Infection and Immunity最新文献

{"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":"https://doi.org/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_SAL and PBP3_SAL, with roles in cell elongation and division, respectively. In the mouse typhoid model, the amount of PBP2_SAL and PBP3_SAL 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":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/10.1128/iai.00276-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Pneumocystis jirovecii&lt;/i&gt; 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 &lt;i&gt;Pneumocystis&lt;/i&gt; while balancing lung inflammation are required. Prior studies have shown that innate immunity to &lt;i&gt;Pneumocystis&lt;/i&gt; 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 &lt;i&gt;Card9&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in &lt;i&gt;Pneumocystis&lt;/i&gt; killing. We further demonstrate in the &lt;i&gt;Pneumocystis&lt;/i&gt; 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&lt;i&gt;Pneumocystis&lt;/i&gt; 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 &lt;i&gt;Pneumocystis&lt;/i&gt;. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of &lt;i&gt;Pneumocystis&lt;/i&gt; 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":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/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":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/10.1128/iai.00445-24","url":null,"abstract":"<p><p>The composition of the respiratory track 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":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A newly developed oral infection mouse model of shigellosis for immunogenicity and protective efficacy studies of a candidate vaccine.","authors":"Risha Haldar, Prolay Halder, Hemanta Koley, Shin-Ichi Miyoshi, Santasabuj Das","doi":"10.1128/iai.00346-24","DOIUrl":"https://doi.org/10.1128/iai.00346-24","url":null,"abstract":"<p><p><i>Shigella</i> infection poses a significant public health challenge in the developing world. However, lack of a widely available mouse model that replicates human shigellosis creates a major bottleneck to better understanding of disease pathogenesis and development of newer drugs and vaccines. BALB/c mice pre-treated with streptomycin and iron (FeCl₃) plus desferrioxamine intraperitoneally followed by oral infection with virulent <i>Shigella flexneri 2a</i> resulted in diarrhea, loss of body weight, bacterial colonization and progressive colitis characterized by disruption of epithelial lining, loss of crypt architecture with goblet cell depletion, increased polymorphonuclear infiltration into the mucosa, submucosal swelling (edema), and raised proinflammatory cytokines and chemokines in the large intestine. To evaluate the usefulness of the model for vaccine efficacy studies, mice were immunized intranasally with a recombinant protein vaccine containing <i>Shigella</i> invasion protein invasion plasmid antigen B (IpaB). Vaccinated mice conferred protection against <i>Shigella</i>, indicating that the model is suitable for testing of vaccine candidates. To protect both <i>Shigella</i> and <i>Salmonella</i>, a chimeric recombinant vaccine (rIpaB-T2544) was developed by fusing IpaB with <i>Salmonella</i> outer membrane protein T2544. Vaccinated mice developed antigen-specific serum IgG and IgA antibodies and a balanced Th1/Th2 response and were protected against oral challenge with <i>Shigella</i> (<i>S. flexneri 2a</i>, <i>Shigella dysenteriae</i>, and <i>Shigella sonnei</i>) using our present mouse model and <i>Salmonella</i> (<i>Salmonella</i> Typhi and Paratyphi) using an iron overload mouse model. We describe here the development of an oral S<i>higella</i> infection model in wild-type mouse. This model was successfully used to demonstrate the immunogenicity and protective efficacy of a candidate protein subunit vaccine against <i>Shigella</i>.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0034624"},"PeriodicalIF":2.