Pub Date : 2025-02-18Epub Date: 2025-01-22DOI: 10.1128/iai.00271-24
Lin Xu, Caiying Wang, Yuhuan Liu, Yanlan Zhang, Zhen Li, Lin Pang
Pertussis, a severe infectious disease in children, has become increasingly prominent in recent years. This study aims to investigate the role of the MASP1 protein in severe pertussis in children through multi-omics analysis, providing a theoretical basis for the development of novel therapeutic strategies. The study retrieved macro-genome and 16S rRNA data of pediatric pertussis from public databases to analyze microbial diversity and specific flora abundance, conducting pathway functional enrichment analysis. Differential expression analysis of transcriptome data and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, combined with machine learning, identified the key gene MASP1. A Bordetella pertussis infection model was established using human bronchial epithelial cell line HBE135-E6E7 to validate MASP1 expression changes and investigate its relationship with airway epithelial cell damage by constructing cell lines overexpressing and knocking down MASP1. Finally, the impact of inhibiting MASP1 expression on infection symptoms was evaluated using a mouse pertussis infection model. The results revealed significant differences in microbial diversity and specific flora abundance between healthy children and those with pertussis, with MASP1 significantly upregulated in severe pertussis and its inhibition alleviating infection symptoms. The study highlights the critical role of MASP1 in pertussis, providing a crucial foundation for developing therapeutic strategies targeting MASP1.
{"title":"MASP1 modulation as a novel therapeutic target in severe pediatric pertussis: insights from a multi-omics approach.","authors":"Lin Xu, Caiying Wang, Yuhuan Liu, Yanlan Zhang, Zhen Li, Lin Pang","doi":"10.1128/iai.00271-24","DOIUrl":"10.1128/iai.00271-24","url":null,"abstract":"<p><p>Pertussis, a severe infectious disease in children, has become increasingly prominent in recent years. This study aims to investigate the role of the MASP1 protein in severe pertussis in children through multi-omics analysis, providing a theoretical basis for the development of novel therapeutic strategies. The study retrieved macro-genome and 16S rRNA data of pediatric pertussis from public databases to analyze microbial diversity and specific flora abundance, conducting pathway functional enrichment analysis. Differential expression analysis of transcriptome data and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, combined with machine learning, identified the key gene MASP1. A <i>Bordetella pertussis</i> infection model was established using human bronchial epithelial cell line HBE135-E6E7 to validate MASP1 expression changes and investigate its relationship with airway epithelial cell damage by constructing cell lines overexpressing and knocking down MASP1. Finally, the impact of inhibiting MASP1 expression on infection symptoms was evaluated using a mouse pertussis infection model. The results revealed significant differences in microbial diversity and specific flora abundance between healthy children and those with pertussis, with MASP1 significantly upregulated in severe pertussis and its inhibition alleviating infection symptoms. The study highlights the critical role of MASP1 in pertussis, providing a crucial foundation for developing therapeutic strategies targeting MASP1.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0027124"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-13DOI: 10.1128/iai.00541-24
{"title":"Expression of Concern for Herrera et al., \"Protection against Malaria in <i>Aotus</i> Monkeys Immunized with a Recombinant Blood-Stage Antigen Fused to a Universal T-Cell Epitope: Correlation of Serum Gamma Interferon Levels with Protection\".","authors":"","doi":"10.1128/iai.00541-24","DOIUrl":"10.1128/iai.00541-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0054124"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2024-12-20DOI: 10.1128/iai.00445-24
Emily Tamkin, Brian P Lorenz, Arianna McCarty, Sam Fulte, Elan Eisenmesser, Alexander R Horswill, Sarah E Clark
The composition of the respiratory tract microbiome is a notable predictor of infection-related morbidities and mortalities among both adults and children. Species of Corynebacterium, which are largely present as commensals in the upper airway and other body sites, are associated with lower colonization rates of opportunistic bacterial pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. In this study, Corynebacterium-mediated protective effects against S. pneumoniae and S. aureus were directly compared using in vivo and in vitro models. Pre-exposure to Corynebacterium pseudodiphtheriticum reduced the ability of S. aureus and S. pneumoniae to infect the lungs of mice, indicating a broadly protective effect. Adherence of both pathogens to human respiratory tract epithelial cells was significantly impaired following pre-exposure to C. pseudodiphtheriticum or Corynebacterium accolens, and this effect was dependent on live Corynebacterium colonizing the epithelial cells. However, Corynebacterium-secreted factors had distinct effects on each pathogen. Corynebacterium lipase activity was bactericidal against S. pneumoniae, but not S. aureus. Instead, the hemolytic activity of pore-forming toxins produced by S. aureus was directly blocked by a novel Corynebacterium-secreted factor with protease activity. Taken together, these results suggest diverse mechanisms by which Corynebacterium contribute to the protective effect of the airway microbiome against opportunistic bacterial pathogens.
