mBio最新文献

{"title":"The alphavirus determinants of intercellular long extension formation.","authors":"Caroline K Martin, Judy J Wan, Peiqi Yin, Thomas E Morrison, William B Messer, Vanessa Rivera-Amill, Jonathan R Lai, Nina Grau, Félix A Rey, Thérèse Couderc, Marc Lecuit, Margaret Kielian","doi":"10.1128/mbio.01986-24","DOIUrl":"https://doi.org/10.1128/mbio.01986-24","url":null,"abstract":"<p><p>The alphavirus chikungunya virus (CHIKV) is a serious human pathogen that can cause large-scale epidemics characterized by fever and joint pain and often resulting in chronic arthritis. Infection by alphaviruses including CHIKV and the closely related Semliki Forest virus (SFV) can induce the formation of filopodia-like intercellular long extensions (ILEs). ILEs emanate from an infected cell, stably attach to a neighboring cell, and mediate cell-to-cell viral transmission that is resistant to neutralizing antibodies. However, our mechanistic understanding of ILE formation is limited, and the potential contribution of ILEs to CHIKV virulence or human CHIKV infection is unknown. Here, we used well-characterized virus mutants and monoclonal antibodies with known epitopes to dissect the virus requirements for ILE formation. Our results showed that both the viral E2 and E1 envelope proteins were required for ILE formation, while viral proteins 6K and transframe, and cytoplasmic nucleocapsid formation were dispensable. A subset of CHIKV monoclonal antibodies reduced ILE formation by masking specific regions particularly on the E2 A domain. Studies of the viral proteins from different CHIKV strains showed that ILE formation is conserved across the four major CHIKV lineages. Sera from convalescent human CHIKV patients inhibited ILE formation in cell culture, providing the first evidence for ILE inhibitory antibody production during human CHIKV infections.IMPORTANCEChikungunya virus (CHIKV) infections can cause severe fever and long-lasting joint pain in humans. CHIKV is disseminated by mosquitoes and is now found world-wide, including in the Americas, Asia, and Africa. In cultured cells, CHIKV can induce the formation of long intercellular extensions that can transmit virus to another cell. However, our understanding of the formation of extensions and their importance in human CHIKV infection is limited. We here identified viral protein requirements for extension formation. We demonstrated that specific monoclonal antibodies against the virus envelope proteins or sera from human CHIKV patients can inhibit extension formation. Our data highlight the importance of evaluation of extension formation in the context of human CHIKV infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0198624"},"PeriodicalIF":5.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854711","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":"An adenoviral vector encoding an inflammation-inducible antagonist, HMGB1 Box A, as a novel therapeutic approach to inflammatory diseases.","authors":"Kari Ann Shirey, John Joseph, Lynda Coughlan, Haye Nijhuis, Alan W Varley, Jorge C G Blanco, Stefanie N Vogel","doi":"10.1128/mbio.03387-24","DOIUrl":"https://doi.org/10.1128/mbio.03387-24","url":null,"abstract":"<p><p>Influenza, as well as other respiratory viruses, can trigger local and systemic inflammation resulting in an overall \"cytokine storm\" that produces serious outcomes such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We hypothesized that gene therapy platforms could be useful in these cases if the production of an anti-inflammatory protein reflects the intensity and duration of the inflammatory condition. The recombinant protein would be produced and released only in the presence of the inciting stimulus, avoiding immunosuppression or other unwanted side effects that may occur when treating infectious diseases with anti-inflammatory drugs. To test this hypothesis, we developed AdV.C3-Tat/HIV-Box A, an inflammation-inducible cassette that remains innocuous in the absence of inflammation but releases HMGB1 Box A, an antagonist of high mobility group box 1 (HMGB1), in response to inflammatory stimuli such as lipopolysaccharide (LPS) or influenza virus infection. We report here that this novel inflammation-inducible HMGB1 Box A construct in a non-replicative adenovirus (AdV) vector mitigates lung and systemic inflammation therapeutically in response