mBio最新文献

{"title":"Identification of two transcription factors that work coordinately to regulate early development in <i>Entamoeba</i>.","authors":"Daniela Lozano-Amado, Upinder Singh","doi":"10.1128/mbio.02250-24","DOIUrl":"https://doi.org/10.1128/mbio.02250-24","url":null,"abstract":"<p><p>The protozoan parasite <i>Entamoeba</i> has a life cycle that switches between infective cysts and invasive trophozoites. Encystation, a crucial process in parasite biology, is controlled by different mechanisms including transcriptional control. We identified two nuclear proteins in <i>Entamoeba invadens</i>, EIN_066100 and EIN_085620, that regulate parasite development by binding to a DNA motif (TCACTTTC) in the promoter regions of genes upregulated in the first 8 h of stage conversion. Overexpression of EIN_066100, a homolog of MAK16 protein, resulted in reduced amoebic proliferation without affecting encystation efficiency. Overexpression of EIN_085620, a protein with an RNA-recognition motif (RRM), led to increased encystation efficiency. Glutathione S-transferase (GST) pull down assays revealed that EIN_066100 interacts with EIN_085620 both <i>in vivo</i> and <i>in vitro,</i> and this interaction is mediated by the EIN_085620 RRM domain. By evaluating truncated proteins with deletions at either the N-terminal or C-terminal regions of EIN_066100, we elucidated the importance of its N-terminal region in proper protein localization, proliferation, encystation, and interaction with EIN_085620. Taken together, these results indicate a coordinated role of EIN_066100 and EIN_085620 in regulating <i>Entamoeba</i> development. This work sheds light on the molecular mechanisms in the earliest stages of <i>Entamoeba</i> encystation.IMPORTANCEAn important biological process in the biology of <i>Entamoeba</i> is stage conversion, which plays a crucial role in disease propagation, facilitating parasite survival outside the host and spreading to new hosts. Multiple mechanisms contribute to controlling the expression of amebic stage-specific genes such as epigenetic and transcriptional control. Identification of early transcriptional control regulators is crucial to understanding the initiation of the encystation cascade. We identified two nuclear proteins, EIN_066100 and EIN_085620, involved in the proliferation and developmental regulation of <i>E. invadens</i>. These proteins work by direct binding to each other and mediating encystation efficiency. Study of new regulators involved in <i>Entamoeba</i> development represents an important advance in a critical aspect of parasite biology.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0225024"},"PeriodicalIF":5.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622438","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":"Evolutionary trajectories of β-lactam resistance in <i>Enterococcus faecalis</i> strains.","authors":"Paul Ugalde Silva, Charlene Desbonnet, Louis B Rice, Mónica García-Solache","doi":"10.1128/mbio.02897-24","DOIUrl":"10.1128/mbio.02897-24","url":null,"abstract":"<p><p>Resistance to ampicillin and imipenem in <i>Enterococcus faecalis</i> is infrequent. However, the evolution of resistance can occur through prolonged antibiotic exposure during the treatment of chronic infections. In this study, we conducted a long-term evolution experiment using four genetically diverse strains of <i>E. faecalis</i> with varying susceptibilities to ampicillin and imipenem. Each strain was subjected to increasing concentrations of either ampicillin or imipenem over 200 days, with three independent replicates for each strain. Selective pressure from imipenem led to the rapid selection of highly resistant lineages across all genetic backgrounds, compared to ampicillin. In addition to high resistance, we describe, for the first time, the evolution of a β-lactam-dependent phenotype observed in lineages from all backgrounds. Whole-genome sequencing and bioinformatic analysis revealed mutations in three main functional classes: genes involved in cell wall synthesis and degradation, genes in the walK/R two-component system, and genes in the c-di-AMP pathway. Our analysis identified new mutations in genes known to be involved in resistance as well as novel genes potentially associated with resistance. Furthermore, the newly described β-lactam-dependent phenotype was correlated with the inactivation of c-di-AMP degradation, resulting in high levels of this second messenger. Together, these data highlight the diverse genetic mechanisms underlying resistance to ampicillin and imipenem in <i>E. faecalis</i>. The emergence of high resistance levels and β-lactam dependency underscores the importance of understanding evolutionary dynamics in the development of antibiotic resistance.</p><p><strong>Importance: </strong><i>Enterococcus faecalis</i> is a major human pathogen, and treatment is frequently compromised by poor response to first-line antibiotics such as ampicillin. Understanding the factors that play a role in susceptibility/resistance to these drugs will help guide the development of much-needed treatments.