{"title":"Airway <i>Corynebacterium</i> interfere with <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i> infection and express secreted factors selectively targeting each pathogen.","authors":"Emily Tamkin, Brian P Lorenz, Arianna McCarty, Sam Fulte, Elan Eisenmesser, Alexander R Horswill, Sarah E Clark","doi":"10.1128/iai.00445-24","DOIUrl":"10.1128/iai.00445-24","url":null,"abstract":"<p><p>The composition of the respiratory tract microbiome is a notable predictor of infection-related morbidities and mortalities among both adults and children. Species of <i>Corynebacterium,</i> which are largely present as commensals in the upper airway and other body sites, are associated with lower colonization rates of opportunistic bacterial pathogens such as <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i>. In this study, <i>Corynebacterium</i>-mediated protective effects against <i>S. pneumoniae</i> and <i>S. aureus</i> were directly compared using <i>in vivo</i> and <i>in vitro</i> models. Pre-exposure to <i>Corynebacterium pseudodiphtheriticum</i> reduced the ability of <i>S. aureus</i> and <i>S. pneumoniae</i> to infect the lungs of mice, indicating a broadly protective effect. Adherence of both pathogens to human respiratory tract epithelial cells was significantly impaired following pre-exposure to C. <i>pseudodiphtheriticum</i> or <i>Corynebacterium accolens</i>, and this effect was dependent on live <i>Corynebacterium</i> colonizing the epithelial cells. However, <i>Corynebacterium</i>-secreted factors had distinct effects on each pathogen. <i>Corynebacterium</i> lipase activity was bactericidal against <i>S. pneumoniae</i>, but not <i>S. aureus</i>. Instead, the hemolytic activity of pore-forming toxins produced by <i>S. aureus</i> was directly blocked by a novel <i>Corynebacterium</i>-secreted factor with protease activity. Taken together, these results suggest diverse mechanisms by which <i>Corynebacterium</i> contribute to the protective effect of the airway microbiome against opportunistic bacterial pathogens.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0044524"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-22DOI: 10.1128/iai.00439-24
Karine Dufresne, Kait F Al, Heather C Craig, Charlotte E M Coleman, Katherine J Kasper, Jeremy P Burton, John K McCormick
Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus and is the determinant of menstrual toxic shock syndrome (mTSS); however, the impact of TSST-1 on the vaginal environment beyond mTSS is not understood. Herein, we assessed how TSST-1 affects vaginal colonization by S. aureus, host inflammatory responses, and changes in microbial communities within the murine vagina. We demonstrated that TSST-1 induced a CD8+ T-cell-dependent inflammatory response in 24 h that correlated with S. aureus persistence within the vaginal tract. This increase was due to superantigen-dependent T-cell activation that triggered a change in microbial composition within the vaginal tract. Altogether, this study demonstrates that within the vaginal tract, TSST-1 modulates the vaginal microbiota to favor the survival of S. aureus in the absence of mTSS.IMPORTANCEToxic shock syndrome toxin-1 (TSST-1) is a superantigen toxin produced from Staphylococcus aureus that causes the menstrual form of toxic shock syndrome. This research demonstrates that TSST-1 also has a wider function within the vaginal tract than previously expected. We show that TSST-1, by activating CD8+ T cells, induces an inflammatory environment that modifies the vaginal microbiota to favor colonization by S. aureus. These are important findings as S. aureus can colonize the human vaginal tract efficiently and subsequently trigger dysbiosis within the microbial communities leading to several adverse outcomes such as decreased fertility, increased risks for sexually transmitted diseases, and issues related to pregnancy and birth.