to influenza infection. We anticipate that this strategy will apply to the treatment of multiple diseases in which HMGB1-mediated signaling is a central driver of inflammation.IMPORTANCEMany inflammatory diseases are mediated by the action of a host-derived protein, HMGB1, on Toll-like receptor 4 (TLR4) to elicit an inflammatory response. We have engineered a non-replicative AdV vector that produces HMGB1 Box A, an antagonist of HMGB1-induced inflammation, under the control of an endogenous complement component C3 (C3) promoter sequence, that is inducible by LPS and influenza <i>in vitro</i> and <i>ex vivo</i> in macrophages (Mϕ) and protects mice and cotton rats therapeutically against infection with mouse-adapted and human non-adapted influenza strains, respectively, <i>in vivo</i>. We anticipate that this novel strategy will apply to the treatment of multiple infectious and non-infectious diseases in which HMGB1-mediated TLR4 signaling is a central driver of inflammation.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0338724"},"PeriodicalIF":5.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854709","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":"A gut-derived <i>Streptococcus salivarius</i> produces the novel nisin variant designated nisin G and inhibits <i>Fusobacterium nucleatum</i> in a model of the human distal colon microbiome.","authors":"Garreth W Lawrence, Enriqueta Garcia-Gutierrez, A Kate O'Mahony, Calum J Walsh, Paula M O'Connor, Máire Begley, Caitriona M Guinane, Paul D Cotter","doi":"10.1128/mbio.01573-24","DOIUrl":"https://doi.org/10.1128/mbio.01573-24","url":null,"abstract":"<p><p><i>Fusobacterium nucleatum</i> is a human pathogen associated with intestinal conditions including colorectal cancer. Screening for gut-derived strains that exhibit anti-<i>F</i>. <i>nucleatum</i> activity <i>in vitro</i> revealed <i>Streptococcus salivarius</i> DPC6487 as a strain of interest. Whole-genome sequencing of <i>S. salivarius</i> DPC6487 identified a nisin operon with a novel structural variant designated nisin G. The structural nisin G peptide differs from the prototypical nisin A with respect to seven amino acids (Ile4Tyr, Ala15Val, Gly18Ala, Asn20His, Met21Leu, His27Asn, and His31Ile), including differences that have not previously been associated with a natural nisin variant. The nisin G gene cluster consists of <i>nsgGEFABTCPRK</i> with transposases encoded between the nisin G structural gene (<i>nsgA</i>) and <i>nsgF</i>, notably lacking an equivalent to the <i>nisI</i> immunity determinant. <i>S. salivarius</i> DPC6487 exhibited a narrower spectrum of activity <i>in vitro</i> compared to the nisin A-producing <i>Lactococcus lactis</i> NZ9700. Nisin G-producing <i>S. salivarius</i> DPC6487 demonstrated the ability to control <i>F. nucleatum</i> DSM15643 in an <i>ex vivo</i> model colonic environment while exerting minimal impact on the surrounding microbiota. The production of this bacteriocin by a gut-derived <i>S. salivarius</i>, its narrow-spectrum activity, and its anti-<i>F. nucleatum</i> activity in a model colonic environment indicates that this strain merits further attention with a view to harnessing its probiotic potential.IMPORTANCE<i>Fusobacterium nucleatum</i> is a human pathogen associated with intestinal conditions, including colorectal cancer, making it a potentially important therapeutic target. Bacteriocin-producing probiotic bacteria demonstrate the potential to target disease-associated taxa <i>in situ</i> in the gut. A gut-derived strain <i>Streptococcus salivarius</i> DPC6487 was found to demonstrate anti-<i>F</i>. <i>nucleatum</i> activity, which was attributable to a gene encoding a novel nisin variant designated nisin G. Nisin G-producing <i>S. salivarius</i> DPC6487 demonstrated the ability to control an infection of <i>F. nucleatum</i> in a simulated model of the human distal colon while exerting minimal impact on the surrounding microbiota. Here, we describe this nisin variant produced by <i>S. salivarius</i>, a species that is frequently a focus for probiotic development. The production of nisin G by a gut-derived <i>S. salivarius</i>, its narrow-spectrum activity against <i>F. nucleatum</i>, and its anti-<i>F</i>. <i>nucleatum</i> activity in a model colonic environment warrants further research to determine its probiotic-related applications.