mSphere最新文献

{"title":"Shining a light on <i>Candida</i>-induced epithelial damage with a luciferase reporter.","authors":"Millen Tesfamariam, Raghav Vij, Verena Trümper, Bernhard Hube, Sascha Brunke","doi":"10.1128/msphere.00509-24","DOIUrl":"10.1128/msphere.00509-24","url":null,"abstract":"<p><p>Host cell damage is a key parameter for research in infection biology, drug testing, and substance safety screening. In this study, we introduce a luciferase reporter system as a new and reliable assay to measure cell damage and validate it with the pathogenic yeast, <i>Candida albicans</i>, as a test case. We transduced human epithelial cell lines with a lentiviral vector to stably express an optimized luciferase enzyme, Nanoluc. Upon cell damage, the release of cytoplasmic luciferase into the extracellular space can be easily detected by a luminometer. We used the luciferase reporter system to investigate the damage caused by <i>C. albicans</i> to different newly generated epithelial reporter cell lines. We found that fungus-induced cell damage, as determined by established methods, correlated tightly with the release of the luciferase. The new luciferase reporter system is a simple, sensitive, robust, and inexpensive method for measuring host cell damage and has a sensitivity comparable to the standard assay, release of lactate dehydrogenase. It is suitable for high-throughput studies of pathogenesis mechanisms of any microbe, for antimicrobial drug screening, and many other applications.IMPORTANCEWe present a quick, easy, inexpensive, and reliable assay to measure damage to mammalian cells. To this end, we created reporter cell lines which artificially express luciferase, an enzyme that can be easily detected in the supernatant when these cells are damaged. We used infections with the well-investigated fungal pathogen of humans, <i>Candida albicans</i>, as a test case of our system. Using our reporter, we were able to recapitulate the known effects of strain variability, gene deletions, and antifungal treatments on host cell damage. This easily adaptable reporter system can be used to screen for damage in infection models with different microbial species, assay cell-damaging potential of substances, discover new non-toxic antibiotics, and many other damage-based applications.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0050924"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 <i>Plasmodium falciparum</i> histone methyltransferase SET10 participates in a chromatin modulation network crucial for intraerythrocytic development.","authors":"Jean-Pierre Musabyimana, Sherihan Musa, Janice Manti, Ute Distler, Stefan Tenzer, Che Julius Ngwa, Gabriele Pradel","doi":"10.1128/msphere.00495-24","DOIUrl":"10.1128/msphere.00495-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The lifecycle progression of the malaria parasite &lt;i&gt;Plasmodium falciparum&lt;/i&gt; requires precise tuning of gene expression including histone methylation. The histone methyltransferase &lt;i&gt;Pf&lt;/i&gt;SET10 was previously described as an H3K4 methyltransferase involved in &lt;i&gt;var&lt;/i&gt; gene regulation, making it a prominent antimalarial target. In this study, we investigated the role of &lt;i&gt;Pf&lt;/i&gt;SET10 in the blood stages of &lt;i&gt;P. falciparum&lt;/i&gt; in more detail, using tagged &lt;i&gt;Pf&lt;/i&gt;SET10-knockout (KO) and -knockdown (KD) lines. We demonstrate a nuclear localization of &lt;i&gt;Pf&lt;/i&gt;SET10 with peak protein levels in schizonts. &lt;i&gt;Pf&lt;/i&gt;SET10 deficiency reduces intraerythrocytic growth but has no effect on gametocyte commitment and maturation. Screening of the &lt;i&gt;Pf&lt;/i&gt;SET10-KO line for histone methylation variations reveals that lack of &lt;i&gt;Pf&lt;/i&gt;SET10 renders the parasites unable to mark H3K18me1, while no reduction in the H3K4 methylation status could be observed. Comparative transcriptomic profiling of &lt;i&gt;Pf&lt;/i&gt;SET10-KO schizonts shows an upregulation of transcripts particularly encoding proteins linked to red blood cell remodeling and antigenic variation, suggesting a repressive function of the histone methylation mark. TurboID coupled with mass spectrometry further highlights an extensive nuclear &lt;i&gt;Pf&lt;/i&gt;SET10 interaction network with roles in transcriptional regulation and mRNA processing, DNA replication and repair, and chromatin remodeling. The main interactors