Infection and Immunity最新文献

{"title":"A type VI secretion system in <i>Burkholderia</i> species <i>cenocepacia</i> and <i>orbicola</i> triggers distinct macrophage death pathways independent of the pyrin inflammasome.","authors":"Nicole A Loeven, Clarrisa Dabi, Joseph P Pennington, Arianna D Reuven, Abigail P McGee, Bethany W Mwaura, James B Bliska","doi":"10.1128/iai.00316-24","DOIUrl":"10.1128/iai.00316-24","url":null,"abstract":"<p><p>The <i>Burkholderia cepacia</i> complex contains opportunistic pathogens that cause chronic infections and inflammation in the lungs of people with cystic fibrosis. Two closely related species within this complex are <i>Burkholderia cenocepacia</i> and the recently classified <i>Burkholderia orbicola. B. cenocepacia</i> and <i>B. orbicola</i> encode a type VI secretion system and the effector TecA, which is detected by the pyrin/caspase-1 inflammasome, and triggers macrophage inflammatory death. We previously showed that the pyrin inflammasome was dispensable for lung inflammation in mice infected with <i>B. orbicola</i> AU1054<i>,</i> indicating this species activates an alternative pathway of macrophage inflammatory death. Notably, <i>B. cenocepacia</i> strains J2315 and K56-2 can damage macrophage phagosomes, and K56-2 triggers activation of the caspase-11 inflammasome, which detects cytosolic lipopolysaccharide. Here, we investigated inflammatory cell death in pyrin- (<i>Mefv</i>^-/-) or caspase-1/caspase-11- (<i>Casp1/11^-/-</i>) deficient mouse macrophages infected with <i>B. cenocepacia</i> J2315 or K56-2 or <i>B. orbicola</i> AU1054 or PC184. Macrophage inflammatory death was measured by cleavage of gasdermin D protein, the release of cytokines IL-1α and IL-1β, and plasma membrane rupture. We found that J2315 and K56-2 are detected by the caspase-11 inflammasome in <i>Mefv</i>^-/- macrophages, resulting in IL-1β release. By contrast, inflammasome activation was not detected in <i>Mefv</i>^-/- macrophages infected with AU1054 or PC184. Instead, AU1054 triggered an alternative macrophage inflammatory death pathway that required TecA and resulted in plasma membrane rupture and IL-1α release. Structural modeling of TecA orthologs in <i>B. cenocepacia</i> and <i>B. orbicola</i> suggested that amino acid changes in the latter may underlie its ability to trigger a non-inflammasome macrophage death pathway.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0031624"},"PeriodicalIF":2.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance.","authors":"Erica C Larson, Amy L Ellis, Mark A Rodgers, Abigail K Gubernat, Janelle L Gleim, Ryan V Moriarty, Alexis J Balgeman, Yonne T de Menezes, Cassaundra L Ameel, Daniel J Fillmore, Skyler M Pergalske, Jennifer A Juno, Pauline Maiello, Harris B Chishti, Philana Ling Lin, Dale I Godfrey, Stephen J Kent, Daniel G Pellicci, Lishomwa C Ndhlovu, Shelby L O'Connor, Charles A Scanga","doi":"10.1128/iai.00313-24","DOIUrl":"10.1128/iai.00313-24","url":null,"abstract":"<p><p>Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium <i>Mycobacterium tuberculosis</i> (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children despite <i>in vitro</i> evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4- to 8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, (<i>n</i> = 5; i.v.) at 3 and 17 days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group (<i>n</i> = 5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy 8 weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0031324"},"PeriodicalIF":2.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Mycoplasma hyopneumoniae</i> inhibits the unfolded protein response to prevent host macrophage apoptosis and M2 polarization.","authors":"Tong Liu, Yujuan Zhang, Huanjun Zhao, Qi Wu, Jiuqing Xin, Qiao Pan","doi":"10.1128/iai.00051-24","DOIUrl":"10.1128/iai.00051-24","url":null,"abstract":"<p><p>Enzootic pneumonia caused by <i>Mycoplasma hyopneumoniae</i> (<i>M. hyopneumoniae</i>) has inflicted substantial economic losses on the global pig industry. The progression of <i>M. hyopneumoniae</i> induced-pneumonia is associated with lung immune cell infiltration and extensive proinflammatory cytokine secretion. Our previous study established that <i>M. hyopneumoniae</i> disrupts the host unfolded protein response (UPR), a process vital for the survival and immune function of macrophages. In this study, we demonstrated that <i>M. hyopneumoniae</i> targets the UPR- and caspase-12-mediated endoplasmic reticulum (ER)-associated classical intrinsic apoptotic pathway to interfere with host cell apoptosis signaling, thereby preserving the survival of host tracheal epithelial cells (PTECs) and alveolar macrophages (PAMs) during the early stages of infection. Even in the presence of apoptosis inducers, host cells infected with <i>M. hyopneumoniae</i> exhibited an anti-apoptotic potential. Further analyses revealed that <i>M. hyopneumoniae</i> suppresses the three UPR branches and their induced apoptosis. Interestingly, while UPR activation typically drives host macrophages toward an M2 polarization phenotype, <i>M. hyopneumoniae</i> specifically obstructs this process to maintain a proinflammatory phenotype in the host macrophages. Overall, our findings propose that <i>M. hyopneumoniae</i> inhibits the host UPR to sustain macrophage survival and a proinflammatory phenotype, which may be implicated in its pathogenesis in inducing host pneumonia.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0005124"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916557","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}