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846619","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>bb0689</i> contributes to the virulence of <i>Borrelia burgdorferi</i> in a murine model of Lyme disease.","authors":"Connor Waldron, Sierra George, Christina Thompson, Yu Hsien Liao, Zhiming Ouyang","doi":"10.1128/iai.00459-24","DOIUrl":"https://doi.org/10.1128/iai.00459-24","url":null,"abstract":"<p><p><i>Borrelia burgdorferi</i>, the Lyme disease pathogen, continuously changes its gene expression profile in order to adapt to ticks and mammalian hosts. The alternative sigma factor RpoS plays a central role in borrelial host adaptation. Global transcriptome analyses suggested that more than 100 genes might be regulated by RpoS, but the main part of the regulon remains unexplored. Here, we showed that the expression of <i>bb0689</i>, a gene encoding an outer surface lipoprotein with unknown function, was activated by RpoS. By analyzing gene expression using luciferase reporter assays and quantitative reverse transcription PCR, we found that expression of <i>bb0689</i> was induced by an elevated temperature, a reduced pH, and increased cell density during <i>in vitro</i> cultivation. The transcriptional start site and a functional promoter for gene expression were identified in the 5' regulatory region of <i>bb0689</i>. The promoter was responsive to environmental stimuli and influenced by RpoS. We also showed that <i>bb0689</i> expression was expressed in <i>B. burgdorferi</i> during animal infection, suggesting the importance of this gene for infection. We further generated a <i>bb0689</i> mutant and found that the infectivity of the mutant was severely attenuated in a murine infection model. Although <i>bb0689</i>-deficient spirochetes exhibited no defect during <i>in vitro</i> growth, they were defective in resistance to osmotic stress. <i>Cis</i>-complementation of the mutant with a wild-type copy of <i>bb0689</i> fully rescued all phenotypes. Collectively, these results demonstrate that the RpoS-regulated gene <i>bb0689</i> is a key contributor to the optimal infection of <i>B. burgdorferi</i> in animals.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0045924"},"PeriodicalIF":2.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827790","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>Rickettsia</i> disrupts and reduces endothelial tight junction protein zonula occludens-1 in association with inflammasome activation.","authors":"Loka Reddy Velatooru, Esteban Arroyave, Meagan D Rippee-Brooks, Megan Burch, Ethan Yang, Bing Zhu, David H Walker, Yang Zhang, Rong Fang","doi":"10.1128/iai.00468-24","DOIUrl":"https://doi.org/10.1128/iai.00468-24","url":null,"abstract":"<p><p><i>Rickettsia</i> spp. cause life-threatening diseases in humans. The fundamental pathophysiological changes in fatal rickettsial diseases are disrupted endothelial barrier and increased microvascular permeability. However, it remains largely unclear how rickettsiae induce microvascular endothelial injury. In the present study, we demonstrated that <i>Rickettsia conorii</i> infection disrupts the continuous immunofluorescence expression of the interendothelial tight junction protein, zonula occludens-1 (ZO-1), in infected monolayers of microvascular endothelial cells (MVECs), accompanied by significantly diminished total expression levels of ZO-1. Interestingly, <i>R. conorii</i> activated inflammasome in MVECs, as evidenced by cleaved caspase-1 and IL-1β in the cell lysates in association with significantly elevated expression levels of nucleotide binding and oligomerization domain, leucine-rich repeat, and pyrin containing protein 3 (NLRP3). Furthermore, selective inhibition of NLRP3 by MCC950 significantly suppressed the activation and cleavage of caspase-1 induced by <i>R. conorii</i> in endothelial cells, which further prevented the disruption of interendothelial junctions and reduction of ZO-1 expression. Of note, pharmaceutical inhibition of NLRP3 mitigated the disrupted endothelial integrity caused by <i>R. conorii</i>, measured by fluorescein isothiocyanate-dextran passage in a Transwell assay, independent of bacterial growth and cellular cytotoxicity. Taken together, our results suggest that <i>R. conorii</i> affected microvascular endothelial junction integrity likely via diminishing and interrupting the junctional protein ZO-1 in association with activating NLRP3 inflammasome. These data not only highlight the potential of ZO-1 as a biomarker for <i>Rickettsia</i>-induced microvascular injury but also provide insight into targeting NLRP3 inflammasome/ZO-1 signaling as a potentially adjunctive therapeutic approach for severe rickettsioses.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0046824"},"PeriodicalIF":2.