Infection and Immunity最新文献

{"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":"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":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784352/pdf/","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":"OA","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":"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":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784141/pdf/","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":"OA","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":"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":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784295/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.","authors":"Aayush Bahl, Saurabh Pandey, Roopshali Rakshit, Sashi Kant, Deeksha Tripathi","doi":"10.1128/iai.00472-24","DOIUrl":"10.1128/iai.00472-24","url":null,"abstract":"<p><p>In contrast to adaptive immunity, which relies on memory T and B cells for long-term pathogen-specific responses, trained immunity involves the enhancement of innate immune responses through cellular reprogramming. Experimental evidence from animal models and human studies supports the concept of trained immunity and its potential therapeutic applications in the development of personalized medicine. However, there remains a huge gap in understanding the mechanisms, identifying specific microbial triggers responsible for the induction of trained immunity. This underscores the importance of investigating the potential role of trained immunity in redefining host defense and highlights future research directions. This minireview will provide a comprehensive summary of the new paradigm of trained immunity or innate memory pathways. It will shed light on infection-induced pathways through non-specific stimulation within macrophages and natural killer cells, which will be further elaborated in multiple disease perspectives caused by infectious agents such as bacteria, fungi, and viruses. The article further elaborates on the biochemical and cellular basis of trained immunity and its impact on disease status during recurrent exposures. The review concludes with a perspective segment discussing potential therapeutic benefits, limitations, and future challenges in this area of study. The review also sheds light upon potential risks involved in the induction of trained immunity.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0047224"},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800612","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 ability of <i>sarA</i> to limit protease production plays a key role in the pathogenesis of <i>Staphylococcus aureus</i> osteomyelitis irrespective of the functional status of <i>agr</i>.","authors":"Karen E Beenken, Mara J Campbell, Mark S Smeltzer","doi":"10.1128/iai.00473-24","DOIUrl":"10.1128/iai.00473-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;We demonstrate that mutation of the staphylococcal accessory regulator A (&lt;i&gt;sarA&lt;/i&gt;) in the USA300 strain LAC limits virulence in a murine osteomyelitis model to a greater extent than mutation of the accessory gene regulator (&lt;i&gt;agr&lt;/i&gt;) and that it does so irrespective of the functional status of &lt;i&gt;agr&lt;/i&gt;. Protease production was decreased in the &lt;i&gt;agr&lt;/i&gt; mutant but increased in &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA/agr&lt;/i&gt; mutants to a degree that limited biofilm formation. Extracellular protein A (eSpa) and full-length extracellular nuclease (Nuc1) were absent in the conditioned medium (CM) from &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA&lt;/i&gt;/&lt;i&gt;agr&lt;/i&gt; mutants, and their abundance was restored in both mutants by eliminating protease production. Cytotoxicity of CM for osteoblasts and osteoclasts was also reduced in both mutants. Cytotoxicity was restored in a protease-deficient &lt;i&gt;sarA&lt;/i&gt; mutant but not in the protease-deficient &lt;i&gt;sarA&lt;/i&gt;/&lt;i&gt;agr&lt;/i&gt; mutant. Reduced cytotoxicity was correlated with the reduced abundance of full-length α-toxin, LukF, and LukS in &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA&lt;/i&gt;/&lt;i&gt;agr&lt;/i&gt; mutants. The abundance of these toxins in their full-length form was increased in the protease-deficient &lt;i&gt;sarA&lt;/i&gt; mutant by comparison to LAC, demonstrating that mutation of &lt;i&gt;sarA&lt;/i&gt; increases the production of these toxins but increased protease production limits their abundance in full-length and presumably functional forms. Most importantly, eliminating protease production enhanced the virulence of &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA/agr&lt;/i&gt; mutants, but had no impact in the &lt;i&gt;agr&lt;/i&gt; mutant. We conclude that a key factor in the attenuation of LAC &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA&lt;/i&gt;/&lt;i&gt;agr&lt;/i&gt; mutants in osteomyelitis is the increased production of extracellular proteases and its impact on virulence factors that contribute to biofilm formation and cytotoxicity.