{"title":"Therapeutic glycan-specific antibody binding mediates protection during primary amoebic meningoencephalitis.","authors":"Annie Park Moseman, Ching-Wen Chen, Xiaoe Liang, Dongmei Liao, Masayuki Kuraoka, E Ashley Moseman","doi":"10.1128/iai.00183-24","DOIUrl":"10.1128/iai.00183-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Naegleria fowleri&lt;/i&gt; (&lt;i&gt;N. fowleri&lt;/i&gt;) infection &lt;i&gt;via&lt;/i&gt; the upper respiratory tract causes a fatal CNS disease known as primary amoebic meningoencephalitis (PAM). The robust &lt;i&gt;in vivo&lt;/i&gt; immune response to &lt;i&gt;N. fowleri infection&lt;/i&gt; underlies the immunopathology that characterizes the disease. However, little is known about why this pathogen evades immune control. Infections occur in seemingly healthy individuals and effective clinical options are lacking, thus a nearly 98% fatality rate. It is unclear how or if host factors may contribute to susceptibility or disease exacerbation, yet mechanistic studies of the &lt;i&gt;in vivo&lt;/i&gt; immune response and disease progression are hampered by a lack of tools. In this study, we have generated monoclonal antibodies to &lt;i&gt;N. fowleri&lt;/i&gt; surface antigens and shown them to be excellent tools for studying the &lt;i&gt;in vivo&lt;/i&gt; immune response. We also identified one monoclonal, 2B6, with potent inherent anti-amoebastatic activity &lt;i&gt;in vitro&lt;/i&gt;. This antibody is also able to therapeutically prolong host survival &lt;i&gt;in vivo&lt;/i&gt; and furthermore, recombinant antibodies with an isotype more capable of directing immune effector activity further improved survival when given therapeutically. Thus, we report the generation of a novel monoclonal antibody to &lt;i&gt;N. fowleri&lt;/i&gt; that can enhance beneficial immune functions, even when given therapeutically during disease. We believe this provides evidence for the potential of therapeutic antibody treatments in PAM.IMPORTANCE&lt;i&gt;Naegleria fowleri&lt;/i&gt; (&lt;i&gt;N. fowleri&lt;/i&gt;) is a free-living amoeba that is found ubiquitously in warm freshwater. While human exposure is common, it rarely results in pathogenesis. However, when &lt;i&gt;N. fowleri&lt;/i&gt; gains access to the upper airway, specifically the olfactory mucosa, infection leads to a lethal disease known as primary amoebic meningoencephalitis (PAM). As a free-living amoeba, &lt;i&gt;N. fowleri&lt;/i&gt; does not need a mammalian host; indeed, it can be accurately described as an accidental opportunistic pathogen. While most opportunistic infections occur in humans who are immunocompromised, there are no reported immune dysfunctions associated with &lt;i&gt;N. fowleri&lt;/i&gt; infection. Therefore, the basis for &lt;i&gt;N. fowleri&lt;/i&gt; opportunism is not known, and the reasons why some humans develop PAM while others do not are simply not well understood. It is reasonable to speculate that local or acute immune failures, potentially even a lack of prior adaptive immunity, are related to disease susceptibility. Careful immune profiling and characterization of the &lt;i&gt;in vivo&lt;/i&gt; immune response to &lt;i&gt;N. fowleri&lt;/i&gt; in a mammalian host are desperately needed to understand which host factors are critical to defense, and how these responses might be compromised in a way that results in lethal infection. To identify genes and pathways that provide resistance against &lt;i&gt;in vivo N. fowleri&lt;/i&gt; infection, we generated surface reactive monoclonal antibodies (A","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0018324"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132619","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}