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827701","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":"Novel broadly reactive monoclonal antibody protects against <i>Pseudomonas aeruginosa</i> infection.","authors":"Margalida Mateu-Borrás, Spencer R Dublin, Jason Kang, Hunter L Monroe, Emel Sen-Kilic, Sarah J Miller, William T Witt, Joshua A Chapman, Gage M Pyles, Shreeram C Nallar, Annalisa B Huckaby, Evita Yang, Carleena Rocuskie-Marker, Megan E Grund, Md Shahrier Amin, Slawomir Lukomski, Greg A Snyder, Krishanu Ray, George K Lewis, Darrell O Ricke, F Heath Damron, Mariette Barbier","doi":"10.1128/iai.00330-24","DOIUrl":"https://doi.org/10.1128/iai.00330-24","url":null,"abstract":"<p><p>The incidence of infections attributed to antimicrobial-resistant (AMR) pathogens has increased exponentially over the recent decades reaching 1.27 million deaths worldwide in 2019. Without intervention, these infections are predicted to cause up to 10 million deaths a year and incur costs of up to 100 trillion US dollars globally by 2050. The emergence of AMR bacteria such as the ESKAPEE pathogens, and in particular <i>Pseudomonas aeruginosa</i> and species from the genus <i>Burkholderia</i>, underscores an urgent need for new therapeutic strategies. Monoclonal antibody (mAb) therapy offers a promising alternative to treat and prevent bacterial infections. In this study, we used peptides from highly conserved areas of the bacterial flagellin to generate monoclonal antibodies capable of broad binding to flagellated Gram-negative bacteria. We generated a broadly reactive IgG2bĸ mAb (WVDC-2109) that recognizes <i>P. aeruginosa, Burkholderia</i> sp., and other Gram-negative pathogens of interest. Characterization of the therapeutic potential of this antibody was determined using <i>P. aeruginosa</i> as model. <i>In vitro</i> characterization of WVDC-2109 demonstrated complement-mediated bactericidal activity and enhanced opsonophagocytosis of <i>P. aeruginosa</i>. Prophylactic administration of WVDC-2109 markedly improved survival and outcome in a lethal sepsis model and a sub-lethal murine pneumonia model of <i>P. aeruginosa</i> infection, reducing bacterial burden and inflammation. These findings suggest that WVDC-2109 and similar FliC-targeting antibodies could be valuable in preventing or treating diseases caused by <i>P. aeruginosa</i> as well as other life-threatening diseases of concern.IMPORTANCEAntimicrobial resistance (AMR) costs hundreds of thousands of lives and billions of dollars annually. To protect the population against these infections, it is imperative to develop new medical countermeasures targeting AMR pathogens like <i>P. aeruginosa</i> and <i>Burkholderia</i> sp. The administration of broadly reactive monoclonal antibodies can represent an alternative to treat and prevent infections caused by multi-drug-resistant bacteria. Unlike vaccines, antibodies can provide protection regardless of the immune status of the infected host. In this study, we generated an antibody capable of recognizing flagellin from <i>P. aeruginosa</i> and <i>B. pseudomallei</i> along with other Gram-negative pathogens of concern. Our findings demonstrate that the administration of the monoclonal antibody WVDC-2109 enhances survival rates and outcomes in different murine models of <i>P. aeruginosa</i> infection. These results carry significant implications in the field given that there are no available vaccines for <i>P. aeruginosa</i>.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0033024"},"PeriodicalIF":2.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817927","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":"Prevalence and features of hypervirulent <i>Klebsiella pneumoniae</i> in respiratory specimens at a US hospital system.","authors":"Christi L McElheny, Alina Iovleva, Nathalie Chen, Dominic Woods, Akansha Pradhan, Jonah L Sonnabend, Aidan R Matunis, Nathan J Raabe, Janet S Lee, Giraldina Trevejo-Nuñez, Daria Van Tyne, Yohei Doi","doi":"10.1128/iai.00486-24","DOIUrl":"https://doi.org/10.1128/iai.00486-24","url":null,"abstract":"<p><p>Hypervirulent <i>Klebsiella pneumoniae</i> (hvKp) strains are considered to be relatively rare in the United States, but cases are increasingly reported. We prospectively and serially collected <i>K. pneumoniae</i> clinical isolates identified in respiratory specimens at a health system in Western Pennsylvania between 2020 and 2022. A