Emerging Microbes & Infections最新文献

Healthcare in low- and middle-income countries is becoming problematic due to the emergence of multidrug-resistant bacteria causing serious morbidity and mortality. Klebsiella variicola carrying multiple antimicrobial resistance (AMR) genes were found significantly among sepsis patients in a study done between October 2019 and September 2020 at four Ethiopian hospitals located in the central (Tikur Anbessa and Yekatit 12), southern (Hawassa), and northern (Dessie) parts. Among 1416 sepsis patients, 74 K. variicola isolates were identified using MALDI-TOF, most of them at Dessie (n = 44) and Hawassa (n = 28) hospitals. Whole genome sequencing showed that K. variicola strains identified at Dessie Hospital displayed phylogenetic clonality, carried an IncM1 plasmid and the majority were ST3924. Many K. variicola identified at Hawassa Hospital were clonally clustered and the majority belonged to novel STs and carried IncFIB(K) and IncFII(K) plasmids concurrently. Fifty K. variicola carried ESBL genes while 2 isolates harboured AmpC. Other frequently found genes were aac(3)-lla, bla_CTX-M-15, bla_TEM-1B, bla_LEN2, bla_OXA-1, bla_SCO-1, catB3, dfrA14, QnrB1, aac(6')-lb-cr and sul2. Virulence genes detected at both sites were mrk operons for biofilm formation and siderophore ABC transporter operons for iron uptake. Capsular alleles varied, with wzi 269 at Dessie and wzi 582 at Hawassa. The isolation of multidrug-resistant K. variicola as an emerging sepsis pathogen calls for strong infection prevention strategies and antimicrobial stewardship supported by advanced bacterial identification techniques.

Therapeutic option for treating methicillin-resistant Staphylococcus aureus (MRSA) infection is urgently required since its resistance to a broad spectrum of currently available antibiotics. Here, we report that isoniazid is able to potentiate the killing efficacy of tigecycline to MRSA. The combination of isoniazid and tigecycline reduces the minimal inhibitory concentration of clinic MRSA strains to tigecycline. The killing activity of tigecycline is further confirmed by killing experiments and murine infection model. We further demonstrate the mechanism that isoniazid increases intracellular accumulation of tigecycline by promoting the influx but limiting the efflux of tigecycline through proton motive force. We also show that isoniazid and tigecycline synergize to increase the abundance of isoniazid-NAD adduct, which in turn damage cell membrane, possibly contributing to the disruption of PMF. Whereas phosphatidylethanolamine and cardiolipin are able to abrogate the synergistic effect of isoniazid plus tigecycline. Thus our study provides a new perspective that antibiotics, e.g. isoniazid, once recognized only to target Mycobacterium tuberculosis, can be repurposed as antibiotic adjuvant to tigecycline, expanding our choice of antibiotic-antibiotic combinations in treating bacterial infectious diseases.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants raise concerns about decreased vaccine efficacy, vaccines continue to confer robust protection in humans, implying that immunity beyond neutralization contributes to vaccine efficacy. In addition to neutralization, antibodies can mediate various Fc-dependent effector functions, including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP) and antibody-dependent cellular cytotoxicity (ADCC). However, the specific role of each Fc-mediated effector function in contributing to COVID-19 disease attenuation in human remains unclear. To fully define the potential immune correlates of Fc-mediated effector functions, we comprehensively analysed the above Fc-mediated effector functions in two study cohorts. In the CoronaVac vaccinee cohort, individuals without breakthrough infection exhibited higher levels of ADCP and ADNP activities with a greater degree of cross-reactivity compared to those who had breakthrough infection. A predictive model was established incorporating ADNP activity and IgG titre, achieving an area under the curve (AUC) of 0.837. In the COVID-19 patient cohort, BA.5-specific ADCP and ADNP responses were significantly reduced in COVID-19 patients with fatal outcomes compared to milder outcomes. The prognostic model incorporating WT, BA.5, and XBB.1.5 spike-specific ADNP demonstrated effective predictive ability, achieving an AUC of 0.890. Meanwhile, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in the acute phases of infection highlighted remarkably upregulation of neutrophil activity and phagocytic function, further reinforcing the essential role of ADNP. Collectively, our findings underscored Fc-mediated effector activities, especially neutrophil phagocytosis, as significant antibody biomarkers for the risk of SARS-CoV-2 breakthrough infection and COVID-19 prognosis.