{"title":"TSST-1 promotes colonization of <i>Staphylococcus aureus</i> within the vaginal tract by activation of CD8<sup>+</sup> T cells.","authors":"Karine Dufresne, Kait F Al, Heather C Craig, Charlotte E M Coleman, Katherine J Kasper, Jeremy P Burton, John K McCormick","doi":"10.1128/iai.00439-24","DOIUrl":"10.1128/iai.00439-24","url":null,"abstract":"<p><p>Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by <i>Staphylococcus aureus</i> and is the determinant of menstrual toxic shock syndrome (mTSS); however, the impact of TSST-1 on the vaginal environment beyond mTSS is not understood. Herein, we assessed how TSST-1 affects vaginal colonization by <i>S. aureus</i>, host inflammatory responses, and changes in microbial communities within the murine vagina. We demonstrated that TSST-1 induced a CD8<sup>+</sup> T-cell-dependent inflammatory response in 24 h that correlated with <i>S. aureus</i> persistence within the vaginal tract. This increase was due to superantigen-dependent T-cell activation that triggered a change in microbial composition within the vaginal tract. Altogether, this study demonstrates that within the vaginal tract, TSST-1 modulates the vaginal microbiota to favor the survival of <i>S. aureus</i> in the absence of mTSS.IMPORTANCEToxic shock syndrome toxin-1 (TSST-1) is a superantigen toxin produced from <i>Staphylococcus aureus</i> that causes the menstrual form of toxic shock syndrome. This research demonstrates that TSST-1 also has a wider function within the vaginal tract than previously expected. We show that TSST-1, by activating CD8<sup>+</sup> T cells, induces an inflammatory environment that modifies the vaginal microbiota to favor colonization by <i>S. aureus</i>. These are important findings as <i>S. aureus</i> can colonize the human vaginal tract efficiently and subsequently trigger dysbiosis within the microbial communities leading to several adverse outcomes such as decreased fertility, increased risks for sexually transmitted diseases, and issues related to pregnancy and birth.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0043924"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-13DOI: 10.1128/iai.00542-24
{"title":"Expression of Concern for Perlaza et al., \"Immunogenicity of Four <i>Plasmodium falciparum</i> Preerythrocytic Antigens in <i>Aotus lemurinus</i> Monkeys\".","authors":"","doi":"10.1128/iai.00542-24","DOIUrl":"10.1128/iai.00542-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0054224"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-13DOI: 10.1128/iai.00532-24
Camille M Riffaud-Widner, Ray E Widner, Scot P Ouellette, Elizabeth A Rucks
Chlamydia is an obligate intracellular bacterial pathogen that develops within a membrane-bound vacuole called an inclusion. Throughout its developmental cycle, Chlamydia modifies the inclusion membrane (IM) with type III secreted (T3S) membrane proteins, known as inclusion membrane proteins (Incs). Via the IM, Chlamydia manipulates the host cell to acquire lipids and nutrients necessary for its growth. One key nutrient is tryptophan (Trp). As a Trp auxotroph, Chlamydia is very sensitive to Trp starvation and, in response to low Trp levels induced by the immune response, enters a viable but nonreplicating state called persistence. To maintain viability during persistence, Chlamydia must necessarily maintain both the integrity of the IM and its ability to modify host cell responses, but how Trp starvation affects IM composition and subsequent interactions with the host cell remains poorly understood. We hypothesize that, under Trp starvation conditions, Inc expression/stability or T3S function during persistence alters IM composition but that key host-Chlamydia interactions will be preserved. To examine host-Chlamydia interactions during persistence, we examined sphingomyelin, cholesterol, and transferrin trafficking to the inclusion, as well as localization of host proteins that bind to specific Incs. We identified IM composition changes during persistence by monitoring endogenous Inc abundance at the IM. Chlamydial T3S is generally functional during persistence. Specific changes in Inc composition in the IM can be linked to Trp content of a specific Inc or effector-specific defects in chlamydial T3S. Overall, our findings reveal that critical host-Chlamydia interactions are maintained during persistence mediated by Trp starvation.