{"title":"The host GTPase Dynamin 2 modulates apical junction structure to control cell-to-cell spread of <i>Listeria monocytogenes</i>.","authors":"Serena Tijoriwalla, Thiloma Liyanage, Thilina U B Herath, Nicole Lee, Attika Rehman, Antonella Gianfelice, Keith Ireton","doi":"10.1128/iai.00136-24","DOIUrl":"10.1128/iai.00136-24","url":null,"abstract":"<p><p>The food-borne pathogen <i>Listeria monocytogenes</i> uses actin-based motility to generate plasma membrane protrusions that mediate the spread of bacteria between host cells. In polarized epithelial cells, efficient protrusion formation by <i>L. monocytogenes</i> requires the secreted bacterial protein InlC, which binds to a carboxyl-terminal Src homology 3 (SH3) domain in the human scaffolding protein Tuba. This interaction antagonizes Tuba, thereby diminishing cortical tension at the apical junctional complex and enhancing <i>L. monocytogenes</i> protrusion formation and spread. Tuba contains five SH3 domains apart from the domain that interacts with InlC. Here, we show that human GTPase Dynamin 2 associates with two SH3 domains in the amino-terminus of Tuba and acts together with this scaffolding protein to control the spread of <i>L. monocytogenes</i>. Genetic or pharmacological inhibition of Dynamin 2 or knockdown of Tuba each restored normal protrusion formation and spread to a bacterial strain deleted for the <i>inlC</i> gene (∆<i>inlC</i>). Dynamin 2 localized to apical junctions in uninfected human cells and protrusions in cells infected with <i>L. monocytogenes</i>. Localization of Dynamin 2 to junctions and protrusions depended on Tuba. Knockdown of Dynamin 2 or Tuba diminished junctional linearity, indicating a role for these proteins in controlling cortical tension. Infection with <i>L. monocytogenes</i> induced InlC-dependent displacement of Dynamin 2 from junctions, suggesting a possible mechanism of antagonism of this GTPase. Collectively, our results show that Dynamin 2 cooperates with Tuba to promote intercellular tension that restricts the spread of ∆<i>inlC Listeria</i>. By expressing InlC, wild-type <i>L. monocytogenes</i> overcomes this restriction.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0013624"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916559","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}

{"title":"The impact of butyrate on group B <i>Streptococcus</i>-induced intestinal barrier disruption.","authors":"Kristen Dominguez, Alexia N Pearah, April K Lindon, Leigh-Anne M Worthington, Rico R Carter, Nichol John-Lewis Edwards, Thao T B Ho, Sophie E Darch, Tara M Randis","doi":"10.1128/iai.00200-24","DOIUrl":"10.1128/iai.00200-24","url":null,"abstract":"<p><p>Group B Streptococcus (<i>Streptococcus agalactiae</i>; GBS) is a leading cause of neonatal sepsis worldwide. As a pathobiont of the intestinal tract, it is capable of translocating across barriers leading to invasive disease. Neonatal susceptibility to invasive disease stems from immature intestinal barriers. GBS intestinal colonization induces major transcriptomic changes in the intestinal epithelium related to barrier function. Butyrate, a microbial metabolite produced by fermentation of dietary fiber, bolsters intestinal barrier function against enteric pathogens, and these effects can be transferred <i>in utero</i> via the placenta to the developing fetus. Our aim was to determine if butyrate mitigates GBS disruption of intestinal barriers. We used human intestinal epithelial cell (IEC) lines to evaluate the impact of butyrate on GBS-induced cell death and GBS adhesion and invasion. IECs and human fetal tissue-derived enteroids were used to evaluate monolayer permeability. We evaluated the impact of maternal butyrate treatment (mButyrate) using our established mouse model of neonatal GBS intestinal colonization and late-onset sepsis. We found that butyrate reduces GBS-induced cell death, GBS invasion, monolayer permeability, and translocation <i>in vitro</i>. In mice, mButyrate decreases GBS intestinal burden in offspring. Our results demonstrate the importance of bacterial metabolites, such as butyrate, in their potential to bolster epithelial barrier function and mitigate neonatal sepsis risk.IMPORTANCEGroup B <i>Streptococcus</i> (GBS) is a leading cause of neonatal morbidity and mortality. It is a commensal of the intestines that can translocate across barriers leading to sepsis in vulnerable newborns. With the rise in antibiotic-resistant strains and no licensed vaccine, there is an urgent need for preventative strategies. Butyrate, a short-chain fatty acid metabolized in the gut, enhances barrier function against pathogens. Importantly, butyrate is transferred <i>in utero</i>, conferring these benefits to infants. Here, we demonstrate that butyrate reduces GBS colonization and epithelial invasion. These effects were not microbiome-driven, suggesting butyrate directly impacts epithelial barrier function. Our results highlight the potential impact of maternal dietary metabolites, like butyrate, as a strategy to mitigate neonatal sepsis risk.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0020024"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916560","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}