of &lt;i&gt;Pf&lt;/i&gt;SET10 include ApiAP2 transcription factors, epigenetic regulators like &lt;i&gt;Pf&lt;/i&gt;HDAC1, chromatin modulators like &lt;i&gt;Pf&lt;/i&gt;MORC and &lt;i&gt;Pf&lt;/i&gt;ISWI, mediators of RNA polymerase II, and DNA replication licensing factors. The combined data pinpoint &lt;i&gt;Pf&lt;/i&gt;SET10 as a histone methyltransferase essential for H3K18 methylation that regulates nucleic acid metabolic processes in the &lt;i&gt;P. falciparum&lt;/i&gt; blood stages as part of a comprehensive chromatin modulation network.IMPORTANCEThe fine-tuned regulation of DNA replication and transcription is particularly crucial for the rapidly multiplying blood stages of malaria parasites and proteins involved in these processes represent important drug targets. This study demonstrates that contrary to previous reports the histone methyltransferase &lt;i&gt;Pf&lt;/i&gt;SET10 of the malaria parasite &lt;i&gt;Plasmodium falciparum&lt;/i&gt; promotes the methylation of histone 3 at lysine K18, a histone mark to date not well understood. Deficiency of &lt;i&gt;Pf&lt;/i&gt;SET10 due to genetic knockout affects genes involved in intraerythrocytic development. Furthermore, in the nuclei of blood-stage parasites, &lt;i&gt;Pf&lt;/i&gt;SET10 interacts with various protein complexes crucial for DNA replication, remodeling, and repair, as well as for transcriptional regulation and mRNA processing. In summary, this study highlights &lt;i&gt;Pf&lt;/i&gt;SET10 as a methyltransferase affecting H3K18 methylation with critical functions in chromatin maintenance during the development of &lt;i&gt;P. falciparum&lt;/i&gt; in red blood cells.&lt;/","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0049524"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mSphere of Influence: Revisiting the central dogma, again!","authors":"Parimal Samir","doi":"10.1128/msphere.00398-24","DOIUrl":"10.1128/msphere.00398-24","url":null,"abstract":"<p><p>Dr. Parimal Samir works in the field of host-pathogen interactions. In this mSphere of Influence article, he reflects on how the manuscript entitled \"<i>De novo</i> gene synthesis by an antiviral reverse transcriptase\" by Samuel Sternberg and colleagues made an impact by reminding him that there is still so much to discover in life sciences.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0039824"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum for Hassall et al., \"Dissecting Individual Interactions between Pathogenic and Commensal Bacteria within a Multispecies Gut Microbial Community\".","authors":"Jack Hassall, Jeffery K J Cheng, Meera Unnikrishnan","doi":"10.1128/msphere.00893-24","DOIUrl":"https://doi.org/10.1128/msphere.00893-24","url":null,"abstract":"","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0089324"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Chlamydia trachomatis</i> Inc Ct226 is vital for FLI1 and LRRF1 recruitment to the chlamydial inclusion.","authors":"Natalie A Sturd, Lindsey A Knight, Macy G Wood, Legacy Durham, Scot P Ouellette, Elizabeth A Rucks","doi":"10.1128/msphere.00473-24","DOIUrl":"10.1128/msphere.00473-24","url":null,"abstract":"<p><p>The obligate intracellular pathogen, <i>Chlamydia trachomatis</i>, establishes an intracellular niche within a host membrane-derived vacuole called the chlamydial inclusion. From within this inclusion, <i>C. trachomatis</i> orchestrates numerous host-pathogen interactions, in part, by utilizing a family of type III secreted effectors, termed inclusion membrane proteins (Incs). Incs are embedded within the inclusion membrane, and some function to recruit host proteins to the inclusion. Two such recruited host proteins are <u>l</u>eucine <u>r</u>ich <u>r</u>epeat <u>F</u>lightless-1 <u>i</u>nteracting <u>p</u>rotein 1 (LRRF1/LRRFIP1) and its binding partner Flightless 1 (FLI1/FLII). Previously, LRRF1 has been shown to interact with Inc protein Ct226/CTL0478. This is the first study to examine interactions of FLI1 with candidate Incs or with LRRF1 during infection. We hypothesized that FLI1 recruitment to the inclusion would be dependent on LRRF1 localization. We demonstrated that FLI1 co-immunoprecipitated with Ct226 but only in the presence of LRRF1. Furthermore, FLI1 localized to the inclusion when LRRF1 was depleted via small interfering RNA, suggesting that FLI1 may have an alternative recruitment mechanism. We further developed a series