected by damage as the readout. This framework has evolved to be a powerful tool for understanding the biology of complex infectious diseases, analyzing emerging and reemerging microbes, and developing therapeutic approaches to combat infections. The DRF is also frequently used to explain research at scientific meetings and to teach microbial pathogenesis to diverse learners. This mGem reviews how the DRF came to be and provides an overview of how it is used. Without a doubt, the scientific community will continue to leverage the DRF to advance research and innovate therapeutic approaches, which is especially important as new and reemerging infectious diseases threaten global health.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0294524"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rickettsial pathogen augments tick vesicular-associated membrane proteins for infection and survival in the vector host.","authors":"Prachi Namjoshi, Jaydeep Kolape, Avni Patel, Hameeda Sultana, Girish Neelakanta","doi":"10.1128/mbio.03549-24","DOIUrl":"10.1128/mbio.03549-24","url":null,"abstract":"<p><p><i>Anaplasma phagocytophilum</i> is an obligate intracellular rickettsial pathogen that infects humans and animals. The black-legged tick <i>Ixodes scapularis</i> acts as a vector and transmits this bacterium to the vertebrate host. Upon entry into a host cell, <i>A. phagocytophilum</i> resides and multiplies in a host-derived vacuole called morulae. There is not much information available on the molecules that play an important role(s) in <i>A. phagocytophilum</i> entry and formation of these morulae in tick cells. In this study, we provide evidence that tick vesicular-associated membrane proteins, VAMP3 and VAMP4, play important roles in this phenomenon. Quantitative real-time polymerase chain reaction (QRT-PCR) analysis showed that both <i>vamp3</i> and <i>vamp4</i> transcripts are significantly upregulated at early time points of <i>A. phagocytophilum</i> infection in tick cells. We noted that both VAMP3 and VAMP4 predominantly localized to the <i>A. phagocytophilum</i>-containing vacuole. RNAi-mediated silencing of <i>vamp3</i> and/or <i>vamp4</i> expression, followed by confocal microscopy and expression analysis, indicated an impairment in <i>A. phagocytophilum</i> morulae formation in tick cells. We also noted that VAMP3 and VAMP4 play a role in the <i>A. phagocytophilum</i> persistent infection of ticks and tick cells. Furthermore, RNAi-mediated silencing of expression of arthropod <i>vamp3</i> and <i>vamp4</i> affected bacterial acquisition from an infected murine host to ticks. Collectively, this study not only provides evidence on the role of arthropod vesicular-associated membrane proteins in <i>A. phagocytophilum</i> morulae formation in tick cells but also demonstrates that these proteins are important for bacterial acquisition from an infected vertebrate host into ticks.</p><p><strong>Importance: </strong><i>Anaplasma phagocytophilu</i>m is a tick-borne pathogen primarily transmitted by black-legged Ixodes scapularis ticks to humans and animals. This bacterium enters host cells, forms a host-derived vacuole, and multiplies within this vacuole. The molecules that are critical in the formation of host-derived vacuole in tick cells is currently not well-characterized. In this study, we provide evidence that arthropod vesicular-associated membrane proteins, VAMP3 and VAMP4, are critical for <i>A. phagocytophilum</i> early and persistent infection in tick cells. These arthropod proteins are important for the formation of host-derived vacuoles in tick cells. Our study also provides evidence that these proteins are important for <i>A. phagocytophilum</i> acquisition from the infected murine host into ticks. Characterization of tick molecules important in bacterial entry and/or survival in the vector host could lead to the development of strategies to target this and perhaps other rickettsial pathogens.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0354924"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FhaA plays a key role in mycobacterial polar elongation and asymmetric growth.","authors":"Jessica Rossello, Bernardina Rivera, Maximiliano Anzibar Fialho, Ingrid Augusto, Magdalena Gil, Marina Andrea Forrellad, Fabiana Bigi, Azalia Rodríguez Taño, Estefanía Urdániz, Mariana Piuri, Kildare Miranda, Anne Marie Wehenkel, Pedro M Alzari, Leonel Malacrida, Rosario Durán","doi":"10.1128/mbio.02526-24","DOIUrl":"10.1128/mbio.02526-24","url":null,"abstract":"<p><p>Mycobacteria, including pathogens like <i>Mycobacterium tuberculosis</i>, exhibit unique growth patterns and cell envelope structures that challenge our understanding of bacterial physiology. This study sheds light on FhaA, a conserved protein in <i>Mycobacteriales</i>, revealing its pivotal role in coordinating cell envelope biogenesis and asymmetric growth. The elucidation of the FhaA interactome in living mycobacterial cells reveals its participation in the protein network orchestrating cell envelope biogenesis and cell elongation/division. By manipulating FhaA levels, we uncovered its influence on cell morphology, cell envelope organization, and the localization of peptidoglycan biosynthesis machinery. Notably, <i>fhaA</i> deletion disrupted the characteristic asymmetric growth of mycobacteria, highlighting its importance in maintaining this distinctive feature. Our findings position FhaA as a key regulator in a complex protein network, orchestrating the asymmetric distribution and activity of cell envelope biosynthetic machinery. This work not only advances our understanding of mycobacterial growth mechanisms but also identifies FhaA as a potential target for future studies on cell envelope biogenesis and bacterial growth regulation. These insights into the fundamental biology of mycobacteria may pave the way for novel approaches to combat mycobacterial infections addressing the ongoing challenge of diseases like tuberculosis in global health.