{"title":"Effect of tryptophan starvation on inclusion membrane composition and chlamydial-host interactions.","authors":"Camille M Riffaud-Widner, Ray E Widner, Scot P Ouellette, Elizabeth A Rucks","doi":"10.1128/iai.00532-24","DOIUrl":"10.1128/iai.00532-24","url":null,"abstract":"<p><p><i>Chlamydia</i> is an obligate intracellular bacterial pathogen that develops within a membrane-bound vacuole called an inclusion. Throughout its developmental cycle, <i>Chlamydia</i> modifies the inclusion membrane (IM) with type III secreted (T3S) membrane proteins, known as inclusion membrane proteins (Incs). Via the IM, <i>Chlamydia</i> manipulates the host cell to acquire lipids and nutrients necessary for its growth. One key nutrient is tryptophan (Trp). As a Trp auxotroph, <i>Chlamydia</i> is very sensitive to Trp starvation and, in response to low Trp levels induced by the immune response, enters a viable but nonreplicating state called persistence. To maintain viability during persistence, <i>Chlamydia</i> must necessarily maintain both the integrity of the IM and its ability to modify host cell responses, but how Trp starvation affects IM composition and subsequent interactions with the host cell remains poorly understood. We hypothesize that, under Trp starvation conditions, Inc expression/stability or T3S function during persistence alters IM composition but that key host-<i>Chlamydia</i> interactions will be preserved. To examine host-<i>Chlamydia</i> interactions during persistence, we examined sphingomyelin, cholesterol, and transferrin trafficking to the inclusion, as well as localization of host proteins that bind to specific Incs. We identified IM composition changes during persistence by monitoring endogenous Inc abundance at the IM. Chlamydial T3S is generally functional during persistence. Specific changes in Inc composition in the IM can be linked to Trp content of a specific Inc or effector-specific defects in chlamydial T3S. Overall, our findings reveal that critical host-<i>Chlamydia</i> interactions are maintained during persistence mediated by Trp starvation.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0053224"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2024-12-23DOI: 10.1128/iai.00487-24
Clara Luna Marina, Raffael J Araújo de Castro, Paula Bellozi, Ana M Cruz, Pedro Henrique Bürgel, Paul G Weightman Potter, Craig Beall, Aldo Henrique Tavares, Andreza De Bem, Alexandre Alanio, Carolina Coelho, Anamélia Lorenzetti Bocca
Dormancy is an adaptation in which cells reduce their metabolism, transcription, and translation to stay alive under stressful conditions, preserving the capacity to reactivate once the environment reverts to favorable conditions. Dormancy and reactivation of Cryptococcus neoformans (Cn) are closely linked to intracellular residency within macrophages. Our previous work showed that in vitro murine macrophages rely on the viable but not cultivable (VBNC-a dormancy phenotype) fungus from active Cn, with striking differences in immunometabolic gene expression. Here, we analyzed the influence of VBNC and active Cn on the immunometabolism of infected macrophages, combining metabolic gene expression, mitochondrial membrane potential (ΔΨm), oxygen consumption analysis, and uptake of glucose and fatty acids. The active fungus induced mitochondrial depolarization, and increased glycolysis and mitochondrial oxygen consumption. VBNC infection in bone marrow-derived macrophage (BMDM) caused an attenuated modification in mitochondrial metabolism. However, we found differences in BMDM infected with VBNC vs those infected with active fungus, where VBNC induced an increment in fatty acid uptake in M0 and M1 BMDM, measured by incorporation of BODIPY-palmitate, accompanied by an increase in expression of fatty acid transporters Fabp1 and Fabp4. Overall, distinct fatty acid-related responses induced by VBNC and active Cn suggest different immunomodulatory reactions, depending on the microbial growth stage. We posit that, for VBNC, some of these macrophage metabolic responses reflect the establishment of prolonged microbial intracellular residency and possibly initial stages of granuloma formation.
