Journal of Infectious Diseases最新文献

Background: HIV-1 remains a global health challenge, emphasizing the need to identify new host factors that influence pathogenesis to serve as drug targets. Identifying genetic determinants of HIV-1 control across diverse populations remains a top priority.

Methods: We conducted a multi-ancestry genome-wide association study (GWAS) of HIV-1 set-point viral load (spVL) leveraging genotype and viral load data from 10,723 individuals living with HIV-1. To prioritize candidate genes and mechanisms, we integrated GWAS findings with transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) data.

Results: We implicate the potential role of zinc finger proteins in pathogenesis through identification of a novel signal in the zinc finger protein 586 (ZNF586) gene on chromosome 19, which is predicted to regulate RNA polymerase II transcription. The top variant, (rs35962362-G) is intronic to the ZNF586 gene, and is associated with an approximate 0.1 log increase in spVL per mutant allele. Our subsequent TWAS along with interrogation of eQTL data suggest that increased ZNF586 expression is associated with increased spVL in whole blood.

Conclusions: Our findings suggest ZNF586 as a novel host factor for HIV-1 control and highlight the role of zinc finger proteins as potential contributors to viral persistence. Although ZNF586 has not previously been linked to HIV pathogenesis, its potential role in maintaining retroviral latency and modulating genomic regulation warrants further investigation.

Background: Vaccination is critical for controlling infectious diseases, however, assessing efficacy solely through neutralizing antibody titers oversimplifies immune protection. The cellular and molecular mechanisms driving variable vaccine-induced immune responses remain underexplored, limiting comprehensive vaccine evaluation.

Methods: Using single-cell sequencing, we profiled and compared cellular dynamic, transcriptomic profiles, immune repertoire and cellular communication in vaccine recipients with high and low antibody titers following Ad5-nCoV booster using PBMC samples collected from a cohort of 144 participants.

Results: Cellular profiling revealed no significant changes in most immune cell subsets. However, high response groups exhibited increased cytotoxic CD8+ lymphocytes (CD8+ CTL) and natural killer T cells (NKT), with reduced CD8+ mucosal-associated invariant T cells (CD8+ MAIT). These groups showed upregulated immune and effector genes, downregulated pro-inflammatory genes, and elevated inhibitory gene expression in clonal NK cells, accompanied by enhanced CD8+ T cell clonal expansion. Additionally, the VJ gene usage of B and T cells in high response groups showed biased patterns, with preferential expression of IGLJ3, IGKJ3, IGHV3-33 and IGHJ4 in B cells, and TRAV27, TRAJ33, TRBV9 and TRBJ2-7 in T cells. Cell communication also indicated balanced pro- and anti-inflammatory cytokine expression in high response groups.

Conclusions: These findings elucidate the cellular and molecular mechanisms underlying robust immune responses to the Ad5-nCoV booster, highlighting the critical role of cellular immunity. By integrating humoral and cellular insights, this study offers a new perspective of comprehensive framework for evaluating vaccine efficacy.

Background: Citrobacter freundii is an emerging nosocomial pathogen, yet its transmission dynamics remain poorly characterized.

Methods: We conducted a retrospective genomic and epidemiological study to investigate the transmission chains of extended-spectrum beta-lactamase (ESBL) and carbapenemase producing C. freundii collected at Geneva University Hospitals during a six-year period (2017-2022). Whole genome sequencing (WGS) using Nanopore long-read sequencing, MLST and plasmid typing, and resistome profiling were performed. Transmission events were defined based on genetic relatedness, plasmid similarity and patient trajectories.

Results: A total of 103 cases of ESBL and carbapenemase-producing C. freundii were identified, of which 79% were hospital-acquired, 72% were isolated from rectal swabs, and bacteremia occurred in six patients. Among 90 isolates available for WGS, 73% were confirmed as C. freundii, whereas the remaining belonged to other Citrobacter species. A high genetic diversity was observed among C. freundii sensu stricto, with 29 distinct sequence types, including predominant ST114, ST98, and ST22. We identified 10 clusters involving multiple Citrobacter species among 35 patients. Transmission chain analysis revealed that 37% of patients were involved in putative clonal transmission and 21% in putative plasmid-mediated dissemination events, particularly in abdominal surgery, geriatrics and septic orthopedics, often involving C. freundii harboring blaCTX-M-15, blaOXA-48/CTX-M-14b and blaOXA-181 on IncHI2-IncHI2A, IncM1 and IncX3 plasmids, respectively.

Conclusions: Our study highlights the role of C. freundii as a vector of both clonal and plasmid-mediated, nosocomial transmission of antimicrobial resistance. It emphasizes the need to include C. freundii in genomic and epidemiological surveillance to detect its silent spread.

Background: Acinetobacter baumannii is a high-priority Gram negative respiratory pathogen associated with high morbidity and mortality. While many components of the innate immune response to A. baumannii have been studied, the specific role of the airway epithelium in coordinating the innate immune response to A. baumannii is largely undefined. In this study we demonstrate that NF-κB signaling within airway epithelial cells is essential for effective pulmonary clearance of A. baumannii.

