Pub Date : 2024-09-10DOI: 10.1371/journal.ppat.1012535
Danping Niu, Yuanming Ma, Pengyu Ren, Sijia Chang, Chenhui Li, Yong Jiang, Chunyan Han, Ke Lan
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.
{"title":"Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation","authors":"Danping Niu, Yuanming Ma, Pengyu Ren, Sijia Chang, Chenhui Li, Yong Jiang, Chunyan Han, Ke Lan","doi":"10.1371/journal.ppat.1012535","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012535","url":null,"abstract":"Kaposi’s sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1371/journal.ppat.1012538
Hamza Arshad, Zeel Patel, Zaid A. M. Al-Azzawi, Genki Amano, Leyao Li, Surabhi Mehra, Shehab Eid, Gerold Schmitt-Ulms, Joel C. Watts
In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon is mediated by the bank vole prion protein (BVPrP). The molecular determinants of BVPrP’s ability to function as a universal prion acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we systematically identified key residues in BVPrP that permit cross-species prion replication. We found that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict prion accumulation following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kinetics in vitro. These findings suggest that BVPrP’s unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication.
{"title":"The molecular determinants of a universal prion acceptor","authors":"Hamza Arshad, Zeel Patel, Zaid A. M. Al-Azzawi, Genki Amano, Leyao Li, Surabhi Mehra, Shehab Eid, Gerold Schmitt-Ulms, Joel C. Watts","doi":"10.1371/journal.ppat.1012538","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012538","url":null,"abstract":"In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon is mediated by the bank vole prion protein (BVPrP). The molecular determinants of BVPrP’s ability to function as a universal prion acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we systematically identified key residues in BVPrP that permit cross-species prion replication. We found that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict prion accumulation following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kinetics <jats:italic>in vitro</jats:italic>. These findings suggest that BVPrP’s unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Citrus huanglongbing (HLB), which is caused by the phloem-colonizing bacteria Candidatus Liberibacter asiaticus (CLas), poses a significant threat to citrus production worldwide. The pathogenicity mechanism of HLB remains poorly understood. SEC-dependent effectors (SDEs) have been suggested to play critical roles in the interaction between citrus and CLas. Here, we explored the function of CLIBASIA_05320 (SDE19), a core SDE from CLas, and its interaction with its host target. Our data revealed that SDE19 is expressed at higher level during infection of citrus than that during infection of the Asian citrus psyllid. Subcellular localization assays showed that SDE19 is localized in the nucleus and cytoplasm and is capable of moving from cell to cell in Nicotiana benthamiana. To investigate whether SDE19 facilitates pathogen infection, we generated transgenic Arabidopsis thaliana and citrus plants overexpressing SDE19. Transgenic A. thaliana and citrus plants were more susceptible to Pseudomonas syringae pv. tomato (Pst) and Xanthomonas citri subsp. citri (Xcc), respectively. In addition, RNA-seq analysis demonstrated that overexpression of SDE19 resulted in a reprogramming of expression of genes related to biotic stimulus responses. SDE19 interacts with Citrus sinensis Sec12, a guanine nucleotide exchange factor responsible for the assembly of plant COPII (coat protein II)-coated vesicles, which mediate vesicle trafficking from the ER to the Golgi. SDE19 colocalizes with Sec12 in the ER by binding to its N-terminal catalytic region, affecting the stability of Sec12 through the 26S proteasome. This interaction hinders the secretion of apoplastic defense-related proteins such as PR1, P69B, GmGIP1, and RCR3. Furthermore, the secretion of PR1 and callose deposition is decreased in SDE19-transgenic A. thaliana. Taken together, SDE19 is a novel virulent SDE secreted by CLas that interacts with Sec12 to disrupt vesicle trafficking, inhibit defense-related proteins secretion, and promote bacterial infection. This study sheds light on how CLas manipulates the host vesicle trafficking pathway to suppress the secretion of defense-related proteins and interfere with plant immunity.