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0157324"},"PeriodicalIF":5.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847113","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":"DDO-adjuvanted influenza A virus nucleoprotein mRNA vaccine induces robust humoral and cellular type 1 immune responses and protects mice from challenge.","authors":"Victoria Gnazzo, Hanaa Saleh, Ítalo A Castro, Adrianus C M Boon, Amelia K Pinto, James D Brien, Carolina B López","doi":"10.1128/mbio.03589-24","DOIUrl":"https://doi.org/10.1128/mbio.03589-24","url":null,"abstract":"<p><p>A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8⁺ T-cells that target conserved viral proteins and can eliminate infected cells to control virus spread. mRNA technology offers an opportunity to design vaccines based on conserved CD8-targeting epitopes, but achieving robust antigen-specific CD8⁺ T-cells remains a challenge. Here, we tested the viral-derived oligonucleotide DDO268 as an adjuvant in the context of a model influenza A virus (IAV) nucleoprotein (NP) mRNA vaccine in C57BL/6 mice. DDO268 when co-packaged with mRNA in lipid nanoparticles is sensed by RIG I-like receptors and safely induces local type I interferon (IFN) production followed by dendritic cells type 1 activation and migration to the draining lymph nodes. This early response triggered by DDO268 improved the generation of IgG2c antibodies and antigen-specific Th1 CD4⁺ and CD8⁺ T-cells (IFNγ⁺TNFα⁺IL2⁺) that provided enhanced protection against lethal IAV challenge. In addition, the inclusion of DDO268 reduced the antigen dose required to achieve protection. These results highlight the potential of DDO268 as an effective mRNA vaccine adjuvant and show that an IAV NP mRNA/DDO268 vaccine is a promising approach for generating protective immunity against conserved internal IAV epitopes.IMPORTANCEVaccines that generate neutralizing antibodies and cytotoxic CD8⁺ T-cells targeting conserved epitopes are ideal for effective protection against viruses. mRNA vaccines combined with the right adjuvant offer a promising solution to this challenge. We show that the virus-derived oligonucleotide DDO268 enhances antibody and T-cell responses to an influenza A virus (IAV) nucleoprotein mRNA vaccine in mice. DDO268 safely induces local type I interferon production and stimulates dendritic cell activation providing enhanced protection against IAV challenge. In addition, the adjuvant activity of DDO268 allows for the use of lower antigen doses during vaccination.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0358924"},"PeriodicalIF":5.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846521","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":"Split-Cre-mediated GFP expression as a permanent marker for flagellar fusion of <i>Trypanosoma brucei</i> in its tsetse fly host.","authors":"Ruth Etzensperger, Mattias Benninger, Berta Pozzi, Ruth Rehmann, Arunasalam Naguleswaran, Gabriela Schumann, Jan Van Den Abbeele, Isabel Roditi","doi":"10.1128/mbio.03375-24","DOIUrl":"https://doi.org/10.1128/mbio.03375-24","url":null,"abstract":"<p><p>Trypanosomes have different ways of communicating with each other. While communication via quorum sensing, or by the release and uptake of extracellular vesicles, is widespread in nature, the phenomenon of flagellar fusion has only been observed in <i>Trypanosoma brucei</i>. We showed previously that a small proportion of procyclic culture forms (corresponding to insect midgut forms) can fuse their flagella and exchange cytosolic and membrane proteins. This happens reproducibly in cell culture. It was not known, however, if flagellar fusion also occurs in the tsetse fly host, and at what stage of the life cycle. We have developed a split-Cre-Lox system to permanently label trypanosomes that undergo flagellar fusion. Specifically, we engineered trypanosomes to contain a GFP gene flanked by Lox sites in the reverse orientation to the promoter. In addition, the cells expressed inactive halves of the Cre recombinase, either N-terminal Cre residues 1-244 (N-Cre) or C-terminal Cre residues 245-343 (C-Cre). Upon flagellar fusion, these Cre halves were exchanged between trypanosomes, forming functional full Cre and flipping reverse-GFP into its forward orientation. We showed that cells that acquired the second half Cre through flagellar fusion were permanently modified and that the cells and their progeny constitutively expressed GFP. When tsetse flies were co-infected with N-Cre and C-Cre cells, GFP-positive trypanosomes were observed in the midgut and proventriculus 28-34 days post-infection. These results show that flagellar fusion not only happens in culture but also during the natural life cycle of trypanosomes in their tsetse fly host.