Emerging Microbes & Infections最新文献

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.

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.

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.

Dengue virus (DENV) is a growing global public health threat. The lack of symptomatic immune-competent animal models for dengue has hindered the screening and development of effective therapeutics that can be used to control dengue virus replication and thereby control the progression to severe dengue disease. To address this, we established an infection model in neonatal C57BL/6 mice and showed that a systemic Dengue challenge leads to ataxia, seizures, paralysis, and death within 15 days. The virus was found predominantly in the eye and brain where DENV infects neurons but not astrocytes and causes extensive infiltration of macrophages and microglia activation. The response to infection included upregulation of multiple genes linked to interferons (Ifna, Ifnb, Ifng, Irf7, Irf8, Mx1, Stat1 and Bst2), inflammation (Il6,Tnfa), complement (Cfb,C1ra,C2, C3), cytolysis (Gzma, Gzmb, Prf1) consistent with antiviral responses and inflammation together with neuroprotective regulatory signals (Il27, Il10, and stat2). The increased proinflammatory signature was associated with downregulation neurodevelopmental genes (Calb2, Pvalb, Olig1 and Olig2). We tested the utility of this mouse model by assessing the protection conferred by direct antivirals JNJ-A07 and ST-148 and host-directed antiviral immunomodulatory CpG oligodeoxynucleotide (ODN), alone or in combination against lethal dengue viral infection. The data showed that immunomodulatory CpG ODN and antiviral JNJ-A07 improved the survival of neonatal mice, and protection from lethal neurotropic infection was optimal when treatments were combined. This study suggests that a combination of an effective dengue antiviral along with a host-directed therapeutic may be a useful strategy to protect against dengue virus infections.

The 2022 global mpox virus (MPXV) outbreak highlights the urgent need for safer, next-generation vaccines. We compared the immunogenicity and protective efficacy of individual and multicomponent membrane proteins of MPXV virions in mice to inform the development of a recombinant subunit vaccine against mpox. BALB/c mice were immunized with eukaryotically expressed A35R, A29L, B6R, and M1R proteins, administered individually or in multicomponent combinations with an Al(OH)₃ + CpG oligodeoxynucleotide adjuvant. Three multicomponent protein vaccines (A29/B6, A29/B6/M1, and A29/B6/M1/A35) provided complete protection, but others (individual protein and A35/M1 combinations) provided partial protection against challenge with high-lethal doses of vaccinia virus Western Reserve (VACV-WR). Additionally, A29/B6 conferred partial protection, whereas A29/B6/M1 and A29/B6/M1/A35 provided complete protection against ectromelia virus (ECTV), with A29/B6/M1 being most effective. All vaccines induced strong antigen-specific immunoglobulin G (IgG) and cellular immunity, whereas only four (M1, A35/M1, A29/B6/M1, A29/B6/M1/A35) exhibited significant neutralizing activity against MPXV, VACV-Tiantan, and ECTV. Correlation analysis suggested that neutralizing antibodies and A35-/A29-/B6-specific cellular immunity act as complementary defense mechanisms, potentially providing first- and second-line protection against MPXV and related orthopoxviruses. Collectively, A29/B6/M1 demonstrated the best protective efficacy. This study provides novel insights into immunogen optimization and potential mechanisms for the development of vaccines against MPXV and other orthopoxviruses.