&lt;b&gt;IMPORTANCE&lt;/b&gt;The persistent emergence of antibiotic-resistant strains has rekindled interest in anti-virulence strategies to combat &lt;i&gt;S. aureus&lt;/i&gt; infections. Numerous reports describe anti-virulence strategies focusing on key regulatory elements that globally influence virulence factor production, the two most commonly targeted being the accessory gene regulator (&lt;i&gt;agr&lt;/i&gt;) and the staphylococcal accessory regulator A (&lt;i&gt;sarA&lt;/i&gt;). We demonstrate that mutation of &lt;i&gt;sarA&lt;/i&gt; limits virulence to a greater extent than mutation of &lt;i&gt;agr&lt;/i&gt; and that this can be attributed to increased protease production in both &lt;i&gt;sarA&lt;/i&gt; and &lt;i&gt;sarA&lt;/i&gt;/&lt;i&gt;agr&lt;/i&gt; mutants. This illustrates the critical role of &lt;i&gt;sarA&lt;/i&gt; in protease-mediated post-translational regulation in &lt;i&gt;S. aureus&lt;/i&gt;. It also suggests that an inhibitor of &lt;i&gt;sarA&lt;/i&gt; would be more effective than an inhibitor of &lt;i&gt;agr&lt;/i&gt; in overcoming the therapeutic recalcitrance of osteomyelitis and that such an inhibitor would remain effective even in the context of &lt;i&gt;agr&lt;/i&gt; mutants known to arise &lt;i&gt;in vivo&lt;/i&gt; during the transition from acute to chronic infection","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0047324"},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750756","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":"Expression of Concern for Galdiero et al., \"<i>Haemophilus influenzae</i> Porin Contributes to Signaling of the Inflammatory Cascade in Rat Brain\".","authors":"","doi":"10.1128/iai.00490-24","DOIUrl":"10.1128/iai.00490-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0049024"},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750713","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":"Proinflammatory synergy between protease and superantigen streptococcal pyogenic exotoxins.","authors":"Anders F Johnson, Summer D Bushman, Doris L LaRock, Juan Manuel Díaz, John K McCormick, Christopher N LaRock","doi":"10.1128/iai.00405-24","DOIUrl":"10.1128/iai.00405-24","url":null,"abstract":"<p><p>Streptococcal pyogenic exotoxins (Spe proteins) secreted by <i>Streptococcus pyogenes</i> (group A <i>Streptococcus</i>, GAS) are responsible for scarlet fever and streptococcal toxic shock syndrome. Most Spes are superantigens that cause excessive inflammation by activating large numbers of T cells. However, Streptococcal pyogenic exotoxin B (SpeB) is an exception, which is pro-inflammatory through its protease activity. Prior work shows that SpeB has the potential to cleave bacterial proteins. If cleavage of superantigens results in their inactivation, this gives the possibility that these two classes of exotoxins work at cross-purposes. We examined SpeB cleavage of the 11 major GAS superantigens and found that lability was not specific to structure, conservation, or, when compared to orthologous superantigens from <i>Staphylococcus aureus</i>, species of origin. We further show that rather than strictly antagonizing superantigen activity through degradation, SpeB can synergistically enhance superantigen-induced inflammation. For SpeB-labile superantigens, such as SmeZ, this is limited due to degradation, but for protease-resistant superantigens like SpeA, activity remains synergistic even at high protease concentrations. These findings suggest two modes by which proteases like SpeB may post-translationally regulate superantigens: positively, as a force amplifier that cooperatively increases inflammation, and negatively, through degradation that could act as a rheostat-like mechanism to limit excessive immune activation. Both mechanisms may contribute to the pathogenesis of GAS and other superantigen-producing pathogens.<b>IMPORTANCE</b><i>Streptococcus pyogenes</i> produces both superantigen and protease virulence factors to subvert host immunity. However, its major protease is highly promiscuous and would potentially limit superantigen activity through its degradation. We profile the sensitivity of the streptococcal superantigens to degradation by the protease SpeB, providing evidence that many are highly resistant. Furthermore, we show that these important toxins can have synergistic proinflammatory activity. This provides insight into diseases like scarlet fever and toxic shock syndrome caused by these toxins and suggests anti-inflammatories that may be therapeutically useful.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0040524"},"PeriodicalIF":2.