{"title":"SDE19, a SEC-dependent effector from ‘Candidatus Liberibacter asiaticus’ suppresses plant immunity and targets Citrus sinensis Sec12 to interfere with vesicle trafficking","authors":"Guiyan Huang, Xiaopeng Chang, Yanan Hu, Fuxuan Li, Nian Wang, Ruimin Li","doi":"10.1371/journal.ppat.1012542","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012542","url":null,"abstract":"Citrus huanglongbing (HLB), which is caused by the phloem-colonizing bacteria <jats:italic>Candidatus</jats:italic> Liberibacter asiaticus (CLas), poses a significant threat to citrus production worldwide. The pathogenicity mechanism of HLB remains poorly understood. SEC-dependent effectors (SDEs) have been suggested to play critical roles in the interaction between citrus and CLas. Here, we explored the function of CLIBASIA_05320 (SDE19), a core SDE from CLas, and its interaction with its host target. Our data revealed that <jats:italic>SDE19</jats:italic> is expressed at higher level during infection of citrus than that during infection of the Asian citrus psyllid. Subcellular localization assays showed that SDE19 is localized in the nucleus and cytoplasm and is capable of moving from cell to cell in <jats:italic>Nicotiana benthamiana</jats:italic>. To investigate whether SDE19 facilitates pathogen infection, we generated transgenic <jats:italic>Arabidopsis thaliana</jats:italic> and citrus plants overexpressing SDE19. Transgenic <jats:italic>A</jats:italic>. <jats:italic>thaliana</jats:italic> and citrus plants were more susceptible to <jats:italic>Pseudomonas syringae</jats:italic> pv. <jats:italic>tomato</jats:italic> (<jats:italic>Pst</jats:italic>) and <jats:italic>Xanthomonas citri</jats:italic> subsp. <jats:italic>citri</jats:italic> (<jats:italic>Xcc</jats:italic>), respectively. In addition, RNA-seq analysis demonstrated that overexpression of <jats:italic>SDE19</jats:italic> resulted in a reprogramming of expression of genes related to biotic stimulus responses. SDE19 interacts with <jats:italic>Citrus sinensis</jats:italic> Sec12, a guanine nucleotide exchange factor responsible for the assembly of plant COPII (coat protein II)-coated vesicles, which mediate vesicle trafficking from the ER to the Golgi. SDE19 colocalizes with Sec12 in the ER by binding to its N-terminal catalytic region, affecting the stability of Sec12 through the 26S proteasome. This interaction hinders the secretion of apoplastic defense-related proteins such as PR1, P69B, GmGIP1, and RCR3. Furthermore, the secretion of PR1 and callose deposition is decreased in <jats:italic>SDE19</jats:italic>-transgenic <jats:italic>A</jats:italic>. <jats:italic>thaliana</jats:italic>. Taken together, SDE19 is a novel virulent SDE secreted by CLas that interacts with Sec12 to disrupt vesicle trafficking, inhibit defense-related proteins secretion, and promote bacterial infection. This study sheds light on how CLas manipulates the host vesicle trafficking pathway to suppress the secretion of defense-related proteins and interfere with plant immunity.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation.
{"title":"Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin","authors":"Guanru Qian, Hui Zang, Jingtong Tang, Hao Zhang, Jiankang Yu, Huibiao Jia, Xinzhuang Zhang, Jianping Zhou","doi":"10.1371/journal.ppat.1012541","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012541","url":null,"abstract":"Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly <jats:italic>Lactobacillus</jats:italic> strains, in managing colitis. However, the mechanisms through which <jats:italic>Lactobacillus</jats:italic> strains ameliorate colitis require further exploration. In our study, we selected <jats:italic>Lactobacillus gasseri</jats:italic> ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and <jats:italic>in vitro</jats:italic> experiments revealed that <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 regulates <jats:italic>CDH1</jats:italic> transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which <jats:italic>Lactobacillus</jats:italic> strains alleviate colitis, offering new insights for the potential use of <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> as an alternative therapy for IBD, particularly in dietary supplementation.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1371/journal.ppat.1012042
Pilar X. Altman, Gabriel Ozorowski, Robyn L. Stanfield, Jeremy Haakenson, Michael Appel, Mara Parren, Wen-Hsin Lee, Huldah Sang, Jordan Woehl, Karen Saye-Francisco, Leigh M. Sewall, Collin Joyce, Ge Song, Katelyn Porter, Elise Landais, Raiees Andrabi, Ian A. Wilson, Andrew B. Ward, Waithaka Mwangi, Vaughn V. Smider, Dennis R. Burton, Devin Sok
The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.