</p><p><strong>Importance: </strong><i>Mycobacterium tuberculosis</i>, the bacterium responsible for tuberculosis, remains a global health concern. Unlike most well-studied model bacilli, mycobacteria possess a distinctive and complex cell envelope, as well as an asymmetric polar growth mode. However, the proteins and mechanisms that drive cell asymmetric elongation in these bacteria are still not well understood. This study sheds light on the role of the protein FhaA in this process. Our findings demonstrate that FhaA localizes at the septum and asymmetrically to the poles, with a preference for the fast-growing pole. Furthermore, we showed that FhaA is essential for population heterogeneity and asymmetric polar elongation and plays a role in the precise subcellular localization of the cell wall biosynthesis machinery. Mycobacterial asymmetric elongation results in a physiologically heterogeneous bacterial population which is important for pathogenicity and response to antibiotics, stressing the relevance of identifying new factors involved in these still poorly characterized processes.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0252624"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles in malaria: proteomics insights, <i>in vitro</i> and <i>in vivo</i> studies indicate the need for transitioning to natural human infections.","authors":"Núria Sima, Alberto Ayllon-Hermida, Carmen Fernández-Becerra, Hernando A Del Portillo","doi":"10.1128/mbio.02304-24","DOIUrl":"10.1128/mbio.02304-24","url":null,"abstract":"<p><p>Globally, an estimated 2.1 billion malaria cases and 11.7 million malaria deaths were averted in the period 2000-2022. Noticeably, despite effective control measurements, in 2022 there were an estimated 249 million malaria cases in 85 malaria-endemic countries and an increase of 5 million cases compared with 2021. Further understanding the biology, epidemiology, and pathogenesis of human malaria is therefore essential for achieving malaria elimination. Extracellular vesicles (EVs) are membrane-enclosed nanoparticles pivotal in intercellular communication and secreted by all cell types. Here, we will review what is currently known about EVs in malaria, from biogenesis and cargo to molecular insights of pathophysiology. Of relevance, a meta-analysis of proteomics cargo, and comparisons between <i>in vitro</i> and <i>in vivo</i> human studies revealed striking differences with those few studies reported from patients. Thus, indicating the need for rigor standardization of methodologies and for transitioning to human infections to elucidate their physiological role. We conclude with a focus on translational aspects in diagnosis and vaccine development and highlight key gaps in the knowledge of EVs in malaria research.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0230424"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen.","authors":"Sajith Raghunandanan, Raj Priya, Gaofeng Lin, Fuad Alanazi, Andrew Zoss, Elise Warren, Philip Stewart, X Frank Yang","doi":"10.1128/mbio.02766-24","DOIUrl":"10.1128/mbio.02766-24","url":null,"abstract":"<p><p>In <i>Borrelia burgdorferi</i>, the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σ^S). Understanding the regulation of RpoS is crucial for elucidating how <i>B. burgdorferi</i> is maintained throughout its enzootic cycle. Our recent studies have shown that the homolog of Fur/PerR repressor/activator BosR functions as an RNA-binding protein that controls the <i>rpoS</i> mRNA stability. However, the mechanisms regulating BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we uncovered a positive feedback loop between RpoS and BosR, wherein RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion of <i>rpoS</i> significantly reduced BosR levels, whereas artificial induction of <i>rpoS</i> resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect <i>bosR</i> mRNA levels but instead modulates the turnover rate of the BosR protein. Moreover, we demonstrated that environmental cues do not directly influence <i>bosR</i> expression but instead induce <i>rpoS</i> transcription and RpoS production, thereby enhancing BosR protein levels. These findings reveal a new layer of complexity in the RpoN-RpoS regulatory pathway, challenging the existing paradigm and suggesting a need to re-evaluate the factors and signals previously implicated in regulating RpoS via BosR. This study provides new insights into the intricate regulatory networks underpinning <i>B. burgdorferi</i>'s adaptation and survival in its enzootic cycle.IMPORTANCELyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent, <i>Borreliella</i> (or <i>Borrelia</i>) <i>burgdorferi</i>, is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection of <i>B. burgdorferi</i>. This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disrupt <i>B. burgdorferi</i>'s enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0276624"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbapenem-resistant <i>Enterobacter hormaechei</i> uses mucus metabolism to facilitate gastrointestinal colonization.","authors":"Ritam Sinha, Elizabeth N Ottosen, Tshegofatso Ngwaga, Stephanie R Shames, Victor J DiRita","doi":"10.1128/mbio.02884-24","DOIUrl":"10.1128/mbio.02884-24","url":null,"abstract":"<p><p>The emergence and global spread of carbapenem-resistant <i>Enterobacter cloacae</i> complex species present a pressing public health challenge. Carbapenem-resistant <i>Enterobacter</i> spp. cause