of CRISPRi knockdown and complementation strains in <i>C. trachomatis</i> serovar L2 targeting ct226 and co-transcribed candidate Incs, ct225 and ct224. Simultaneous knockdown of ct226, ct225, and ct224 prevented localization of both FLI1 and LRRF1 to the inclusion, and only complementation of ct226 restored their localization. Thus, we demonstrated Ct226 is critical for FLI1 and LRRF1 localization to the inclusion. Our results also indicate an LRRF1-independent localization mechanism for FLI1, which likely influence their mechanism(s) of action during chlamydial infection.IMPORTANCE<i>Chlamydia trachomatis</i> is a leading cause of both bacterial sexually transmitted infections and preventable infectious blindness worldwide. As an obligate intracellular pathogen, <i>C. trachomatis</i> has evolved multiple ways of manipulating the host to establish a successful infection. As such, it is important to understand host-chlamydial protein-protein interactions as these reveal strategies that <i>C. trachomatis</i> uses to shape its intracellular environment. This study looks in detail at interactions of two host proteins, FLI1 and LRRF1, during chlamydial infection. Importantly, the series of CRISPR inference knockdown and complement strains developed in this study suggest these proteins have both independent and overlapping mechanisms for localization, which ultimately will dictate how these proteins function during chlamydial infection.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0047324"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 <i>Plasmodium falciparum</i> histone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood-stage parasites.","authors":"Matthias Wyss, Abhishek Kanyal, Igor Niederwieser, Richard Bartfai, Till S Voss","doi":"10.1128/msphere.00546-24","DOIUrl":"10.1128/msphere.00546-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The malaria parasite &lt;i&gt;Plasmodium falciparum&lt;/i&gt; employs antigenic variation of the virulence factor &lt;i&gt;P. falciparum&lt;/i&gt; erythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copy &lt;i&gt;var&lt;/i&gt; gene family. &lt;i&gt;var&lt;/i&gt; genes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singular &lt;i&gt;var&lt;/i&gt; gene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator of &lt;i&gt;var&lt;/i&gt; gene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 in &lt;i&gt;var&lt;/i&gt; gene regulation. We demonstrate that PfSET10 is not required for mutually exclusive &lt;i&gt;var&lt;/i&gt; gene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulating &lt;i&gt;var&lt;/i&gt; gene expression and is not required for blood-stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.IMPORTANCEThe malaria parasite &lt;i&gt;Plasmodium falciparum&lt;/i&gt; infects hundreds of millions of people every year. To survive and proliferate in the human bloodstream, the parasites need to escape recognition by the host's immune system. To achieve this, &lt;i&gt;P. falciparum&lt;/i&gt; can change the expression of surface antigens &lt;i&gt;via&lt;/i&gt; a process called antigenic variation. This fascinating survival strategy is based on infrequent switches in the expression of single members of the &lt;i&gt;var&lt;/i&gt; multigene family. Previous research reported conflicting results on the role of the epigenetic regulator PfSET10 in controlling mutually exclusive &lt;i&gt;var&lt;/i&gt; gene expression and switching. Here, we unequivocally demonstrate that PfSET10 is neither required for antigenic variation nor the expression of any other proteins during blood-stage infection. This information is critical in directing our attention toward exploring alternative molecular mechanisms underlying the control of antigenic variation and investigating the","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0054624"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse innate resistance to <i>Neospora caninum</i> infection is driven by early production of IFNγ by NK cells in response to parasite ligands.","authors":"R S Coombs, A E Overacre-Delgoffe, A Bhattacharjee, T W Hand, J P Boyle","doi":"10.1128/msphere.00255-24","DOIUrl":"10.1128/msphere.00255-24","url":null,"abstract":"<p><p><i>Toxoplasma gondii</i> is capable of being transmitted by nearly all warm-blooded animals, and rodents are a major source of parasite dissemination, yet mechanisms driving its broad host range are poorly