Journal of Infectious Diseases最新文献

{"title":"Modeling predicts shortening of DAA treatment duration to 5 weeks in individuals with recent or chronic infection with HCV RNA negativity at day 7 on treatment.","authors":"Ashish Goyal, Scott J Cotler, Gail V Matthews, Kimberly Page, Tatyana Kushner, Ohad Etzion, Marianne Martinello, Harel Dahari","doi":"10.1093/infdis/jiag260","DOIUrl":"https://doi.org/10.1093/infdis/jiag260","url":null,"abstract":"<p><strong>Background: </strong>Identifying individuals with hepatitis C virus (HCV) infection who could be cured with a shorter duration of direct-acting antivirals (DAA) therapy would support the effort to reach HCV elimination goals. To date, clinical studies of short duration DAA therapy based on early (e.g., days 2 or 7) HCV RNA levels (e.g., <500 IU/ml) have used arbitrary timepoints and viral load thresholds and yielded suboptimal cure rates.</p><p><strong>Methods: </strong>A database of HCV-host parameters was built based on mathematically modeling time to cure in about 300 individuals with recent (duration <12 months) or chronic infection treated with DAAs. 200,000 parameter combinations of viral-host and treatment parameters were generated, each representing an in-silico HCV patient under DAA treatment.</p><p><strong>Results: </strong>We assessed response-guided treatment (RGT) strategies based on whether HCV RNA was undetectable on day 7 or day 14 on-treatment. The analysis predicted that treatment duration could be shortened to 5 or 7 weeks for people with recent or chronic infection who have undetectable HCV RNA at day 7 or day 14 of treatment, respectively.</p><p><strong>Conclusions: </strong>Modeling suggested that most people with recent or chronic HCV treated with DAAs will have undetectable HCV RNA by day 7 or 14 andcould have their treatment duration reduced to 5 or 7 weeks. This modeling-independent RGT approach could improve treatment access, facilitate HCV elimination, and reduce cost, particularly in key populations most affected by HCV, such as people who inject drugs.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postnatal Cytomegalovirus Infection in Preterm Infants ≤28 Weeks: Maternal IgG Effector Function, Risk Factors, Viral Kinetics in Relation to Symptom Onset, and Clinical Outcomes in a Prospective Multicenter Study.","authors":"Yuichiro Sugiyama, Juri Koizumi, Hiroki Kondo, Keita Takahashi, Ryuichi Tanaka, Michio Suzuki, Takako Suzuki, Tetsuo Hattori, Makoto Oshiro, Yoshiaki Sato, Masahiro Hayakawa, Yoshinori Ito, Yuka Torii, Tetsuo Koshizuka","doi":"10.1093/infdis/jiag259","DOIUrl":"https://doi.org/10.1093/infdis/jiag259","url":null,"abstract":"<p><strong>Background: </strong>Postnatal cytomegalovirus (pCMV) infection is a major concern in extremely preterm infants. However, the clinical and maternal immunological factors involved in pCMV transmission and related manifestations remain unclear.</p><p><strong>Methods: </strong>This multicenter prospective cohort study included infants born at ≤28 weeks of gestation. Urine samples were collected within 13 days of life to exclude congenital CMV infection. Serial urine, blood, and breast milk were tested biweekly for CMV load. Maternal serum and breast milk were analyzed for CMV-specific antibodies, IgG subclasses, neutralizing activity, and Fc-mediated effector functions, including antibody-dependent cellular phagocytosis (ADCP). Postnatal CMV infection risk factors and hematological, respiratory, and neurological outcomes were analyzed.</p><p><strong>Results: </strong>Among 139 infants, 84 (60%) had seropositive mothers. pCMV occurred in 14 cases, including 13 (15%) from seropositive mothers and one with an unknown serostatus. Risk factors included short gestational age, premature rupture of membranes (PROM >24 h), repeated antenatal betamethasone administration, and high breast milk CMV load. Notably, 46% (6/13) infants with pCMV experienced prolonged PROM (> 1 week). Maternal ADCP activity was significantly reduced in the pCMV group, whereas neutralizing titers were not predictive. Neutropenia was the most frequent manifestation, and its onset coincided with viremia. Electroencephalographic abnormalities were more common in infants with pCMV.