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0289724"},"PeriodicalIF":5.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621724","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":"Dosage constraint of the ribosome-associated molecular chaperone drives the evolution and fates of its duplicates in bacteria.","authors":"Tianyu Wan, Li Zhuo, Zhuo Pan, Rui-Yun Chen, Han Ma, Ying Cao, Jianing Wang, Jing-Jing Wang, Wei-Feng Hu, Ya-Jun Lai, Muhammad Hayat, Yue-Zhong Li","doi":"10.1128/mbio.01994-24","DOIUrl":"10.1128/mbio.01994-24","url":null,"abstract":"<p><p>Gene duplication events happen prevalently during evolution, and the mechanisms governing the loss or retention of duplicated genes are mostly elusive. Our genome scanning analysis revealed that trigger factor (TF), the one and only bacterial ribosome-associated molecular chaperone, is singly copied in virtually every bacterium except for a very few that possess two or more copies. However, even in these exceptions, only one complete TF copy exists, while other homologs lack the N-terminal domain that contains the conserved ribosome binding site (RBS) motif. Consistently, we demonstrated that the overproduction of the N-terminal complete TF proteins is detrimental to the cell, which can be rescued by removing the N-terminal domain. Our findings also indicated that TF overproduction leads to a decrease in protein productivity and profile changes in proteome due to its characteristic ribosome binding and holdase activities. Additionally, these N-terminal deficient TF homologs in bacteria with multiple TF homologs partition the function of TF via subfunctionalization. Our results revealed that TF is subjected to a dosage constraint that originates from its own intrinsic functions, which may drive the evolution and fates of duplicated TFs in bacteria.</p><p><strong>Importance: </strong>Gene duplication events presumably occur in <i>tig</i>, which encodes the ribosome-associated molecular chaperone trigger factor (TF). However, TF is singly copied in virtually every bacterium, and these exceptions with multiple TF homologs always retain only one complete copy while other homologs lack the N-terminal domain. Here, we reveal the manner and mechanism underlying the evolution and fates of TF duplicates in bacteria. We discovered that the mutation-to-loss or retention-to-sub/neofunctionalization of TF duplicates is associated with the dosage constraint of N-terminal complete TF. The dosage constraint of TF is attributed to its characteristic ribosome binding and substrate-holding activities, causing a decrease in protein productivity and profile changes in cellular proteome.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0199424"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381247","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":"<i>Aedes aegypti</i> adiponectin receptor-like protein signaling facilitates Zika virus infection.","authors":"Tse-Yu Chen, Alejandro Marín-López, Hamidah Raduwan, Erol Fikrig","doi":"10.1128/mbio.02433-24","DOIUrl":"10.1128/mbio.02433-24","url":null,"abstract":"<p><p>The <i>Aedes aegypti</i> mosquito plays a critical role in the transmission of viral diseases, including Zika virus, which poses significant public health challenges. Understanding the complex interactions between mosquitoes and viruses is paramount for the development of effective control strategies. In this study, we demonstrate that silencing the <i>A. aegypti</i> adiponectin receptor-like protein (AaARLP) results in a reduction of Zika virus infection. Transcriptomic analysis identified alterations in several trypsin genes and further revealed that <i>AaARLP</i>-knockdown mosquitoes had diminished trypsin activity. Moreover, silencing of selected <i>trypsins</i> resulted in a similar delay in Zika virus infection in mosquitoes, further highlighting the connection between the AaARLP and trypsin. Overall, our findings demonstrate that AaARLP signaling is important for Zika virus infection of <i>A. aegypti</i>.</p><p><strong>Importance: </strong>Arboviruses pose a significant threat to public health, with mosquitoes, especially <i>Aedes aegypti</i>, being a major vector for their transmission. Gaining insight into the complex interaction between mosquitoes and viruses is essential to build successful control strategies. In this study, we identified a novel pathway connecting the <i>A. aegypti</i> adiponectin receptor-like protein and its association with trypsin, key enzymes involved in blood digestion. Furthermore, we demonstrated the significance of signaling via the adiponectin receptor-like protein in virus infection within the mosquito. Together, our discoveries illuminate mosquito metabolic pathways essential in viral infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0243324"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381245","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":"The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host's