a wide variety of infections, including septic shock fatalities in newborns and immunocompromised adults. The intestine may be a major reservoir for these resistant strains, either by facilitating contamination of fomites and transfer to susceptible individuals, or through translocation from the gut to the bloodstream. For this reason, we sought to establish a neonatal mouse model to investigate the mechanisms underpinning gut colonization by carbapenem-resistant <i>Enterobacter hormaechei</i>. We describe a new mouse model to study gut colonization by <i>Enterobacter</i> spp., leading to vital insights into the adaptation of carbapenem-resistant <i>E. hormaechei</i> to the gut environment during the early stages of intestinal colonization. We observed successful colonization and proliferation of <i>E. hormaechei</i> in the 5-day-old infant mouse gut, with primary localization to the colon following oral inoculation. We also uncovered evidence that <i>E. hormaechei</i> uses mucus as a carbon source during colonization of the colon. Our findings underscore the importance of oxygen-dependent metabolic pathways, including the pyruvate dehydrogenase complex and <i>N-</i>acetyl-D-glucosamine metabolism, in gut colonization and proliferation, which aligns with previous human studies. These insights are essential for developing novel therapeutic strategies that can serve as decolonization therapies in at-risk populations.IMPORTANCEBloodstream infections caused by <i>Enterobacter</i> spp. pose a significant clinical threat. The intestine acts as the primary site for colonization and serves as a reservoir for infection. To combat this pathogen, it is crucial to understand how carbapenem-resistant <i>Enterobacter</i> spp. colonize the gut, as such knowledge can pave the way for alternative therapeutic targets. In this study, we developed a novel neonatal mouse model for gastrointestinal colonization by <i>Enterobacter</i> spp. and discovered that mucus plays a key role as a carbon source during colonization. Additionally, we identified two mucus catabolism pathways that contribute to intestinal colonization by carbapenem-resistant <i>E. hormaechei</i>. This new mouse model offers valuable insights into host-pathogen interactions and helps identify critical gastrointestinal fitness factors of <i>Enterobacter</i>, potentially guiding the development of vaccines and alternative therapeutic strategies to minimize intestinal carriage in patient populations at risk of infection with <i>Enterobacter</i> spp.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0288424"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-resolution view of the immune and stromal cell response to <i>Haemophilus ducreyi</i> infection in human volunteers.","authors":"Julie A Brothwell, Yuhui Wei, Jia Wang, Tingbo Guo, Chi Zhang, Kate R Fortney, Rory Duplantier, Li Chen, Teresa A Batteiger, Mark H Kaplan, Stanley M Spinola, Sha Cao","doi":"10.1128/mbio.03885-24","DOIUrl":"10.1128/mbio.03885-24","url":null,"abstract":"<p><p><i>Haemophilus ducreyi</i> causes the genital ulcer disease chancroid and cutaneous ulcers in children. To study its pathogenesis, we developed a human challenge model in which we infect the skin on the upper arm of human volunteers with <i>H. ducreyi</i> to the pustular stage of disease. The model has been used to define lesional architecture, describe the immune infiltrate into the infected sites using flow cytometry, and explore the molecular basis of the immune response using bulk RNA-seq. Here, we used single cell RNA-seq (scRNA-seq) and spatial transcriptomics to simultaneously characterize multiple cell types within infected human skin and determine the cellular origin of differentially expressed transcripts that we had previously identified by bulk RNA-seq. We obtained paired biopsies of pustules and wounded (mock infected) sites from five volunteers for scRNA-seq. We identified 13 major cell types, including T- and NK-like cells, macrophages, dendritic cells, as well as other cell types typically found in the skin. Immune cell types were enriched in pustules, and some subtypes within the major cell types were exclusive to pustules. Sufficient tissue specimens for spatial transcriptomics were available from four of the volunteers. T- and NK-like cells were highly associated with multiple antigen presentation cell types. In pustules, type I interferon stimulation was high in areas that were high in antigen presentation-especially in macrophages near the abscess-compared to wounds. Together, our data provide a high-resolution view of the cellular immune response to the infection of the skin with a human pathogen.IMPORTANCEA high-resolution view of the immune infiltrate due to infection with an extracellular bacterial pathogen in human skin has not yet been defined. Here, we used the human skin pathogen <i>Haemophilus ducreyi</i> in a human challenge model to identify on a single cell level the types of cells that are present in volunteers who fail to spontaneously clear infection and form pustules. We identified 13 major cell types. Immune cells and immune-activated stromal cells were enriched in pustules compared to wounded (mock infected) sites. Pustules formed despite the expression of multiple pro-inflammatory cytokines, such as IL-1β and type I interferon. Interferon stimulation was most evident in macrophages, which were proximal to the abscess. The pro-inflammatory response within the pustule may be tempered by regulatory T cells and cells that express indoleamine 2,3-dioxygenase, leading to failure of the immune system to clear <i>H. ducreyi</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0388524"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}