</p><p><strong>Conclusions: </strong>pCMV infection in extremely preterm infants is associated with specific maternal factors and impaired maternal Fcγ-mediated effector function. High pCMV incidence in infants of seropositive mothers with prolonged PROM suggests intrapartum transmission. These findings may help in implementing targeted prevention and guide evaluations of neurodevelopmental outcomes.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A missed early signal of the HIV-tuberculosis syndemic in a 1982 MMWR report.","authors":"Arthur E Pitchenik","doi":"10.1093/infdis/jiag261","DOIUrl":"https://doi.org/10.1093/infdis/jiag261","url":null,"abstract":"","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased in-hospital mortality in immunocompromised individuals hospitalized with COVID-19 during the global pandemic, a multinational cohort study in the EuCARE project.","authors":"Ashley O Roen, Pontus Hedberg, Joana P Ventura Pereira, Maurizio Zazzi, Dovile Juozapaite, Milosz Parczewski, João Domingos, Francis Drobniewski, Giulia Marchetti, Luca Carioti, Pontus Nauclér, Anders Sönnerborg, Björn-Erik Ole Jensen, Francesca Incardona, Alessandro Cozzi-Lepri","doi":"10.1093/infdis/jiag254","DOIUrl":"https://doi.org/10.1093/infdis/jiag254","url":null,"abstract":"<p><strong>Background: </strong>Although COVID-19 is no longer a public health emergency, it remains the most prevalent circulating infectious-like-illness in Europe. Whether immunocompromising conditions (ICCs) still carry increased mortality risk during the Omicron era is unclear.</p><p><strong>Methods: </strong>We conducted a cohort study across EuCARE sites in 8 countries among adults admitted to hospital with COVID-19 between 2020-2023. ICCs and COVID-19 pneumonia at hospitalization were defined using clinical information and ICD-10 codes. Logistic regression and counterfactual mediation analysis was used to compare 28-day in-hospital mortality risk associated with ICCs using COVID-19 pneumonia and vaccination at hospital entry as intermediates. Proportion of the total effect of ICCs mediated and the controlled direct effects (CDEs) were calculated. We also formally tested for interaction between SARS CoV-2 variants and ICCs for mortality risk.</p><p><strong>Findings: </strong>42,488 individuals were included, of which 1,675 (3.9%) had an ICC. 55% were male, median (IQR) age was 67 (52, 79) years. Overall, 4,344 (10.2%) individuals died in hospital. ICCs were associated with increased mortality, OR = 1.49 (1.25, 1.79) with no evidence for an attenuation during the Omicron phase (p-interaction=0.60). Mediation analyses showed that the total effect of ICCs was mediated by vaccination but only weakly by pneumonia. With Omicron, the excess mortality associated with ICC was higher under the scenario that everyone in the cohort was to develop COVID-19 pneumonia [CDE =1.22 (0.09, 1.65)].</p><p><strong>Interpretation: </strong>ICC remains a significant risk factor for in-hospital death, even during the Omicron era, particularly if the infection led to the development of pneumonia.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Declining efficacy of moxifloxacin for Mycoplasma genitalium infection: time for fluoroquinolone-resistance guided therapy?","authors":"Laura G Matthews, Lenka A Vodstrcil, Natasha L Wild, Erica L Plummer, Ivette Aguirre, Kay Htaik, Gerald L Murray, Vesna De Petra, Michelle Sait, Norelle Sherry, Catriona S Bradshaw","doi":"10.1093/infdis/jiag251","DOIUrl":"https://doi.org/10.1093/infdis/jiag251","url":null,"abstract":"<p><strong>Background: </strong>We assessed trends in moxifloxacin-use and efficacy for MG over a decade at Melbourne Sexual Health Centre (MSHC). Specific Mycoplasma genitalium (MG) mutations, namely ParC-S83I, have been associated with moxifloxacin failure. In 2024 MSHC introduced ParC-S83 testing, recommending moxifloxacin for ParC-S83 wildtype infections and alternative regimens if the ParC-S83I mutation was detected. We present preliminary impacts of ParC-S83 testing on moxifloxacin-use and efficacy.