understood. Although a phylogenetically close relative of <i>T. gondii</i>, <i>Neospora caninum</i> differs from <i>T. gondii</i> in that it does not infect mice and only infects a small number of ruminant and canine species. We recently showed that <i>T. gondii</i> and <i>N. caninum</i> grow similarly in mice during the first 24 h post-infection, but only <i>N. caninum</i> induces an IFNγ-driven response within hours that controls the infection. The goal of the present study was to understand the cellular basis of this rapid response to <i>N. caninum</i>. To do this, we compared immune cell populations at the site of infection 4 h after <i>T. gondii</i> or <i>N. caninum</i> infection in mice. We found that both parasites induced similar frequencies of peritoneal monocytes, while macrophages and dendritic cell populations were not increased compared to uninfected mice. Through a series of knockout mouse experiments, we show that B, T, and NKT cells are not required for immediate IFNγ production and ultimate control of <i>N. caninum</i> infection, suggesting that natural killer (NK) cells are the primary inducers of immediate IFNγ in response to <i>N. caninum. N. caninum</i> infections exhibited significantly more IFNγ⁺ NK cells in the peritoneum compared with <i>T. gondii</i>-infected and uninfected mice. Finally, we demonstrate that differences in early IFNγ production during <i>N. caninum</i> and <i>T. gondii</i> infections in mice are at least partly due to differences in soluble antigen(s) produced by tachyzoites.</p><p><strong>Importance: </strong>Pathogen differences in host range are poorly understood at the molecular level even though even closely related pathogen species can have dramatically distinct host ranges. Here, we study two related parasite species that have a dramatic difference in their ability to infect mice. Here, we show that soluble proteins from these species determine one driver of this difference: induction of interferon gamma by cells of the innate immune system.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0025524"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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>Candida glabrata</i> maintains two <i>HAP1</i> ohnologs, <i>HAP1A</i> and <i>HAP1B</i>, for distinct roles in ergosterol gene regulation to mediate sterol homeostasis under azole and hypoxic conditions.","authors":"Debasmita Saha, Justin B Gregor, Smriti Hoda, Katharine E Eastman, Victor A Gutierrez-Schultz, Mindy Navarrete, Jennifer H Wisecaver, Scott D Briggs","doi":"10.1128/msphere.00524-24","DOIUrl":"10.1128/msphere.00524-24","url":null,"abstract":"<p><p><i>Candida glabrata</i> exhibits innate resistance to azole antifungal drugs but also has the propensity to rapidly develop clinical drug resistance. Azole drugs, which target Erg11, is one of the major classes of antifungals used to treat <i>Candida</i> infections. Despite their widespread use, the mechanism controlling azole-induced <i>ERG</i> gene expression and drug resistance in <i>C. glabrata</i> has primarily revolved around Upc2 and/or Pdr1. Phylogenetic and syntenic analyses revealed that <i>C. glabrata</i>, following a whole genome duplication event, maintained <i>HAP1A</i> and <i>HAP1B</i>, whereas <i>Saccharomyces cerevisiae</i> only retained the <i>HAP1A</i> ortholog, <i>HAP1</i>. In this study, we determined the function of two zinc cluster transcription factors, Hap1A and Hap1B, as direct regulators of <i>ERG</i> genes. In <i>S. cerevisiae,</i> Hap1, an ortholog of Hap1A, is a known transcription factor controlling <i>ERG</i> gene expression under aerobic and hypoxic conditions. Interestingly, deleting <i>HAP1</i> or <i>HAP1B</i> in either <i>S. cerevisiae</i> or <i>C. glabrata,</i> respectively, showed altered susceptibility to azoles. In contrast, the strain deleted for <i>HAP1A</i> did not exhibit azole susceptibility. We also determined that the increased azole susceptibility in a <i>hap1B</i>Δ strain is attributed to decreased azole-induced expression of <i>ERG</i> genes, resulting in decreased levels of total ergosterol. Surprisingly, Hap1A protein expression is barely detected under aerobic conditions but is specifically induced under hypoxic conditions, where Hap1A is required for the repression of <i>ERG</i> genes. However, in the absence of Hap1A, Hap1B can compensate as a transcriptional repressor. Our study shows that Hap1A and Hap1B is utilized by <i>C. glabrata</i> to adapt to specific host and environmental conditions.