{"title":"Protective innate immunity against <i>Pneumocystis</i> does not require Stat6-dependent macrophage polarization.","authors":"T Mousso, S J Pollock, P C Inzerillo, F Gigliotti, T W Wright","doi":"10.1128/iai.00222-24","DOIUrl":"10.1128/iai.00222-24","url":null,"abstract":"<p><p><i>Pneumocystis</i> species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. <i>Pneumocystis</i> typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against <i>Pneumocystis</i>, and remain resistant to infection even in the absence of CD4⁺ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with <i>Pneumocystis</i>, suggesting that macrophage polarization may dictate the outcome of the <i>Pneumocystis</i>-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6^-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6^-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6^-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with <i>Pneumocystis</i>. Additional FVB/NJ knockout strains were generated, but only FVB MerTK^-/- mice showed a marginally increased susceptibility to <i>Pneumocystis</i> infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against <i>Pneumocystis</i> does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0022224"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987856","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}

{"title":"Articles of Significant Interest in This Issue.","authors":"","doi":"10.1128/iai.00437-24","DOIUrl":"https://doi.org/10.1128/iai.00437-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":"92 10","pages":"e0043724"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464293","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}

{"title":"NLRP3 inflammasome inhibition decreases <i>Schistosomiasis japonica</i>-induced granulomatous inflammation and fibrosis in BALB/c mice.","authors":"Yaqi Lu, Jing Liu, Wangxian Tang, Heng Zhang","doi":"10.1128/iai.00055-24","DOIUrl":"10.1128/iai.00055-24","url":null,"abstract":"<p><p>To research the role of the NLRP3 inflammasome in <i>Schistosoma japonicum</i>-induced granuloma formation and liver fibrosis. In <i>in vivo</i> tests, BALB/c mice were used. shNLRP3 plasmid based on adeno-associated virus serotype 8 (AAV8-shNLRP3) was injected to block NLRP3 inflammasome via tail vein. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected to assess liver injury. H&E staining was used for routine histopathological assessment; Masson's trichrome staining was used to detect fibrous tissues and collagen fibers. Hepatic expression of NLRP3, procaspase-1, bioactive caspase-1, collagen-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot. Serum levels of IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The inflammatory cell infiltration and hepatic expression of IL-1β around the granuloma were detected by immunohistochemistry staining. Treatment of <i>S. japonicum</i> infected mice with AAV8-shNLRP3 significantly reduced the hepatic levels of bioactive caspase-1 and IL-1β, as well as circulating IL-1β concentrations, while reducing the amounts of myeloperoxidase (MPO) and F4/80 positive cells around the granuloma. Moreover, collagen deposition, TIMP-1, and α-SMA, which are markers of hepatic stellate cell (HSC) activation, were reduced around the liver granuloma. These findings highlight a therapeutic potential of AAV8-shNLRP3 in schistosomiasis cirrhosis.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0005524"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999846","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}

{"title":"<i>Akkermansia muciniphila</i> alleviates abdominal aortic aneurysms via restoring CITED2 activated by EPAS1.","authors":"Siqing Wang, Hang Shi, Yue Cheng, Lei Jiang, Yang Lou, Manish Kumar, Mingfei Sun, Xianze Shao, Xuan Zhao, Baichun Wang","doi":"10.1128/iai.00172-24","DOIUrl":"10.1128/iai.00172-24","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease that has been linked to gut microbiome dysbiosis. Therefore, this study aims to investigate the effects of <i>Akkermansia muciniphila</i> (<i>Am</i>) on AAA mice and the biomolecules involved. AAA mice were generated using angiotensin II (Ang II), and 16sRNA sequencing was used to identify an altered abundance of microbiota in the feces of AAA mice. Vascular smooth muscle cell (VSMC) markers and apoptosis, and macrophage infiltration in mouse aortic tissues were examined. The abundance of <i>Am</i> was reduced in AAA mouse feces, and endothelial PAS domain-containing protein 1 (EPAS1) was downregulated in AAA mice and VSMC induced with Ang II. <i>Am</i> delayed AAA progression in mice, which was blunted by knockdown of EPAS1. EPAS1 was bound to the Cbp/p300-interacting transactivator 2 (CITED2) promoter and promoted CITED2 transcription. CITED2 reduced VSMC apoptosis and delayed AAA progression. Moreover, EPAS1 inhibited macrophage inflammatory response by promoting CITED2 transcription. In conclusion, gut microbiome dysbiosis in AAA induces EPAS1-mediated dysregulation of CITED2 to promote macrophage inflammatory response and VSMC apoptosis.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0017224"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107026","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}