</p><p><strong>Methods: </strong>Clients with MG from 2015-2024 were treated with doxycycline preceding macrolide-resistance guided azithromycin or moxifloxacin. Clients with a test-of-cure 14-90 days after completing moxifloxacin who reported >50% adherence and no condomless sex prior to test-of-cure were eligible for efficacy analyses. Proportions with 95% confidence intervals (CIs) were calculated for moxifloxacin-use and efficacy, with trends assessed by logistic regression. Moxifloxacin-use and efficacy were compared in the 12-months before and after introduction of the ParC-S83 assay.</p><p><strong>Results: </strong>From 2015-2024, 2,611/5,739 MG infections received moxifloxacin. Moxifloxacin-use increased from 6.7% (n=19/282; 95%CI:4.1-10.3%) in 2015 to 60.3% (n=482/800; 95%CI:56.8-63.7%) in 2023 (ptrend<0.0001). Efficacy analyses included 1,623 infections. Moxifloxacin-efficacy decreased from 100% (n=11/11) in 2015 to 79.3% (n=238/300, 95%CI:74.3-83.8%) in 2023 (ptrend=0.007). After introduction of the ParC-S83 assay, moxifloxacin-use decreased from 60.3% (n=482/800, 95%CI:56.8-63.7%) in 2023 to 49.2% (n=438/890, 95%CI:45.9-52.6%) in 2024 (p<0.0001) and cure increased from 79.3% (n=238/300, 95%CI:74.3-83.8%) in 2023 to 89.2% (n=116/130, 95%CI:82.6-94.0%, p=0.013) in ParC-S83 wildtype infections.</p><p><strong>Conclusions: </strong>Increasing moxifloxacin-use and declining efficacy reflects rising resistance in our region. Preliminary data suggests a ParC-S83 assay has the potential to improve moxifloxacin- use and cure in this setting.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enterotoxigenic Bacteroides fragilis induces host genotype-specific colonic epithelial and immune responses in mice.","authors":"Taylor Southward, Yongbao Zhuang, Ada Tam, Hana Minsky, Jacqueline Ferri, John Michel, Shaoguang Wu, Xinqun Wu, Tatianna Larman, Franck Housseau, James R White, Cynthia L Sears, Jessica Queen","doi":"10.1093/infdis/jiag247","DOIUrl":"https://doi.org/10.1093/infdis/jiag247","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer pathogenesis involves complex interactions between multiple risk factors including somatic mutations and microbial dysbiosis. A number of individual microbiota members have been implicated in colorectal cancer, including enterotoxigenic strains of Bacteroides fragilis (ETBF). ETBF promotes inflammation in mouse models, which has been mechanistically linked to colon tumorigenesis. We hypothesized that ETBF would promote distinct patterns of colonic damage and inflammation in mice expressing different oncogenic mutations.</p><p><strong>Methods: </strong>Mice expressing mutations in the Apc tumor suppressor gene or the BRAF or Kras oncogenes were colonized with ETBF to induce acute colitis. Seven days after colonization, tissues and stools were collected to assess for colonization, epithelial damage, and local and systemic immune responses.</p><p><strong>Results: </strong>Despite uniform colonization of ETBF across all genotypes and some common features of colitis across groups, Apc, BRAF, and Kras mutations were associated with distinct patterns of colonic epithelial cell injury and goblet cell loss in response to ETBF. RNA sequencing analysis revealed varied transcriptional profiles based on mouse genotype and colon region. Flow cytometry of intra-epithelial leukocytes revealed differential recruitment of myeloid cells based on oncogenic mutation. In particular, mutant BRAF expression was uniquely associated with more systemic inflammation, resistance to goblet cell loss, an interferon-gamma gene signature, and recruitment of a macrophage-like polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) population in the midproximal colon.</p><p><strong>Conclusions: </strong>ETBF promotes acute colitis in mice expressing different oncogenic mutations, but with distinct patterns of colonic epithelial cell damage and inflammation dependent on host oncogene context.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen cyanide generation by Pseudomonas aeruginosa blunts the host innate immune response.","authors":"Csaba Szabo, Sidnéia Sousa Santos, Jacqueline Findlay, Olivier Bremer, Maria Petrosino, Thilo Magnus Philipp, Anna Kierońska-Rudek, Karim Zuhra, Gerry R Boss, Patrice Nordmann","doi":"10.1093/infdis/jiag244","DOIUrl":"https://doi.org/10.1093/infdis/jiag244","url":null,"abstract":"<p><strong>Background: </strong>The biological mediator hydrogen cyanide (HCN) is produced by certain pathogenic bacteria. HCN exerts multiple effects in mammalian cells: at low concentrations it has cytoprotective regulatory effects, whereas at high concentrations it blocks mitochondrial electron transport by inhibiting cytochrome c oxidase, thereby halting cellular metabolism. Here, we evaluated whether bacterial HCN confers resistance to the host immune response. We used Pseudomonas aeruginosa as a model organism, since it is a clinically significant HCN-generating bacterial species and a common cause of nosocomial infections.