</p><p><strong>Importance: </strong>We have established a procedure to permanently label pairs of trypanosomes that transiently fuse their flagella and exchange proteins. When this occurs, a reporter gene is permanently flipped from the \"off\" to the \"on\" position, resulting in the production of green fluorescent protein. Crucially, green trypanosomes can be detected in tsetse flies co-infected with the two cell lines, proving that flagellar fusion occurs in the host. To our knowledge, we are the first to describe a split-Cre-Lox system for lineage tracing and selection in trypanosomes. In addition to its use in trypanosomes, this system could be adapted for other parasites and in other contexts. For example, it could be used to determine whether flagellar fusion occurs in related parasites such as Leishmania and <i>Trypanosoma cruzi</i> or to monitor whether intracellular parasites and their hosts exchange proteins.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0337524"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837458","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":"From structure prediction to function: defining the domain on the African swine fever virus CD2v protein required for binding to erythrocytes.","authors":"Ana Luisa Reis, Anusyah Rathakrishnan, Vlad Petrovan, Muneeb Islam, Lynnette Goatley, Katy Moffat, Mai Tuyet Vuong, Yuan Lui, Simon J Davis, Shinji Ikemizu, Linda K Dixon","doi":"10.1128/mbio.01655-24","DOIUrl":"https://doi.org/10.1128/mbio.01655-24","url":null,"abstract":"<p><p>African swine fever virus (ASFV) is a high-consequence pathogen posing a substantial threat to global food security. This large DNA virus encodes more than 150 open reading frames, many of which are uncharacterized. The <i>EP402R</i> gene encodes CD2v, a glycoprotein expressed on the surface of infected cells and the only viral protein known to be present in the virus external envelope. This protein mediates binding of erythrocytes to both cells and virions. This interaction is known to prolong virus persistence in blood thus facilitating viral transmission. The sequence of the extracellular domain of CD2v shows similarity with that of mammalian CD2 proteins and is therefore likely to feature two immunoglobulin (Ig)-like domains. A combination of protein structure modeling and extensive mutagenesis was used to identify residues mediating binding of transiently expressed CD2v to erythrocytes. The N-terminal Ig-like domain AGFCC'C″ β sheet was identified as the putative CD2v erythrocyte-binding area. This region differed from the putative CD58 ligand binding site of host CD2, suggesting that CD2v may bind to a ligand(s) other than CD58. An attenuated genotype I ASFV was constructed by replacing the wild-type <i>EP402R</i> gene for a mutant form expressing CD2v bearing a single amino acid substitution, which abrogated the binding to erythrocytes. Pigs immunized with the recombinant virus developed early antibody and cellular responses, low levels of viremia, mild clinical signs post-immunization, and high levels of protection against challenge. These findings improve our understanding of virus-host interactions and provide a promising approach to modified live vaccine development.</p><p><strong>Importance: </strong>A better understanding of the interactions between viruses and their hosts is a crucial step in the development of strategies for controlling viral diseases, such as vaccines and antivirals. African swine fever, a pig disease with fatality rates approaching 100%, causes very substantial economic losses in affected countries, and new control measures are clearly needed. In this study, we characterized the interaction between the ASFV CD2v protein and host erythrocytes. The interaction plays a key role in viral persistence in blood since it can allow the virus to \"hide\" from the host immune system. We identified the amino acids in the viral protein that mediate the interaction with erythrocytes and used this information to construct a mutant virus that is no longer able to bind these cells. This virus induces strong immune responses that provide high levels of protection against infection with the deadly parental virus.