</p><p><strong>Importance: </strong>Invasive and drug-resistant fungal infections pose a significant public health concern. <i>Candida glabrata</i>, a human fungal pathogen, is often difficult to treat due to its intrinsic resistance to azole antifungal drugs and its capacity to develop clinical drug resistance. Therefore, understanding the pathways that facilitate fungal growth and environmental adaptation may lead to novel drug targets and/or more efficacious antifungal therapies. While the mechanisms of azole resistance in <i>Candida</i> species have been extensively studied, the roles of zinc cluster transcription factors, such as Hap1A and Hap1B, in <i>C. glabrata</i> have remained largely unexplored until now. Our research shows that these factors play distinct yet crucial roles in regulating ergosterol homeostasis under azole drug treatment and oxygen-limiting growth conditions. These findings offer new insights into how this pathogen adapts to different environmental conditions and enhances our understanding of factors that alter drug susceptibility and/or resistance.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0052424"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis.","authors":"Asami Nishimori, Kiyohiko Andoh, Yuichi Matsuura, Tomohiro Okagawa, Satoru Konnai","doi":"10.1128/msphere.00216-24","DOIUrl":"10.1128/msphere.00216-24","url":null,"abstract":"<p><p>Oncogenic transformation of normal cells is caused by mutations and chromosomal abnormalities in cancer-related genes. Enzootic bovine leukosis (EBL) is a malignant B-cell lymphoma caused by bovine leukemia virus (BLV) infection in cattle. Although a small fraction of BLV-infected cattle develops EBL after a long latent period, the mechanisms for oncogenesis in EBL cattle remain largely unknown. In this study, we analyzed the types and patterns of somatic mutations in cancer cells from 36 EBL cases, targeting 21 cancer-related genes. Various somatic mutations were identified in eight genes, <i>TP53</i>, <i>KMT2D</i>, <i>CREBBP</i>, <i>KRAS</i>, <i>PTEN</i>, <i>NOTCH1</i>, <i>MYD88</i>, and <i>CARD11</i>. In addition, <i>TP53</i> gene was found to be mutated in 69.4% of EBL cases, with most being biallelic mutations. In some cases, associations were observed between the ages at which cattle had developed EBL and somatic mutation patterns; young onset of EBL possibly occurs due to high impact mutations affecting protein translation and biallelic mutations. Furthermore, nucleotide substitution patterns indicated that cytosine at CpG sites tended to be converted to thymine in many EBL cases, which was considered to be the result of spontaneous deamination of 5-methylcytosine. These results demonstrate how somatic mutations have occurred in cancer cells leading to EBL development, thereby explaining its pathogenic mechanism. These findings will contribute to a better understanding and future elucidation of disease progression in BLV infection.IMPORTANCEEnzootic bovine leukosis (EBL) is a malignant and lethal disease in cattle. Currently, there are no effective vaccines or therapeutic methods against bovine leukemia virus (BLV) infection, resulting in severe economic losses in livestock industry. This study provides a renewed hypothesis to explain the general mechanisms of EBL onset by combining the previous finding that several integration sites of BLV provirus can affect the increase in survival and proliferation of infected cells. We demonstrate that two additional random events are necessary for oncogenic transformation in infected cell clones, elucidating the reason why only few infected cattle develop EBL. Further exploration of somatic mutation and BLV integration sites could support this hypothesis more firmly, potentially contributing to the development of novel control methods for EBL onset.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0021624"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum for Hasan et al., \"Role of glycogen metabolism in <i>Clostridioides difficile</i> virulence\".","authors":"Md Kamrul Hasan, Marjorie Pizarro-Guajardo, Javier Sanchez, Revathi Govind","doi":"10.1128/msphere.00835-24","DOIUrl":"10.1128/msphere.00835-24","url":null,"abstract":"","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0083524"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}