upper respiratory epithelial barrier.","authors":"E Van Crombrugge, X Ren, S Glorieux, I Zarak, W Van den Broeck, C Bachert, N Zhang, T Van Zele, D Kim, G A Smith, K Laval, H Nauwynck","doi":"10.1128/mbio.01873-24","DOIUrl":"10.1128/mbio.01873-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invasion are not fully understood. This study investigates the role of the gE/gI glycoprotein complex and proteases in mucosal invasion by these viruses. Using species-specific respiratory mucosal explants, we observed that the removal of extracellular calcium disrupts epithelial junction integrity, enhancing viral infection across all viruses and suggesting a common mechanism of targeting a basolaterally located receptor. PRV exhibited significantly faster replication and deeper invasion compared to HSV-1 and BoHV-1. The gE glycoprotein was consistently polarized at the basement membrane across all viruses, indicating a critical role in the process of viral entry and subsequent spread through the epithelium. In this context, \"infection\" refers to the virus's attachment to its cell-surface receptor, entry into the cell, and completion of the viral life cycle, culminating in the production of progeny virions. Notably, in gE/gI null mutants of PRV and HSV-1, while the infection was not abortive and the viral life cycle was completed, the infection was delayed, and the invasion into the deeper layers of the epithelium and underlying mucosa was significantly reduced. In BoHV-1 mutants, this effect was even more pronounced, with infection restricted to the apical cells, failing to progress to the basal cells. In addition, PRV and HSV-1 invasion involved serine protease activity, unlike BoHV-1, which correlates with its slower invasion pace. Notably, the protease facilitating PRV invasion was identified as a urokinase plasminogen activator (uPA), while the specific protease for HSV-1 remains unidentified. These findings highlight the critical roles of the gE/gI complex and proteases in alphaherpesvirus pathogenesis, offering potential targets for therapeutic intervention.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Herpes simplex virus type 1 (HSV-1) infections are a worldwide issue. More than three billion people are infected with HSV-1 globally. Although most infections with HSV-1 occur subclinically, severe symptoms and complications are numerous and can be life-threatening. Complications include encephalitis and blindness. Recently, HSV-1 infections have been associated with the development of Alzheimer's Disease. To date, no effective vaccines against HSV-1 are on the market. Pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1) are two alphaherpesviruses of major veterinary importance. Although efforts have been made to eradicate these viruses from livestock animals, clinical problems still occur, resulting in great economic losses for farmers. It is evident that new insights into the pathogenesis of alphaherpesviruses are needed, to develop effective treatme","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0187324"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391685","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":"The riboflavin biosynthetic pathway as a novel target for antifungal drugs against <i>Candida</i> species.","authors":"Jana Nysten, Arne Peetermans, Dries Vaneynde, Stef Jacobs, Liesbeth Demuyser, Patrick Van Dijck","doi":"10.1128/mbio.02502-24","DOIUrl":"10.1128/mbio.02502-24","url":null,"abstract":"<p><p>In recent decades, there has been an increase in the occurrence of fungal infections; yet, the arsenal of drugs available to fight invasive infections remains very limited. The development of new antifungal agents is hindered by the restricted number of molecular targets that can be exploited, given the shared eukaryotic nature of fungi and their hosts which often leads to host toxicity. In this paper, we examine the riboflavin biosynthetic pathway as a potential novel drug target. Riboflavin is an essential nutrient for all living organisms. Its biosynthetic pathway does not exist in humans, who obtain riboflavin through their diet. Our findings demonstrate that all enzymes in the pathway are essential for <i>Candida albicans</i>, <i>Candida glabrata,</i> and <i>Saccharomyces cerevisiae.</i> Auxotrophic strains, which mimic a drug targeting the biosynthesis pathway, experience rapid mortality in the absence of supplemented riboflavin. Furthermore, <i>RIB1</i> is essential for virulence in both <i>C. albicans</i> and <i>C. glabrata</i> in a systemic mouse model. The fungal burden of a <i>RIB1</i> deletion strain is significantly reduced in the kidneys and brain of infected mice, and this reduction becomes more pronounced over time. Nevertheless, auxotrophic cells can still take up external riboflavin when supplemented. We identified Orf19.4337 as the riboflavin importer in <i>C. albicans</i> and named it Rut1. We found that Rut1 only facilitates growth at external riboflavin concentrations that exceed the physiological concentrations in the human body. This suggests that riboflavin uptake is unlikely to serve as a resistance mechanism against drugs targeting the biosynthesis pathway. Interestingly, the uptake system in <i>S. cerevisiae</i> is more effective than in <i>C. albicans</i> and <i>C. glabrata,</i> enabling an auxotrophic <i>S. cerevisiae</i> strain to outcompete an auxotrophic <i>C. albicans</i> strain in lower riboflavin concentrations.