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0165524"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837251","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":"Regulation of human papillomavirus E6 oncoprotein function via a novel ubiquitin ligase FBXO4.","authors":"Arushi Vats, Luca Braga, Nezka Kavcic, Paola Massimi, Edoardo Schneider, Mauro Giacca, Laimonis A Laimins, Lawrence Banks","doi":"10.1128/mbio.02783-24","DOIUrl":"https://doi.org/10.1128/mbio.02783-24","url":null,"abstract":"<p><p>Previous studies have shown that E6 interacts with the E6-associated protein (E6AP) ubiquitin-protein ligase and directs its ubiquitylation activity toward several specific cellular proteins, one of the most important of which is p53. Interestingly, E6AP not only aids in the E6-directed degradation of cellular substrates but also stabilizes the E6 protein by protecting it from proteasome-mediated degradation. However, there is no information available about the ubiquitin ligases that regulate the stability and activity of the human papillomavirus (HPV) E6 oncoprotein in the absence of E6AP. Therefore, to identify these novel ubiquitin ligases, we performed high-throughput human siRNA library screen against ubiquitin ligases in clustered regularly interspaced palindromic repeat (CRISPR)-edited E6AP-knockout human embryonic kidney (HEK) 293 cells, stably expressing green fluorescent protein (GFP)-tagged HPV-18E6. We found a number of ubiquitin ligases that increase the expression of GFP-tagged 18E6 upon their knockdown in the absence of E6AP. Upon validation of the interaction of 18E6 with these ubiquitin ligases in cervical cancer-derived cell lines, we found that the knockdown of ubiquitin ligase F-box protein 4 (FBXO4), together with E6AP knockdown, leads to a dramatic increase in the levels of endogenous HPV-18E6 oncoprotein. Furthermore, our data demonstrate that the combined knockdown of FBXO4 and E6AP not only rescues the protein levels of E6 but also induces high levels of cell death in a p53-dependent manner in the HPV-positive cervical cancer cell line, HeLa. These results indicate a close interplay between FBXO4, E6AP, and p53 in the regulation of cell survival in HPV-positive cervical tumor-derived cells.</p><p><strong>Importance: </strong>E6-associated protein (E6AP)-mediated stabilization of human papillomavirus (HPV) E6 plays a crucial role in the development and progression of cervical and other HPV-associated cancers. This study, for the first time, identifies a novel ubiquitin ligase, FBXO4 that targets the degradation of HPV E6 oncoprotein in the absence of E6AP in cervical cancer-derived cell lines. This may have significant implications for our understanding of HPV-associated cancers by providing deeper insights into the intricate interplay between viral proteins and host cellular machinery and the development of targeted therapies.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0278324"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837449","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":"Sdd3 regulates the biofilm formation of <i>Candida albicans</i> via the Rho1-PKC-MAPK pathway.","authors":"Li Mei Pang, Guisheng Zeng, Eve Wai Ling Chow, Xiaoli Xu, Ning Li, Yee Jiun Kok, Shu Chen Chong, Xuezhi Bi, Jiaxin Gao, Chaminda Jayampath Seneviratne, Yue Wang","doi":"10.1128/mbio.03283-24","DOIUrl":"https://doi.org/10.1128/mbio.03283-24","url":null,"abstract":"<p><p><i>Candida albicans</i>, the most frequently isolated fungal pathogen in humans, forms biofilms that enhance resistance to antifungal drugs and host immunity, leading to frequent treatment failure. Understanding the molecular mechanisms governing biofilm formation is crucial for developing anti-biofilm therapies. In this study, we conducted a genetic screen to identify novel genes that regulate biofilm formation in <i>C. albicans</i>. One identified gene is <i>ORF19.6693</i>, a homolog of the <i>Saccharomyces cerevisiae SDD3</i> gene. The <i>sdd3</i>∆/∆ mutant exhibited severe defects in biofilm formation and significantly reduced chitin content in the cell wall. Overexpression of the constitutively active