High variability of influenza B virus (IBV) hemagglutinin (HA) impairs the cross- neutralization ability of vaccines, leading to reduce efficacy. We identified significant differences in cross-neutralization between IBV strains B/Wyoming/06/2014 and B/Brisbane/60/2008, which differ in only three amino acid residues. The 214 T point mutation was found to dramatically enhance cross-neutralization (>10-fold). Antibody-based reverse validation also revealed that this mutation significantly increased the neutralization capacity (500-62,500-fold). Furthermore, monitoring revealed that the mutation rate at this site has reached its highest level in nearly 20 years, with a prevalence exceeding 80% in sequences submitted from certain regions. Our findings provide new evidence for the selection of vaccine strains with improved cross- neutralization effects, which will aid the development of broad-spectrum vaccines by modifying minimal antigenic epitopes.

A 2019 nationwide study in Japan revealed the predominant methicillin-resistant Staphylococcus aureus (MRSA) types in bloodstream infections (BSIs) to be sequence type (ST)8-carrying SCCmec type IV (ST8-MRSA-IV) and clonal complex 1-carrying SCCmec type IV (CC1-MRSA-IV). However, detailed patient characteristics and how these MRSA types evolve over time remain largely unknown. In this long-term single-center study, MRSA strains isolated from blood cultures at Nagasaki University Hospital from 2012 to 2019 were sequenced and analyzed. Additionally, we compared the SCCmec types and patient characteristics identified in this study with previous data from our hospital spanning 2003-2007 and 2008-2011. Over this 16-year period, SCCmec type II decreased significantly from 79.2% to 15.5%, while type IV increased from 18.2% to 65.5%. This shift in SCCmec types was associated with notable changes in severity and outcomes; the sequential organ failure assessment (SOFA) score decreased from 5.8 to 3.1; in-hospital mortality declined from 39.8% to 15.5%. In contrast, no significant changes in patient demographics, such as age, sex, or underlying diseases, were observed. Between 2012 and 2019, the major combinations of SCCmec type and sequence type were ST8-MRSA-IV, ST8-MRSA-I, CC1-MRSA-IV, and ST5-MRSA-II. Additionally, ST8-MRSA-IV was divided into CA-MRSA/J, t5071-ST8-MRSA-IV, and USA300-like clone based on the results of molecular analysis. These major combinations showed similar drug resistance patterns, molecular characteristics, and phylogenetic features to those identified in nationwide surveillance. This study highlights the evolving nature of MRSA types in bloodstream infections, correlating with improved patient outcomes over time.

Marburg virus disease (MVD) is a severe infectious disease caused by the Marburg virus (MARV), posing a significant threat to humans. MARV needs to be operated under strict biosafety Level 4 (BSL-4) laboratory conditions. Therefore, accessible and practical animal models are urgently needed to advance prophylactic and therapeutic strategies for MARV. In this study, we constructed a recombinant vesicular stomatitis virus (VSV) expressing the Marburg virus glycoprotein (VSV-MARV/GP). Syrian hamsters infected with VSV-MARV/GP presented symptoms such as thrombocytopenia, lymphopenia, haemophilia, and multiorgan failure, developing a severe systemic disease akin to that observed in human MARV patients. Notably, the pathogenicity was found to be species-specific, age-related, sex-associated, and challenge route-dependent. Subsequently, the therapeutic efficacy of the MR191 monoclonal antibody was validated in this model. In summary, this alternative model is an effective tool for rapidly screening medical countermeasures against MARV GP in vivo under BSL-2 conditions.