</p><p><strong>Methods: </strong>The study used bacterial mutants, macrophage co-cultures, cyanide quantification, phagocytosis and bioenergetics assays, and mouse infection models to assess HCN's role in immune evasion.</p><p><strong>Results: </strong>Compared to wild type P. aeruginosa, genetically HCN-deficient bacteria were more susceptible to killing by immune cells in vitro and were cleared more rapidly in mouse models of systemic infection. Increased leukocyte killing was not due to increased phagocytosis. Pharmacological scavenging of HCN (by vitamin B12 or trihistidyl cobinamide) also enhanced leukocyte bacterial killing.</p><p><strong>Conclusions: </strong>These findings support the concept that HCN acts as a bacterial defense mechanism against the host's immune response. Targeting bacterial HCN (through inhibition of its biogenesis or by scavenging) could be a potential therapeutic strategy to improve the immune clearance of P. aeruginosa infections.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host plasma protein biomarkers for tuberculosis disease screening in febrile adults in Tanzania.","authors":"Michael Prodanuk, Noemie Boillat-Blanco, Valérie D'Acremont, Alastair Fung, Kevin C Kain, Theckla Kazimoto, Ian Kitai, Tarsis Mlaganile, Josephine Samaka, Shaun K Morris, Melissa Richard-Greenblatt","doi":"10.1093/infdis/jiag238","DOIUrl":"https://doi.org/10.1093/infdis/jiag238","url":null,"abstract":"<p><strong>Background: </strong>Host circulating biomarkers may enhance access to tuberculosis (TB) diagnostics in low-resource settings. We sought to identify host plasma proteins that differentiate TB disease from other infectious causes of fever.</p><p><strong>Methods: </strong>This secondary analysis of a prospective cohort included outpatients ≥18 years in urban Tanzania presenting with ≤7 days of fever. Fourteen plasma proteins reflecting endothelial and immunoregulatory pathways were evaluated against a composite reference standard including sputum Xpert MTB/RIF, urine lipoarabinomannan, and/or chest x-ray. Multivariable models assessed proteins and symptoms associated with TB diagnosis.</p><p><strong>Results: </strong>Of 507 participants, 40 (7.9%) had TB disease and 467 (92.1%) had other causes of fever. Eight proteins were significantly elevated (p<0.05) in people with TB. Regression modeling identified a four-protein biosignature (sTREM-1, CHI3L1, sTNFR-1, and CRP) with a cross-validated median AUC of 0.81 (2.5th-97.5th percentiles: 0.65-0.93), sensitivity of 80.0% (2.5th-97.5th percentiles: 41.4-100%), and specificity of 65.5% (2.5th-97.5th percentiles: 54.2-76.6%); however, discrimination was lower in people living with HIV (AUC 0.71; 95% CI 0.61-0.81). Classification and regression tree analysis yielded a simplified algorithm incorporating cough and sTREM-1, with a cross-validated AUC of 0.79 (95% CI: 0.69-0.88), sensitivity of 77.5% (95% CI: 61.6-89.2%), and specificity of 84.2% (95% CI: 80.5-87.4%); this approach may be more pragmatic for low-resource settings.</p><p><strong>Conclusions: </strong>This exploratory analysis identified a parsimonious biosignature and biomarker-based algorithm for TB evaluation among febrile adults in a high-burden setting. With further development, host protein-based assays may enhance TB case detection in resource-limited settings.