total of 273 <i>K</i>. <i>pneumoniae</i> isolates from 216 unique patients were analyzed for markers of hypervirulence by both string test for a hypermucoid phenotype and multiplex PCR to detect isolates carrying cardinal virulence genes <i>rmpA</i>, <i>rmpA2</i>, <i>iutA</i>, and <i>iro</i>. Of the 273 isolates, 13 (4.8%) tested positive by string test including 11 nonduplicate <i>K. pneumoniae</i> isolates, and two of these (0.7%) were positive by PCR for virulence genes <i>rmpA</i>, <i>rmpA2</i>, <i>iutA</i>, and <i>iro</i>. The latter two putative hvKp strains, belonging to sequence types ST23-K1 and ST86-SLV-K2, possessed pLVPK-like plasmids, and were collected from community-associated infections in individuals without known travel histories. Both putative hvKp strains and two additional string test-positive strains were resistant to killing by human serum. The hvKp strains caused significant pneumonia in mice infected by oropharyngeal aspiration, with significantly higher weight loss and increased bacterial burden in the lungs of mice infected with the KL1 (ST23) strain compared to the KL2 (ST86-SLV) strain. We also observed decreased survival of mice infected with the KL1 strain compared to the KL2 strain. These findings add to the growing body of evidence suggesting that hvKp strains, once considered endemic to Asia, may now be circulating in North America.IMPORTANCECertain lineages of <i>Klebsiella pneumoniae</i> are increasingly recognized to cause severe community-associated infection, but information on their prevalence in the United States is limited. In a prospective, sequential cohort of 273 <i>K</i>. <i>pneumoniae</i> respiratory isolates, we identified two of them as genetically defined hypervirulent <i>K. pneumoniae</i>. The isolates were from local residents who developed community-onset pneumonia, suggesting that hypervirulent <i>K. pneumoniae</i> may already be present in the community.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0048624"},"PeriodicalIF":2.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806986","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":"Polycytotoxic T cells mediate antimicrobial activity against intracellular <i>Mycobacterium tuberculosis</i>.","authors":"Marc Zumwinkel, Aaron Chirambo, Markus Zähnle, Max Bürger, Mark Grieshober, Vincent Romahn, Henry Mwandumba, Steffen Stenger","doi":"10.1128/iai.00297-24","DOIUrl":"https://doi.org/10.1128/iai.00297-24","url":null,"abstract":"<p><p>Protection against infections with intracellular bacteria requires the interaction of macrophages and T-lymphocytes, including CD8⁺ T cells. Recently, the expression of natural killer cell receptors NKG2A and NKG2C was introduced as markers of CD8⁺ T-cell subsets. The goal of this study was to functionally characterize human NKG2A and NKG2C-expressing T cells using the major pathogen <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) as a model organism. Sorted NKG2 populations were analyzed for their capacity to proliferate and degranulate and their intracellular expression of cytotoxic molecules. Cytokine release and the effect on bacterial growth were assessed after coculture of NKG2 populations with <i>Mtb</i>-infected macrophages. NKG2A⁺ T cells released higher levels of IFN-γ and IL-10, whereas NKG2C⁺ T cells released higher levels of IL-2, contained the greatest reservoir of intracellular granzyme B and showed a remarkable constitutive level of degranulation. Both subsets inhibited the intracellular growth of <i>Mtb</i> more efficiently than NKG2-negative CD8⁺ T cells. Antimicrobial activity of NKG2⁺ T cells was not associated with the release of cytokines or cytotoxic molecules. However, the frequency of polycytotoxic T cells (P-CTL), defined as CD8⁺ T cells co-expressing granzyme B, perforin, and granulysin, positively correlated with the ability of NKG2-expressing T cells to control <i>Mtb</i>-growth in macrophages. Our results highlight the potential of NKG2-expressing P-CTL to trigger the antibacterial activity of human macrophages. Targeting this population by preventive or therapeutic immune interventions could provide a novel strategy to combat severe infectious diseases such as tuberculosis.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0029724"},"PeriodicalIF":2.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806984","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}