Journal of Infectious Diseases最新文献

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.

Background: Our understanding of Mycobacterium tuberculosis (Mtb) natural history and infection dynamics is evolving, including recognition that many individuals previously infected with Mtb may clear their infections or experience substantially reduced progression risks with time since infection. Such dynamics suggest that recent transmission is more important in driving TB incidence in high-burden settings than previously estimated; thus, the impact of interventions to reduce transmission (e.g., community-based active case-finding) may also be greater than previously thought.

Methods: We constructed two models of Mtb transmission that differed only in that one model included a clearance mechanism while the other did not. We then calibrated these models independently to the same set of epidemiological data representative of a high-TB-burden setting (India) and compared metrics of infection dynamics absent intervention. Finally, we used the calibrated models to project the impact of illustrative biennial active case-finding campaigns (achieving 75% population coverage with 65% screening sensitivity).

Results: The estimated annual risk of Mtb infection and prevalence of recent infection were both substantially higher in the model that allowed for Mtb clearance, despite being fit to the same data. The model with clearance projected a greater impact of case-finding on the incidence of TB disease: 45% [95% uncertainty interval 28-57%] reduction compared to no intervention after 10 years, versus 11% [6-18%] in the model without a clearance mechanism.

Conclusions: Models that allow for Mtb clearance are supported by biological and epidemiological evidence and project greater impact from active case-finding than models that do not include these dynamics.

Background: High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection.

Methods: Intensive and sparse pharmacokinetic sub-studies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared two months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with four months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥10 years. Venous blood samples were collected after four weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling.

Results: Among 1368 trial participants, 440 were included in model development (51 intensive, 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A one-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. Disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada (-21.8% [95%CI -27.9 to -18.0%]) and Vietnam (-12.3% [95%CI -17.7 to -7.9%]) compared with Indonesia. The 24-hour area under the concentration-time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada.

Conclusion: High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to non-linear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.