Methods: To understand the role of epithelial signaling, we utilized several mouse models of infection.

Results: Using both pharmacological and conditional knockouts of the NF-κB subunit RelA (p65) in airway epithelial cells of mice, we observed substantial defects in bacterial clearance from the airways and lungs. This impaired clearance was associated with significant reductions in early neutrophil recruitment to the airway, which was linked to decreased expression of key neutrophil chemokines-G-CSF, GM-CSF and CCL20 at both the transcript and protein levels. RNA-sequencing of sorted airway epithelial cells revealed that NF-κB activity was required for transcription of inflammatory and chemotactic genes. Administration of exogenous neutrophil chemokines was able to restore early neutrophil recruitment in epithelial RelA-deficient mice, but only partially rescued bacterial clearance, suggesting additional mechanisms beyond granulocyte chemokine induction. We also show that airway epithelial expression of TLR4 and its adaptor protein, MyD88 are also required for effective bacterial clearance from the airway, identifying a TLR4-MyD88-NF-κB axis.

Conclusion: These findings highlight the airway epithelium as a critical site of innate immune sensing and coordinating the pulmonary host defense against A. baumannii.

Chlamydia trachomatis (Ct) is a sexually transmitted infection (STI) linked to ectopic pregnancy, infertility, invasive lymphogranuloma venereum (LGV) and the blinding disease trachoma. STI, LGV and trachoma are associated with disease-specific Ct genovars. Serology is an important surveillance tool for estimating exposure, but the impact of genome variation on the antigenicity of Ct proteins is unclear. Two-dimensional antigenicity profiling of Pgp3 antigens representing LGV, STI and trachoma demonstrated differential antigenicity using antigen-specific murine sera, but geometric distances were not considered significant (≤2 fold) for human infection sera. Pgp3 should be considered a single serotype for the purposes of Ct serosurveillance.

Introduction: Seasonal influenza causes significant global morbidity, mortality, and economic burden. Ongoing viral evolution can lead to vaccine mismatch and the emergence of antiviral resistance, highlighting the importance of genomic surveillance. The 2024-2025 influenza season was characterized by high incidence and increased hospitalizations.

Methods: We analyzed influenza A virus (IAV) genomes and clinical characteristics from the 2024-2025 season. Whole-genome sequencing was performed on 648 influenza A-positive clinical specimens collected between October 2024 and April 2025.

Results: Hemagglutinin (HA) sequences were recovered from 74.23% (481/648) of samples and used for subtyping and phylogenetic analysis. A(H1N1)pdm09 and A(H3N2) viruses co-circulated, representing 55.5% and 44.5% of cases, respectively. Among A(H1N1)pdm09 viruses, the HA1 substitution T120A, located near the Sa antigenic site, increased more than twofold compared with the prior season. Circulating A(H3N2) viruses belonged to multiple HA subclades and exhibited distinct amino acid substitutions at key antigenic sites. Neutralization assays using sera from individuals vaccinated with the 2024-2025 seasonal influenza vaccine demonstrated reduced neutralization of three dominant A(H1N1)pdm09 isolates and two A(H3N2) isolates compared with vaccine strains, consistent with antigenic drift. In addition, the neuraminidase substitution S247N, previously associated with reduced oseltamivir susceptibility, was detected in 13.9% of A(H1N1)pdm09 samples.

Discussion: These findings demonstrate ongoing antigenic drift and the presence of antiviral resistance-associated mutations during the 2024-2025 influenza season, underscoring the need for continued genomic surveillance to guide vaccine and antiviral strategies.

Background: The vaginal microbiome plays an important role for women's health. Changes in its composition have been associated with several sexually transmitted infections, including human papillomavirus (HPV) or parasitic infections such as Schistosoma haematobium (Sh). In Madagascar, gynaecological conditions such as chronic manifestations of Sh infections (female genital schistosomiasis, FGS), HPV infections, and cervical cancer are highly prevalent; however, data on the interplay between these conditions and the vaginal microbiota (VM) is still scarce. Additionally, the majority of data originates from the Global North, generating a biased understanding of "healthy" VM across different geographical and social contexts. The objective of our study was to characterize for the first time the VM of adult women of reproductive age in Madagascar and to describe the variability of the vaginal environment in presence of three conditions affecting the urogenital tract.

Methods and results: We characterized the VM of 443 participants, identifying the five community state types (CSTs I - V) with CST IV (57.1 %, diverse) and CST III (34.1 %, Lactobacillus iners-dominated) as the most prevalent. CSTs were associated with previous antibiotics usage, while variability in the alpha and beta diversity was associated with dietary behaviour and previous antibiotics usage. Differential abundance analysis showed variations among specific taxa in HPV- and FGS-positive participants.

Conclusion: With this first study of the VM in Madagascar we contribute to a broader understanding of vaginal health as well as narrowing the gap of VM research in sub-Saharan Africa by enriching microbiota databases.