{"title":"Immunometabolic reprogramming in macrophages infected with active and dormant <i>Cryptococcus neoformans</i>: differential modulation of respiration, glycolysis, and fatty acid utilization.","authors":"Clara Luna Marina, Raffael J Araújo de Castro, Paula Bellozi, Ana M Cruz, Pedro Henrique Bürgel, Paul G Weightman Potter, Craig Beall, Aldo Henrique Tavares, Andreza De Bem, Alexandre Alanio, Carolina Coelho, Anamélia Lorenzetti Bocca","doi":"10.1128/iai.00487-24","DOIUrl":"10.1128/iai.00487-24","url":null,"abstract":"<p><p>Dormancy is an adaptation in which cells reduce their metabolism, transcription, and translation to stay alive under stressful conditions, preserving the capacity to reactivate once the environment reverts to favorable conditions. Dormancy and reactivation of <i>Cryptococcus neoformans</i> (<i>Cn</i>) are closely linked to intracellular residency within macrophages. Our previous work showed that <i>in vitro</i> murine macrophages rely on the viable but not cultivable (VBNC-a dormancy phenotype) fungus from active <i>Cn</i>, with striking differences in immunometabolic gene expression. Here, we analyzed the influence of VBNC and active <i>Cn</i> on the immunometabolism of infected macrophages, combining metabolic gene expression, mitochondrial membrane potential (ΔΨm), oxygen consumption analysis, and uptake of glucose and fatty acids. The active fungus induced mitochondrial depolarization, and increased glycolysis and mitochondrial oxygen consumption. VBNC infection in bone marrow-derived macrophage (BMDM) caused an attenuated modification in mitochondrial metabolism. However, we found differences in BMDM infected with VBNC vs those infected with active fungus, where VBNC induced an increment in fatty acid uptake in M0 and M1 BMDM, measured by incorporation of BODIPY-palmitate, accompanied by an increase in expression of fatty acid transporters <i>Fabp1</i> and <i>Fabp4</i>. Overall, distinct fatty acid-related responses induced by VBNC and active <i>Cn</i> suggest different immunomodulatory reactions, depending on the microbial growth stage. We posit that, for VBNC, some of these macrophage metabolic responses reflect the establishment of prolonged microbial intracellular residency and possibly initial stages of granuloma formation.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0048724"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-13DOI: 10.1128/iai.00545-24
{"title":"Expression of Concern for Lopez-Perez et al., \"IgG Responses to the <i>Plasmodium falciparum</i> Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to <i>Plasmodium vivax</i>\".","authors":"","doi":"10.1128/iai.00545-24","DOIUrl":"10.1128/iai.00545-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0054524"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2024-12-31DOI: 10.1128/iai.00276-24
Theodore J Kottom, Eva M Carmona, Kyle Schaefbauer, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Andrew H Limper
<p><p><i>Pneumocystis jirovecii</i> pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of <i>Pneumocystis</i> while balancing lung inflammation are required. Prior studies have shown that innate immunity to <i>Pneumocystis</i> is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with <i>Card9</i><sup>-/-</sup> infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in <i>Pneumocystis</i> killing. We further demonstrate in the <i>Pneumocystis</i> pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor.IMPORTANCE<i>Pneumocystis</i> pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against <i>Pneumocystis</i>. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of <i>Pneumocystis</i> organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral
{"title":"The importance of Fcγ and C-type lectin receptors in host immune responses during <i>Pneumocystis</i> pneumonia.","authors":"Theodore J Kottom, Eva M Carmona, Kyle Schaefbauer, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Andrew H Limper","doi":"10.1128/iai.00276-24","DOIUrl":"10.1128/iai.00276-24","url":null,"abstract":"<p><p><i>Pneumocystis jirovecii</i> pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of <i>Pneumocystis</i> while balancing lung inflammation are required. Prior studies have shown that innate immunity to <i>Pneumocystis</i> is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with <i>Card9</i><sup>-/-</sup> infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in <i>Pneumocystis</i> killing. We further demonstrate in the <i>Pneumocystis</i> pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor.IMPORTANCE<i>Pneumocystis</i> pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against <i>Pneumocystis</i>. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of <i>Pneumocystis</i> organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0027624"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2024-12-31DOI: 10.1128/iai.00555-24