Insertion sequences (IS) represent mobile genetic elements that have been shown to be associated with bacterial evolution and adaptation due to their effects on genome plasticity. In Bordetella pertussis, the causative agent of whooping cough, the numerous IS elements induce genomic rearrangements and contribute to the diversity of the global B. pertussis population. Previously, we have shown that the majority of IS-specific endogenous promoters induce the synthesis of alternative transcripts and thereby affect the transcriptional landscape of B. pertussis. Here, we describe the regulatory RNA Rfi2, which is transcribed from the P_out promoter of the IS481 gene BP1118 antisense to the adjacent fim2 gene encoding the major serotype 2 fimbrial subunit of B. pertussis. Among the classical bordetellae, Rfi2 is unique to B. pertussis, suggesting its specific role in virulence. We show that Rfi2 RNA attenuates fim2 transcription and, consequently, the production of the Fim2 protein. Interestingly, the mutant that does not produce Rfi2 displayed significantly increased cytotoxicity towards human macrophages compared to the parental strain. This observation suggests that the Rfi2-mediated reduction in cytotoxicity represents an evolutionary adaptation of B. pertussis that fine-tunes its interaction with the human host. Given the immunogenicity of Fim2, we further hypothesize that Rfi2-mediated modulation of Fim2 production contributes to immune evasion. To our knowledge, Rfi2 represents the first functionally characterized IS element-driven antisense RNA that modulates the expression of a virulence gene.

Antimicrobial resistance has recently increased due to emerging carbapenem-resistant Klebsiella pneumoniae and extended-spectrum β-lactamase (ESBL)-producing strains of K. pneumoniae, especially among hypermucoviscous K. pneumoniae (hmKp) strains. To evaluate the prevalence of ESBL-producing and carbapenem-resistant strains in hmKp and non-hmKp clinical isolates through a systematic review and meta-analysis. We searched PubMed, Scopus, and Cochrane Library databases from January 2000 to June 2023. Clinical and in vivo/in vitro studies involving confirmed K. pneumoniae clinical isolates differentiated into hmKP and non-hmKP strains based on string test results. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the number of individuals in each target group. Forest plots were used to visualize the effect sizes and 95% CIs of individual studies estimated using the inverse variance and DerSimonian - Laird methods with fixed - and random-effects models, respectively. Heterogeneity was assessed using Cochran's Q test (I² ≥ 50%). Fifteen studies comprising 2049 clinical isolates of K. pneumoniae met the inclusion criteria. Meta-analysis revealed that hmKp strains were associated with a significantly lower prevalence of ESBL-producing strains (pooled OR: 0.26, 95% CI: 0.11-0.63, P = 0.003) and a slightly lower prevalence of carbapenem-resistant strains than non-hmKp strains (pooled OR: 0.63, 95% CI: 0.40-0.97, P = 0.038). hmKp strains exhibited lower and slightly lower prevalence of ESBL production and carbapenem resistance, respectively, than non-hmKp strains. However, given the rising prevalence of ESBL-producing and carbapenem-resistant hmKp strains, patients infected by string-test-positive K. pneumoniae must be managed prudently, considering the potential for highly resistant strains.

Coronaviruses (CoVs) pose a significant threat to public health, causing a wide spectrum of clinical manifestations and outcomes. Beyond precipitating global outbreaks, Human CoVs (HCoVs) are frequently found among patients with respiratory infections. To date, limited attention has been directed towards alphacoronaviruses due to their low prevalence and fatality rates. Nasal swab and serum samples were collected from a paediatric patient, and an epidemiological survey was conducted. Retrospective surveillance investigated the molecular prevalence of CoV in 880 rodents collected in the Republic of Korea (ROK) from 2018 to 2022. Next-generation sequencing (NGS) and phylogenetic analyses characterized the novel HCoV and closely related CoVs harboured by Apodemus spp. On 15 December 2022, a 103-day-old infant was admitted with fever, cough, sputum production, and rhinorrhea, diagnosed with human parainfluenza virus 1 (HPIV-1) and rhinovirus co-infection. Elevated AST/ALT levels indicated transient liver dysfunction on the fourth day of hospitalization. Metagenomic NGS (mNGS) identified a novel HCoV in nasal swab and serum samples. Retrospective rodent surveillance and phylogenetic analyses showed the novel HCoV was closely related to alphacoronaviruses carried by Apodemus spp. in the ROK and China. This case highlights the potential of mNGS to identify emerging pathogens and raises awareness of possible extra-respiratory manifestations, such as transient liver dysfunction, associated with novel HCoVs. While the liver injury in this case may be attributable to the novel HCoV, further research is necessary to elucidate its clinical significance, epidemiological prevalence, and zoonotic origins.