{"title":"Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire","authors":"Pilar X. Altman, Gabriel Ozorowski, Robyn L. Stanfield, Jeremy Haakenson, Michael Appel, Mara Parren, Wen-Hsin Lee, Huldah Sang, Jordan Woehl, Karen Saye-Francisco, Leigh M. Sewall, Collin Joyce, Ge Song, Katelyn Porter, Elise Landais, Raiees Andrabi, Ian A. Wilson, Andrew B. Ward, Waithaka Mwangi, Vaughn V. Smider, Dennis R. Burton, Devin Sok","doi":"10.1371/journal.ppat.1012042","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012042","url":null,"abstract":"The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1371/journal.ppat.1012544
Soobin Shin, Seonghun Bong, Heeji Moon, Hosung Jeon, Hun Kim, Gyung Ja Choi, Do Yup Lee, Hokyoung Son
Anaplerosis refers to enzymatic reactions or pathways replenishing metabolic intermediates in the tricarboxylic acid (TCA) cycle. Pyruvate carboxylase (PYC) plays an important anaplerotic role by catalyzing pyruvate carboxylation, forming oxaloacetate. Although PYC orthologs are well conserved in prokaryotes and eukaryotes, their pathobiological functions in filamentous pathogenic fungi have yet to be fully understood. Here, we delve into the molecular functions of the ortholog gene PYC1 in Fusarium graminearum and F. oxysporum, prominent fungal plant pathogens with distinct pathosystems, demonstrating variations in carbon metabolism for pathogenesis. Surprisingly, the PYC1 deletion mutant of F. oxysporum exhibited pleiotropic defects in hyphal growth, conidiation, and virulence, unlike F. graminearum, where PYC1 deletion did not significantly impact virulence. To further explore the species-specific effects of PYC1 deletion on pathogenicity, we conducted comprehensive metabolic profiling. Despite shared metabolic changes, distinct reprogramming in central carbon and nitrogen metabolism was identified. Specifically, alpha-ketoglutarate, a key link between the TCA cycle and amino acid metabolism, showed significant down-regulation exclusively in the PYC1 deletion mutant of F. oxysporum. The metabolic response associated with pathogenicity was notably characterized by S-methyl-5-thioadenosine and S-adenosyl-L-methionine. This research sheds light on how PYC1-mediated anaplerosis affects fungal metabolism and reveals species-specific variations, exemplified in F. graminearum and F. oxysporum.
{"title":"Oxaloacetate anaplerosis differently contributes to pathogenicity in plant pathogenic fungi Fusarium graminearum and F. oxysporum","authors":"Soobin Shin, Seonghun Bong, Heeji Moon, Hosung Jeon, Hun Kim, Gyung Ja Choi, Do Yup Lee, Hokyoung Son","doi":"10.1371/journal.ppat.1012544","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012544","url":null,"abstract":"Anaplerosis refers to enzymatic reactions or pathways replenishing metabolic intermediates in the tricarboxylic acid (TCA) cycle. Pyruvate carboxylase (PYC) plays an important anaplerotic role by catalyzing pyruvate carboxylation, forming oxaloacetate. Although PYC orthologs are well conserved in prokaryotes and eukaryotes, their pathobiological functions in filamentous pathogenic fungi have yet to be fully understood. Here, we delve into the molecular functions of the ortholog gene <jats:italic>PYC1</jats:italic> in <jats:italic>Fusarium graminearum</jats:italic> and <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>, prominent fungal plant pathogens with distinct pathosystems, demonstrating variations in carbon metabolism for pathogenesis. Surprisingly, the <jats:italic>PYC1</jats:italic> deletion mutant of <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic> exhibited pleiotropic defects in hyphal growth, conidiation, and virulence, unlike <jats:italic>F</jats:italic>. <jats:italic>graminearum</jats:italic>, where <jats:italic>PYC1</jats:italic> deletion did not significantly impact virulence. To further explore the species-specific effects of <jats:italic>PYC1</jats:italic> deletion on pathogenicity, we conducted comprehensive metabolic profiling. Despite shared metabolic changes, distinct reprogramming in central carbon and nitrogen metabolism was identified. Specifically, alpha-ketoglutarate, a key link between the TCA cycle and amino acid metabolism, showed significant down-regulation exclusively in the <jats:italic>PYC1</jats:italic> deletion mutant of <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>. The metabolic response associated with pathogenicity was notably characterized by S-methyl-5-thioadenosine and S-adenosyl-L-methionine. This research sheds light on how <jats:italic>PYC1</jats:italic>-mediated anaplerosis affects fungal metabolism and reveals species-specific variations, exemplified in <jats:italic>F</jats:italic>. <jats:italic>graminearum</jats:italic> and <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1371/journal.ppat.1012521
Yasmine Hassoun, Ariel A. Aptekmann, Mikhail V. Keniya, Rosa Y. Gomez, Nicole Alayo, Giovanna Novi, Christopher Quinteros, Firat Kaya, Matthew Zimmerman, Diego H. Caceres, Nancy A. Chow, David S. Perlin, Erika Shor
Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata.