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059024","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":"Evidence that staphylococcal superantigens promote within-patient bacterial persistence following post-operative surgical site infection.","authors":"Karine Dufresne, Stephen W Tuffs, Nicholas R Walton, Katherine J Kasper, Ivor Mohorovic, Farah Hasan, Tracey Bentall, David E Heinrichs, Johan Delport, Tina S Mele, John K McCormick","doi":"10.1128/iai.00407-24","DOIUrl":"https://doi.org/10.1128/iai.00407-24","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> is a predominant cause of post-operative surgical site infections and persistent bacteremia. Here, we describe a patient who experienced three episodes of <i>S. aureus</i> infection over a period of 4 months following a total knee arthroplasty. The initial bloodstream isolate (SAB-0429) was a clonal complex 5 (CC5) and methicillin-resistant <i>S. aureus</i> (MRSA), whereas two subsequent isolates (SAB-0485 and SAB-0495) were CC5 isolates but methicillin-sensitive <i>S. aureus</i>. The two latter isolates harbored a plasmid encoding three superantigen genes that were not present in the primary MRSA isolate. SAB-0485 and SAB-0495 both expressed the plasmid-encoded staphylococcal enterotoxin R exotoxin and demonstrated increased superantigen activity compared with SAB-0429. Compared to SAB-0429, the latter isolates also demonstrated an increased bacterial burden in a mouse bacteremia model that was dependent on increased interferon-γ production. Curing of the plasmid from SAB-0485 reduced this virulence phenotype. These findings suggest that the superantigen exotoxins may provide a selective advantage in chronic post-surgical infections.IMPORTANCEIn this study, we investigated bacterial isolates from a patient who experienced three recurrent <i>S. aureus</i> infections over a 4 month period following total knee arthroplasty. Genomic and phenotypic characterization of these isolates revealed that they all belonged to clonal complex 5, yet the latter two strains contained an additional plasmid encoding superantigen exotoxins. Subsequent experimental infection experiments in mice demonstrated that the plasmid-encoded superantigens exacerbated bacteremia by promoting liver abscess formation. These experiments suggest that despite appropriate antibiotic therapy, bacterial superantigens may be able to promote persistent infection following post-surgery.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0040724"},"PeriodicalIF":2.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059023","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 interplay between <i>Acinetobacter baumannii</i> ZigA and SltB promotes zinc homeostasis and cell envelope integrity.","authors":"Jeanette M Critchlow, Juan P Barraza, Matthew J Munneke, Evan Krystofiak, Erin R Green, Eric P Skaar","doi":"10.1128/iai.00422-24","DOIUrl":"10.1128/iai.00422-24","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is an opportunistic human pathogen that acquires nutrient metals from the vertebrate host amid infection. During zinc (Zn) scarcity, <i>A. baumannii</i> upregulates the expression of the predicted Zn metallochaperone, <i>zigA</i>. Loss of <i>zigA</i> compromises fitness during Zn deficiency, highlighting its role in this condition. To assess the contribution of ZigA to Zn-deficient <i>A. baumannii</i>, a multiparallel transposon sequencing and genetic interaction mapping approach was used. Transposon insertions in <i>A1S_3027</i>, encoding a predicted soluble lytic transglycosylase that tailors the bacterial cell wall, were enriched in the Zn-starved Δ<i>zigA</i> transposon library. Based on previous studies as well as structural and sequence homology, we designated A1S_3027 as <u>s</u>oluble <u>l</u>ytic <u>t</u>ransglycosylase <u>B</u> (SltB). Further analyses revealed that inactivating <i>sltB</i> rescued Δ<i>zigA</i> fitness defects during Zn starvation. An <i>A. baumannii</i> Δ<i>zigA</i>Δ<i>sltB</i> mutant demonstrated altered cell envelope structures and increased cellular permeability, highlighting the roles of ZigA and SltB in maintaining cell envelope integrity. Furthermore, these mutants exhibited heightened resistance to β-lactam antibiotics and other cell wall-targeting agents. Alterations in cell envelope integrity in the Δ<i>zigA</i>Δ<i>sltB</i> mutant improved fitness in a murine pneumonia infection model, emphasizing the contribution of ZigA and SltB to <i>A. baumannii</i> pathogenesis. This study elucidates how functional interactions between ZigA and SltB modulate cell envelope integrity and pathogenesis of <i>A. baumannii</i> during Zn depletion. These findings reveal an interplay between metal homeostasis and cell envelope integrity, offering insights into how <i>A. baumannii</i> ZigA contributes to these critical cellular processes.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0042224"},"PeriodicalIF":2.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023256","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":"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":"https://doi.org/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":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}