</p><p><strong>Importance: </strong><i>Candida</i> species are a common cause of invasive fungal infections. <i>Candida albicans</i>, in particular, poses a significant threat to immunocompromised individuals. This opportunistic pathogen typically lives as a commensal on mucosal surfaces of healthy individuals but it can also cause invasive infections associated with high morbidity and mortality. Currently, there are only three major classes of antifungal drugs available to treat these infections. In addition, the efficacy of these antifungal agents is restricted by host toxicity, suboptimal pharmacokinetics, a narrow spectrum of activity, intrinsic resistance of fungal species, such as <i>Candida glabrata</i>, to certain drugs, and the acquisition of resistance over time. Therefore, it is crucial to identify new antifungal drug targets with novel modes of action to add to the limited armamentarium.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0250224"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469446","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":"Role of VapBC4 toxin-antitoxin system of <i>Sulfolobus acidocaldarius</i> in heat stress adaptation.","authors":"Arghya Bhowmick, Alejandra Recalde, Chandrima Bhattacharyya, Ankita Banerjee, Jagriti Das, Ulises E Rodriguez-Cruz, Sonja-Verena Albers, Abhrajyoti Ghosh","doi":"10.1128/mbio.02753-24","DOIUrl":"https://doi.org/10.1128/mbio.02753-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Toxin-antitoxin (TA) systems are important for stress adaptation in prokaryotes, including persistence, antibiotic resistance, pathogenicity, and biofilm formation. Toxins can cause cell death, reversible growth stasis, and direct inhibition of crucial cellular processes through various mechanisms, while antitoxins neutralize the effects of toxins. In bacteria, these systems have been studied in detail, whereas their function in archaea remains elusive. During heat stress, the thermoacidophilic archaeon &lt;i&gt;Sulfolobus acidocaldarius&lt;/i&gt; exhibited an increase in the expression of several bicistronic type II &lt;i&gt;vapBC&lt;/i&gt; TA systems, with the highest expression observed in the &lt;i&gt;vapBC4&lt;/i&gt; system. In the current study, we performed a comprehensive biochemical characterization of the VapBC4 TA system, establishing it as a bonafide type II toxin-antitoxin system. The VapC4 toxin is shown to have high-temperature catalyzed RNase activity specific for mRNA and rRNA, while the VapB4 antitoxin inhibits the toxic activity of VapC4 by interacting with it. VapC4 toxin expression led to heat-induced persister-like cell formation, allowing the cell to cope with the stress. Furthermore, this study explored the impact of &lt;i&gt;vapBC4&lt;/i&gt; deletion on biofilm formation, whereby deletion of &lt;i&gt;vapC4&lt;/i&gt; led to increased biofilm formation, suggesting its role in regulating biofilm formation. Thus, during heat stress, the liberated VapC4 toxin in cells could potentially signal a preference for persister cell formation over biofilm growth. Thus, our findings shed light on the diverse roles of the VapC4 toxin in inhibiting translation, inducing persister cell formation, and regulating biofilm formation in &lt;i&gt;S. acidocaldarius&lt;/i&gt;, enhancing our understanding of TA systems in archaea.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;This research enhances our knowledge of toxin-antitoxin (TA) systems in archaea, specifically in the thermoacidophilic archaeon &lt;i&gt;Sulfolobus acidocaldarius&lt;/i&gt;. TA systems are widespread in both bacterial and archaeal genomes, indicating their evolutionary importance. However, their exact functions in archaeal cellular physiology are still not well understood. This study sheds light on the complex roles of TA systems and their critical involvement in archaeal stress adaptation, including persistence and biofilm formation. By focusing on &lt;i&gt;S. acidocaldarius&lt;/i&gt;, which lives in habitats with fluctuating temperatures that can reach up to 90°C, the study reveals the unique challenges and survival mechanisms of this organism. The detailed biochemical analysis of the VapBC4 TA system, and its crucial role during heat stress, provides insights into how extremophiles can survive in harsh conditions. The findings of this study show the various functions of the VapC4 toxin, including inhibiting translation, inducing persister-like cell formation, and regulating biofilm formation. This knowledge improves our understanding of TA systems in