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic surveillance of human metapneumovirus in the United States, 2010-2025.","authors":"Emily E Bendall, William J Fitzsimmons, Weronika Damek Valvano, Rachel Truscon, Wesley H Self, Natasha Halasa, James D Chappell, Yuwei Zhu, Basmah Safdar, Adit A Ginde, Ithan D Peltan, Manjusha Gaglani, Cristie Columbus, Nathan I Shapiro, Kevin W Gibbs, David N Hager, Matthew E Prekker, Amira Mohamed, Nicholas J Johnson, Jay S Steingrub, Akram Khan, Abhijit Duggal, Jennifer G Wilson, Nida Qadir, Laurence W Busse, Jennie H Kwon, Matthew C Exline, Ivana A Vaughn, Jarrod M Mosier, Estelle S Harris, Fatimah S Dawood, Kevin C Ma, Diya Surie, Arnold S Monto, Emily T Martin, Adam S Lauring","doi":"10.1093/infdis/jiag249","DOIUrl":"https://doi.org/10.1093/infdis/jiag249","url":null,"abstract":"<p><strong>Background: </strong>Human metapneumovirus (HMPV) is a significant cause of acute respiratory illness in both children and adults, yet its genomic epidemiology remains understudied compared to other respiratory viruses.</p><p><strong>Methods: </strong>Hybrid capture and whole genome sequencing were performed on 616 HMPV positive specimens from two cohorts: the household-based HIVE study (2010-2022) in Michigan and the multicenter IVY network (2022-2025) of hospitalized adults. Consensus sequences were generated using IRMA, clades were annotated using Nextclade, and phylogenetic trees were constructed separately for HMPV-A and HMPV-B using IQTree and TreeTime. Analysis of selection by dN/dS was performed using SLAC.</p><p><strong>Results: </strong>We obtained complete genomes from 325 specimens. Our analyses revealed the continued predominance of the A2.2.2 clade and little geographic structure in the US. Genomic diversity was highest in the glycoprotein (G); we identified a shift from variants bearing the 180nt duplication to ones with a 111nt duplication. Phylogenetic analyses supported the duplication-deletion model for the origin of the duplications. The conserved fusion (F) protein showed limited antigenic variation and low rates of nonsynonymous substitutions.</p><p><strong>Conclusions: </strong>These findings underscore the utility of enhanced genomic surveillance for understanding HMPV evolution and informing vaccine development. There was little genomic diversity in epitopes targeted by vaccine candidates.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the disease response with NlpD and LytM for effective non-antibiotic treatment of urinary tract infections.","authors":"Hien Thi Tran, Inês Gomes, Arunima Chaudhuri, Atefeh Nazari, Shahram Ahmadi, Hanna Végh, António N B M Carneiro, Urban Höglund, Christian Krintel, Catharina Svanborg, Ines Ambite","doi":"10.1093/infdis/jiag243","DOIUrl":"https://doi.org/10.1093/infdis/jiag243","url":null,"abstract":"<p><strong>Background: </strong>Finding new ways of treating bacterial infections is essential. The NlpD protein, which inhibits RNA Polymerase II (Pol II), has shown therapeutic efficacy against urinary tract infection. This study investigated the mechanism of Pol II inhibition and protection by NlpD and its LytM peptide.</p><p><strong>Methods: </strong>Recombinant NlpD and LytM were screened for interactions with constituents of the RNA Polymerase II complex, using AlphaFold predictions and protein interaction technology. Treatment effects were quantified in infected tissues and regulated host response pathways identified by genome-wide transcriptomics analysis in models of acute pyelonephritis and acute cystitis in Irf3-/- and Asc-/- mice, respectively.</p><p><strong>Results: </strong>LytM was shown to interact with constituents of the Pol II multiprotein complex, inhibiting the CDK12 kinase from phosphorylating the Pol II subunit RPB1 and disrupting Pol II complex formation by interfering with the interaction between PAF1C and RPB1. The protection by LytM against acute pyelonephritis was accompanied by a reduction in gene expression in infected kidneys from >1,900 significantly regulated genes (FC>6) in the placebo group to about 150 in LytM treated mice. The inhibition of gene expression in infected kidneys particularly targeted the excessive innate immune response. A similar effect was observed in acute cystitis. Bacterial clearance was accelerated in both model by LytM treatment, with effects against antibiotic sensitive and resistant Escherichia coli strains.</p><p><strong>Conclusions: </strong>The results suggest that inhibiting the disease response of the host, using NlpD or LytM, may offer an efficient alternative to antibiotics in these models.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}