Sónia Castanheira, Sara Torronteras, Juan J Cestero, Francisco García-Del Portillo
Type III protein secretion systems (T3SSs) function as multiprotein devices that span the envelope of Gram-negative bacteria using the peptidoglycan (PG) layer as scaffold. This spatial arrangement explains why modifications in PG structure can alter T3SS activity. In Salmonella, incorporation of non-canonical D-amino acids in the PG was shown to decrease the activity of the T3SS encoded by the pathogenicity island-1 (SPI-1) without affecting other T3SS, like the flagellum apparatus. Enigmatically, following invasion of host cell Salmonella enterica serovar Typhimurium modifies PG synthesis by upregulating two pathogen-specific enzymes, the penicillin-binding proteins PBP2SAL and PBP3SAL, with roles in cell elongation and division, respectively. In the mouse typhoid model, the amount of PBP2SAL and PBP3SAL produced by the pathogen exceeds by large those of the canonical enzymes PBP2 and PBP3. This change responds to acidity and high osmolarity, the same cues that intra-phagosomal S. Typhimurium perceives to switch the SPI-1 T3SS by that encoded in SPI-2. Using isogenic mutants lacking each of the four morphogenetic PBPs, we tested whether their activities and those of the T3SS encoded by SPI-1 and SPI-2, are interconnected. Our data show that PBP2 is required for proper function of SPI-1 T3SS but dispensable for motility, whereas the lack of any of the morphogenetic PBPs increases SPI-2 T3SS activity. The positive control exerted by PBP2 on SPI-1 takes place via the SPI-1-specific regulators HilA and InvF. To our knowledge, these findings provide the first evidence linking morphogenetic enzymes that synthesize PG with T3SS associated to virulence.
{"title":"Morphogenetic penicillin-binding proteins control virulence-associated type III secretion systems in <i>Salmonella</i>.","authors":"Sónia Castanheira, Sara Torronteras, Juan J Cestero, Francisco García-Del Portillo","doi":"10.1128/iai.00555-24","DOIUrl":"10.1128/iai.00555-24","url":null,"abstract":"<p><p>Type III protein secretion systems (T3SSs) function as multiprotein devices that span the envelope of Gram-negative bacteria using the peptidoglycan (PG) layer as scaffold. This spatial arrangement explains why modifications in PG structure can alter T3SS activity. In <i>Salmonella,</i> incorporation of non-canonical D-amino acids in the PG was shown to decrease the activity of the T3SS encoded by the pathogenicity island-1 (SPI-1) without affecting other T3SS, like the flagellum apparatus. Enigmatically, following invasion of host cell <i>Salmonella enterica</i> serovar Typhimurium modifies PG synthesis by upregulating two pathogen-specific enzymes, the penicillin-binding proteins PBP2<sub>SAL</sub> and PBP3<sub>SAL</sub>, with roles in cell elongation and division, respectively. In the mouse typhoid model, the amount of PBP2<sub>SAL</sub> and PBP3<sub>SAL</sub> produced by the pathogen exceeds by large those of the canonical enzymes PBP2 and PBP3. This change responds to acidity and high osmolarity, the same cues that intra-phagosomal <i>S</i>. Typhimurium perceives to switch the SPI-1 T3SS by that encoded in SPI-2. Using isogenic mutants lacking each of the four morphogenetic PBPs, we tested whether their activities and those of the T3SS encoded by SPI-1 and SPI-2, are interconnected. Our data show that PBP2 is required for proper function of SPI-1 T3SS but dispensable for motility, whereas the lack of any of the morphogenetic PBPs increases SPI-2 T3SS activity. The positive control exerted by PBP2 on SPI-1 takes place via the SPI-1-specific regulators HilA and InvF. To our knowledge, these findings provide the first evidence linking morphogenetic enzymes that synthesize PG with T3SS associated to virulence.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0055524"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}