thermoacidophiles and ","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0275324"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622348","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":"Phosphorylation of Ser711 residue in the hypervariable region of zoonotic genotype 3 hepatitis E virus is important for virus replication.","authors":"Bo Wang, Sakthivel Subramaniam, Debin Tian, Hassan M Mahsoub, C Lynn Heffron, Xiang-Jin Meng","doi":"10.1128/mbio.02635-24","DOIUrl":"10.1128/mbio.02635-24","url":null,"abstract":"<p><p>Hepatitis E virus (HEV) is distinct from other hepatotropic viruses because it is zoonotic. HEV-1 and HEV-2 exclusively infect humans, whereas HEV-3 and HEV-4 are zoonotic. However, the viral and/or host factors responsible for cross-species HEV transmission remain elusive. The hypervariable region (HVR) in HEV is extremely heterogenetic and is implicated in HEV adaptation. Here, we investigated the potential role of Serine phosphorylation in the HVR in HEV replication. We first analyzed HVR sequences across different HEV genotypes and identified a unique region at the N-terminus of the HVR, which is variable in the human-exclusive HEV genotypes but relatively conserved in zoonotic HEV genotypes. Using predictive tools, we identified four potential phosphorylation sites that are highly conserved in zoonotic HEV-3 and HEV-4 genomes but absent in human-exclusive HEV-1 strains. To explore the functional significance of these putative phosphorylation sites, we introduced mutations into the HEV-3 infectious clone and indicator replicon, replacing each Serine residue individually with alanine or aspartic acid, and assessed the impact of these substitutions on HEV-3 replication. We found that the phospho-blatant S711A mutant significantly reduced virus replication, whereas the phospho-mimetic S711D mutant modestly reduced virus replication. Conversely, mutations in the other three Serine residues did not significantly affect HEV-3 replication. Furthermore, we demonstrated that Ser711 phosphorylation did not alter host cell tropism of zoonotic HEV-3. In conclusion, our results showed that potential phosphorylation of the Ser711 residue significantly affects HEV-3 replication <i>in vitro</i>, providing new insights into the potential mechanisms of zoonotic HEV transmission.IMPORTANCEHEV is an important zoonotic pathogen, causing both acute and chronic hepatitis E and extrahepatic manifestation of diseases, such as neurological sequelae. The zoonotic HEV-3 is linked to chronic infection and neurological diseases. The specific viral and/or host factors facilitating cross-species HEV infection are unknown. The intrinsically disordered HVR in ORF1 is crucial for viral fitness and adaptation, both <i>in vitro</i> and <i>in vivo</i>. We hypothesized that phosphorylation of Serine residues in the HVR of zoonotic HEV by unknown host cellular kinases is associated with cross-species HEV transmission. In this study, we identified a conserved region within the HVR of zoonotic HEV strains but absent in the human-exclusive HEV-1 and HEV-2. We elucidated the important role of phosphorylation at the Ser711 residue in zoonotic HEV-3 replication, without altering the host cell tropism. These findings contribute to our understanding the mechanisms of cross-species HEV transmission.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0263524"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391684","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":"<i>Cryptococcus neoformans</i> infections: aspartyl protease potential to improve outcome in susceptible hosts.","authors":"Frédérique Vernel-Pauillac, Christine Laurent-Winter, Laurence Fiette, Guilhem Janbon, Vishukumar Aimanianda, Françoise Dromer","doi":"10.1128/mbio.02733-24","DOIUrl":"10.1128/mbio.02733-24","url":null,"abstract":"<p><p>Though a confined or a broad population is exposed respectively to endemic or pandemic infections, in the same environment, some individuals resist the development of infections. The attributed reason is the inheritance of a set of immune system genes that can efficiently deal with the pathogens. In this study, we show how outbred mice differentially respond to <i>Cryptococcus neoformans,</i> a fungal pathogen, and the mechanism through which the surviving mice mount a protective immune defense. We identified that those mice developing antibodies specifically against Pep1p, an aspartic protease secreted by <i>C. neoformans</i>, had significantly improved survival. Vaccination (either prophylactic or therapeutic) with a recombinant Pep1p significantly increased the survival of the mice by decreasing the fungal load and stimulating a protective immune response. Passive immunization of <i>C. neoformans-</i>infected mice with monoclonal antibodies developed against Pep1p also improves the survival of the mice by increasing phagocytosis of <i>C. neoformans</i> and decreasing the multiplication of this fungus. Together, these data demonstrate the prophylactic and therapeutic potentials of the <i>C. neoformans</i> antigenic protein Pep1p or Pep1p-specific antibodies against this fungal infection. Also, this study suggests that the immunological interaction and thereby the responses developed against a pathogen guide the hosts to behave differentially against microbial pathogenicity.