{"title":"Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis","authors":"Yasmine Hassoun, Ariel A. Aptekmann, Mikhail V. Keniya, Rosa Y. Gomez, Nicole Alayo, Giovanna Novi, Christopher Quinteros, Firat Kaya, Matthew Zimmerman, Diego H. Caceres, Nancy A. Chow, David S. Perlin, Erika Shor","doi":"10.1371/journal.ppat.1012521","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012521","url":null,"abstract":"Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like <jats:italic>Candida glabrata</jats:italic>, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (<jats:italic>FKS1</jats:italic> and <jats:italic>FKS2</jats:italic> in <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic>) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> population during treatment and the emergence of both drug target (<jats:italic>FKS2</jats:italic>) and non-drug target mutations, the latter predominantly in the <jats:italic>FEN1</jats:italic> gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The <jats:italic>fen1</jats:italic> mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of <jats:italic>YPC1</jats:italic> gene hypersensitized the wild type strain to caspofungin and was epistatic to <jats:italic>fen1Δ</jats:italic>. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in <jats:italic>fen1Δ</jats:italic> cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different <jats:italic>fen1</jats:italic> mutations in clinical <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> isolates, which phenocopied the <jats:italic>fen1Δ</jats:italic> mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic>.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1371/journal.ppat.1012545
Jennifer Simpson, Brittany Dulek, Paul Schaughency, Jason M. Brenchley
CD8+ T cells exert immunological pressure against immunodeficiency lentiviruses. In previous studies, we examined the TCR repertoire of CD8+ T cells specific for a single SIV immunodominant epitope, Gag-CM9, throughout SIV infection or after vaccination, and across multiple anatomic sites. We identified both tissue specific TCR sequences and TCRs shared by multiple anatomical sites. Here we use single cell RNA sequencing to evaluate if the tissue localization or TCR sequence of a CM9-specific CD8+ T cell corresponds with unique transcriptomics. CM9-specific CD8+ T cells were sorted from blood, lymph nodes, spleen, and liver from SIV infected rhesus macaques with progressive SIV infection and in animals who spontaneously control SIV replication after cessation of antiretroviral therapy. The cells were processed through a single cell sequencing protocol, creating a TCR amplified library and an RNA gene expression library corresponding to individual cells. Gene set enrichment analysis revealed no distinct transcriptional profiles for CM9 specific CD8+ T cells between different anatomical sites and between cells with shared or tissue specific TCRs. Similarly, no clear transcriptional profiles were associated with clonotypes which were shared across individual animals. However, CM9 specific CD8+ T cells from posttreatment controllers did exhibit enrichment of pathways associated with cellular activation compared to progressively infected animals, suggesting that altered transcription in distinct cellular pathways in antigen specific CD8+ T cells may associate with viral control. Together, these studies represent a thorough analysis of the relationship between anatomical and clonal origin, and the transcriptional profile of antigen specific CD8+ T cells and unravel pathways that may be important for CD8+ T cell mediated control of SIV replication.
CD8+ T细胞对免疫缺陷慢病毒产生免疫压力。在之前的研究中，我们研究了在整个 SIV 感染过程中或接种疫苗后，CD8+ T 细胞对单一 SIV 免疫优势表位（Gag-CM9）特异性的 TCR 反应谱，以及跨多个解剖部位的 TCR 反应谱。我们发现了组织特异性 TCR 序列和多个解剖部位共有的 TCR。在此，我们使用单细胞 RNA 测序来评估 CM9 特异性 CD8+ T 细胞的组织定位或 TCR 序列是否与独特的转录组学相对应。我们从SIV感染猕猴的血液、淋巴结、脾脏和肝脏中分拣出了CM9特异性CD8+ T细胞，这些猕猴患有进行性SIV感染，而且在停止抗逆转录病毒治疗后自发控制了SIV复制。这些细胞通过单细胞测序方案进行处理，建立了与单个细胞相对应的 TCR 扩增文库和 RNA 基因表达文库。基因组富集分析显示，CM9 特异性 CD8+ T 细胞在不同解剖部位之间、具有共享或组织特异性 TCR 的细胞之间没有明显的转录特征。同样，动物个体间共享的克隆型也没有明显的转录特征。不过，与渐进感染的动物相比，治疗后控制者的 CM9 特异性 CD8+ T 细胞确实表现出与细胞活化相关的通路富集，这表明抗原特异性 CD8+ T 细胞中不同细胞通路的转录改变可能与病毒控制有关。总之，这些研究全面分析了解剖和克隆起源与抗原特异性 CD8+ T 细胞转录特征之间的关系，并揭示了可能对 CD8+ T 细胞介导的 SIV 复制控制很重要的途径。