version of the Rho1 GTPase Rho1^G18V, an upstream activator of the protein kinase C (PKC)-mitogen-activated protein kinase (MAPK) cell-wall integrity pathway, rescued these defects. Affinity purification, mass spectrometry, and co-immunoprecipitation revealed Sdd3's physical interaction with Bem2, the GTPase-activating protein of Rho1. Deletion of <i>SDD3</i> significantly reduced the amount of the active GTP-bound form of Rho1, thereby diminishing PKC-MAPK signaling and downregulating chitin synthase genes <i>CHS2</i> and <i>CHS8</i>. Taken together, our studies identify a new biofilm regulator, Sdd3, in <i>C. albicans</i> that modulates Rho1 activity through its inhibitory interaction with Bem2, thereby regulating the PKC-MAPK pathway to control chitin biosynthesis, which is critical for biofilm formation. As an upstream component of the pathway and lacking a homolog in mammals, Sdd3 has the potential to serve as an antifungal target for biofilm infections.IMPORTANCEThe human fungal pathogen <i>Candida albicans</i> is categorized as a critical priority pathogen on the World Health Organization's Fungal Priority Pathogens List. A key virulence attribute of this pathogen is its ability to form biofilms on the surfaces of indwelling medical devices. Fungal cells in biofilms are highly resistant to antifungal drugs and host immunity, leading to treatment failure. This study conducted a genetic screen to discover novel genes that regulate biofilm formation. We found that deletion of the <i>SDD3</i> gene caused severe biofilm defects. Sdd3 negatively regulates the Rho1 GTPase, an upstream activator of the protein kinase C-mitogen-activated protein kinase pathway, through direct interaction with Bem2, the GTPase-activating protein of Rho1, resulting in a significant decrease in chitin content in the fungal cell wall. This chitin synthesis defect leads to biofilm formation failure. Given its essential role in biofilm formation, Sdd3 could serve as an antifungal target for biofilm infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0328324"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837451","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":"Correction for Choy et al., \"Ergosterol distribution controls surface structure formation and fungal pathogenicity\".","authors":"Hau Lam Choy, Elizabeth A Gaylord, Tamara L Doering","doi":"10.1128/mbio.03550-24","DOIUrl":"https://doi.org/10.1128/mbio.03550-24","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0355024"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837242","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":"Protein <i>S</i>-palmitoylation regulates the virulence of plant pathogenic fungi.","authors":"Mengmeng Guo, Leeza Tariq, Fengming Song","doi":"10.1128/mbio.03472-24","DOIUrl":"https://doi.org/10.1128/mbio.03472-24","url":null,"abstract":"<p><p>Protein <i>S</i>-palmitoylation, a universal posttranslational modification catalyzed by a specific group of palmitoyltransferases, plays crucial roles in diverse biological processes across organisms by modulating protein functions. However, its roles in the virulence of plant pathogenic fungi remain underexplored. In a recent study, Y. Duan, P. Li, D. Zhang, L. Wang, et al. (mBio 15:e02704-24, 2024, https://doi.org/10.1128/mbio.02704-24) reported that the palmitoyltransferases UvPfa3 and UvPfa4 regulate the virulence of the rice false smut pathogen <i>Ustilaginoidea virens</i>. Through comprehensive characterization of <i>S</i>-palmitoylation sites, they revealed that <i>S</i>-palmitoylated proteins in <i>U. virens</i> are enriched in mitogen-activated protein (MAP) kinase and autophagy pathways, with MAP kinase UvSlt2 being a key target of UvPfa4-mediated <i>S</i>-palmitoylation. Further investigation demonstrated that <i>S</i>-palmitoylation of UvSlt2 is critical for its kinase activity, substrate interaction ability, and virulence function in <i>U. virens</i>. These findings reveal UvPfa4-mediated <i>S</i>-palmitoylation as a vital regulatory mechanism in <i>U. virens</i> virulence, highlighting the importance of protein <i>S</i>-palmitoylation in the pathogenicity of plant pathogenic fungi.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0347224"},"PeriodicalIF":5.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837443","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}