</p><p><strong>Importance: </strong>Vaccination and immunotherapies against fungal pathogens still remain a challenge. Here, we show using an <i>in vivo</i> model based on outbred mice that development of antibodies against Pep1p, an antigenic protein of the fungal pathogen <i>Cryptococcus neoformans</i>, confers resistance to this fungal infection. In support of this observation, prophylactic or therapeutic immunization of the mice with recombinant Pep1p could improve their survival when infected with a lethal dose of <i>C. neoformans</i>. Moreover, passive therapy with monoclonal anti-Pep1p antibodies also enhanced survival of the mice from <i>C. neoformans</i> infection. The associated antifungal mechanisms were mounting of a protective immune response and the development of fungal specific antibodies that decrease the fungal burden due to an increase in their phagocytosis and/or inhibit the fungal multiplication. Together, our study demonstrates (a) the mode of host-fungal interaction and the immune response developed thereby play a crucial role in developing resistance against <i>C. neoformans</i>; (b) Pep1p, an aspartic protease as well as an antigenic protein secreted by <i>C. neoformans</i>, can be exploited for vaccination (both prophylactic and therapeutic) or immunotherapy to improve the host defense during this fungal infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0273324"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503520","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":"Metal availability shapes early life microbial ecology and community succession.","authors":"Joshua Soto Ocaña, Elliot S Friedman, Orlaith Keenan, Nile U Bayard, Eileen Ford, Ceylan Tanes, Matthew J Munneke, William N Beavers, Eric P Skaar, Kyle Bittinger, Babette S Zemel, Gary D Wu, Joseph P Zackular","doi":"10.1128/mbio.01534-24","DOIUrl":"10.1128/mbio.01534-24","url":null,"abstract":"<p><p>The gut microbiota plays a critical role in human health and disease. Microbial community assembly and succession early in life are influenced by numerous factors. In turn, assembly of this microbial community is known to influence the host, including immune system development, and has been linked to outcomes later in life. To date, the role of host-mediated nutritional immunity and metal availability in shaping microbial community assembly and succession early in life has not been explored in depth. Using a human infant cohort, we show that the metal-chelating protein calprotectin is highly abundant in infants. Taxa previously shown to be successful early colonizers of the infant gut, such as <i>Enterococcus</i>, <i>Enterobacteriaceae,</i> and <i>Bacteroides,</i> are highly resistant to experimental metal starvation in culture. <i>Lactobacillus</i>, meanwhile, is highly susceptible to metal restriction, pointing to a possible mechanism by which host-mediated metal limitation shapes the fitness of early colonizing taxa in the infant gut. We further demonstrate that formula-fed infants harbor markedly higher levels of metals in their gastrointestinal tract compared to breastfed infants. Formula-fed infants with high levels of metals harbor distinct microbial communities compared to breastfed infants, with higher levels of <i>Enterococcus</i>, <i>Enterobacter,</i> and <i>Klebsiella</i>, taxa which show increased resistance to the toxic effects of high metal concentrations. These data highlight a new paradigm in microbial community assembly and suggest an unappreciated role for nutritional immunity and dietary metals in shaping the earliest colonization events of the microbiota.IMPORTANCEEarly life represents a critical window for microbial colonization of the human gastrointestinal tract. Surprisingly, we still know little about the rules that govern the successful colonization of infants and the factors that shape the success of early life microbial colonizers. In this study, we report that metal availability is an important factor in the assembly and succession of the early life microbiota. We show that the host-derived metal-chelating protein, calprotectin, is highly abundant in infants and successful early life colonizers can overcome metal restriction. We further demonstrate that feeding modality (breastmilk vs formula) markedly impacts metal levels in the gut, potentially influencing microbial community succession. Our work suggests that metals, a previously unexplored aspect of early life ecology, may play a critical role in shaping the early events of microbiota assembly in infants.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0153424"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503526","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}