{"title":"Multi-omics analysis of SIV-specific CD8+ T cells in multiple anatomical sites","authors":"Jennifer Simpson, Brittany Dulek, Paul Schaughency, Jason M. Brenchley","doi":"10.1371/journal.ppat.1012545","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012545","url":null,"abstract":"CD8<jats:sup>+</jats:sup> T cells exert immunological pressure against immunodeficiency lentiviruses. In previous studies, we examined the TCR repertoire of CD8<jats:sup>+</jats:sup> T cells specific for a single SIV immunodominant epitope, Gag-CM9, throughout SIV infection or after vaccination, and across multiple anatomic sites. We identified both tissue specific TCR sequences and TCRs shared by multiple anatomical sites. Here we use single cell RNA sequencing to evaluate if the tissue localization or TCR sequence of a CM9-specific CD8<jats:sup>+</jats:sup> T cell corresponds with unique transcriptomics. CM9-specific CD8<jats:sup>+</jats:sup> T cells were sorted from blood, lymph nodes, spleen, and liver from SIV infected rhesus macaques with progressive SIV infection and in animals who spontaneously control SIV replication after cessation of antiretroviral therapy. The cells were processed through a single cell sequencing protocol, creating a TCR amplified library and an RNA gene expression library corresponding to individual cells. Gene set enrichment analysis revealed no distinct transcriptional profiles for CM9 specific CD8<jats:sup>+</jats:sup> T cells between different anatomical sites and between cells with shared or tissue specific TCRs. Similarly, no clear transcriptional profiles were associated with clonotypes which were shared across individual animals. However, CM9 specific CD8<jats:sup>+</jats:sup> T cells from posttreatment controllers did exhibit enrichment of pathways associated with cellular activation compared to progressively infected animals, suggesting that altered transcription in distinct cellular pathways in antigen specific CD8<jats:sup>+</jats:sup> T cells may associate with viral control. Together, these studies represent a thorough analysis of the relationship between anatomical and clonal origin, and the transcriptional profile of antigen specific CD8<jats:sup>+</jats:sup> T cells and unravel pathways that may be important for CD8<jats:sup>+</jats:sup> T cell mediated control of SIV replication.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1371/journal.ppat.1012527
Michiel Goris, Katiuska Passelli, Sanam Peyvandi, Miriam Díaz-Varela, Oaklyne Billion, Borja Prat-Luri, Benjamin Demarco, Chantal Desponds, Manon Termote, Eva Iniguez, Somaditya Dey, Bernard Malissen, Shaden Kamhawi, Benjamin P. Hurrell, Petr Broz, Fabienne Tacchini-Cottier
Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell’s killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology.
{"title":"NLRP1-dependent activation of Gasdermin D in neutrophils controls cutaneous leishmaniasis","authors":"Michiel Goris, Katiuska Passelli, Sanam Peyvandi, Miriam Díaz-Varela, Oaklyne Billion, Borja Prat-Luri, Benjamin Demarco, Chantal Desponds, Manon Termote, Eva Iniguez, Somaditya Dey, Bernard Malissen, Shaden Kamhawi, Benjamin P. Hurrell, Petr Broz, Fabienne Tacchini-Cottier","doi":"10.1371/journal.ppat.1012527","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012527","url":null,"abstract":"Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell’s killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular <jats:italic>Leishmania</jats:italic> parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that <jats:italic>Leishmania mexicana</jats:italic> induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.
{"title":"Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages","authors":"Qing Wang, Yining Cao, Songyi Ye, Maoyuan Ding, Wenliang Ge, Yuejin Liang, Jinling Chen","doi":"10.1371/journal.ppat.1012543","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012543","url":null,"abstract":"Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of <jats:italic>Toxoplasma gondii</jats:italic> (<jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>) in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection remain elusive. In the present study, we found that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection downregulated Trem2 expression and that Trem2<jats:sup>-/-</jats:sup> mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2<jats:sup>-/-</jats:sup> pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> antigens through macrophages as an \"intermediate bridge\", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of <jats:italic>Tg</jats:italic>Ag on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> antigens-treated BMDMs. Furthermore, compelling evidence from animal models and <jats:italic>in vitro</jats:italic> cell experiments suggests that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-induced adverse pregnancy.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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