Emerging Microbes & Infections最新文献

Cluster analysis of HIV sequence can provide insights into viral transmission patterns in border regions. This study aims to illuminate the HIV-1 subtype distribution and transmission dynamics among newly diagnosed individuals in Dehong prefecture, a region along the China-Myanmar border. Among 948 participants with pol gene sequences, 36 HIV-1 subtypes were identified, with URFs (18.8%, 178/948) being the dominant strain, followed by CRF01_AE (18.5%, 175/948) and CRF07_BC (10.9%, 103/948). Additionally, 287 sequences (30.3%, 287/948) were grouped into 91 clusters, 31 of which contained both Chinese and Burmese individuals. Multivariable logistic regression indicated that men who have sex with men (MSM), CD4 + cell count of 200∼499, and 500 cells/μl and above, and CRF01_AE were risk factors for entering the network. Through the Chord diagram, we found frequent transmission relationships among heterosexual China male group, especially those over 35 years of age. Additionally, the correlation between heterosexual Myanmar female group and heterosexual China male group among cross-risk groups deserved to be emphasized. Furthermore, the network exhibited a growing trend over time, with the largest active transmission cluster identified in Ruili county. In conclusion, the HIV-1 subtype landscape in Dehong has become increasingly complex, and the region has faced risks of transmission from both domestic and international sources. Targeted intervention strategies should be implemented for MSM, heterosexual Chinese middle-aged and elderly men, and heterosexual Burmese young adults to mitigate these risks. These findings provided evidence-based insights for local government to formulate coordinated transnational intervention approaches.

We identified a novel ceftazidime/avibactam (CAZ/AVI) resistance mechanism in endemic sequence type 11 hypervirulent and carbapenem-resistant Klebsiella pneumoniae isolated from a patient who had not been exposed CAZ/AVI. Overexpression of bla_SHV-12 caused by tandem gene amplification contributed to CAZ/AVI resistance instead of the carriage of bla_KPC-2. Enhanced genomic surveillance is essential to identify emerging variants.

The extensive use of β-lactam antibiotics has led to significant resistance, primarily due to hydrolysis by β-lactamases. OXA class D β-lactamases can hydrolyze a wide range of β-lactam antibiotics, rendering many treatments ineffective. We investigated the effects of single amino acid substitutions in OXA-10 on its substrate spectrum. Broad-spectrum variants with point mutations were searched and biochemically verified. Three key residues, G157D, A124T, and N73S, were confirmed in the variants, and their crystal structures were determined. Based on an enzyme kinetics study, the hydrolytic activity against broad-spectrum cephalosporins, particularly ceftazidime, was significantly enhanced by the G157D mutation in loop 2. The A124T or N73S mutation close to loop 2 also resulted in higher ceftazidime activity. All structures of variants with point mutations in loop 2 or nearby exhibited increased loop 2 flexibility, which facilitated the binding of ceftazidime. These results highlight the effect of a single amino acid substitution in OXA-10 on broad-spectrum drug resistance. Structure-activity relationship studies will help us understand the drug resistance spectrum of β-lactamases, enhance the effectiveness of existing β-lactam antibiotics, and develop new drugs.

SARS-CoV-2 ancestral strain-induced immune imprinting poses great challenges to updating vaccines for new variants. Studies showed that repeated Omicron exposures could override immune imprinting induced by inactivated vaccines but not mRNA vaccines, a disparity yet to be understood. Here, we analyzed the immune imprinting alleviation in inactivated vaccine (CoronaVac) cohorts after a long-term period following breakthrough infections (BTI). We observed in CoronaVac-vaccinated individuals who experienced BA.5/BF.7 BTI, the proportion of Omicron-specific memory B cells (MBCs) substantially increased after an extended period post-Omicron BTI, with their antibodies displaying enhanced somatic hypermutation and neutralizing potency. Consequently, the neutralizing antibody epitope distribution encoded by MBCs post-BA.5/BF.7 BTI after prolonged maturation closely mirrors that in BA.5/BF.7-infected unvaccinated individuals. Together, these results indicate the activation and expansion of Omicron-specific naïve B cells generated by first-time Omicron exposure helped to alleviate CoronaVac-induced immune imprinting, and the absence of this process should have caused the persistent immune imprinting seen in mRNA vaccine recipients.

Increased CD4⁺GNLY⁺ T cells have been confirmed to be inversely associated with CD4⁺ T cell count in immunological non-responders (INRs), however, the underlying mechanisms are unknown. This study aimed to elucidate the characteristics of CD4⁺GNLY⁺ T cells and their relationship with immune restoration. Single-cell RNA sequencing, single-cell TCR sequencing, and flow cytometry were used to analyze the frequency, phenotypes, and function of CD4⁺GNLY⁺ T cells. Moreover, Enzyme linked immunosorbent assay was performed to detect plasma cytokines production in patients. CD4⁺GNLY⁺ T cells were found to be highly clonally expanded, characterized by higher levels of cytotoxicity, senescence, P24, and HIV-1 DNA than CD4⁺GNLY^- T cells. Additionally, the frequency of CD4⁺GNLY⁺ T cells increased after ART, and further increased in INRs, and were positively associated with the antiretroviral therapy duration in INR. Furthermore, increased IL-15 levels in INRs positively correlated with the frequency and senescence of CD4⁺GNLY⁺ T cells, suggesting that CD4⁺GNLY⁺ T cells may provide new insights for understanding the poor immune reconstitution of INRs. In conclusion, increased, highly clonally expanded, and senescent CD4⁺GNLY⁺ T cells may contribute to poor immune reconstitution in HIV-1 infection.

Candida parapsilosis is known to cause severe and persistent outbreaks in clinical settings. Patients infected with multidrug-resistant C. parapsilosis (MDR Cp) isolates were identified in a large Turkish hospital from 2017-2020. We subsequently identified three additional patients infected with MDR Cp isolates in 2022 from the same hospital and two echinocandin-resistant (ECR) isolates from a single patient in another hospital. The increasing number of MDR and ECR isolates contradicts the general principle that the severe fitness cost associated with these phenotypes could prevent their dominance in clinical settings. Here, we employed a multidimensional approach to systematically assess the fitness costs of MDR and ECR C. parapsilosis isolates. Whole-genome sequencing revealed a novel MDR genotype infecting two patients in 2022. Despite severe in vitro defects, the levels and tolerances of the biofilms of our ECR and MDR isolates were generally comparable to those of susceptible wild-type isolates. Surprisingly, the MDR and ECR isolates showed major alterations in their cell wall components, and some of the MDR isolates consistently displayed increased tolerance to the fungicidal activities of primary human neutrophils and were more immunoevasive during exposure to primary human macrophages. Our systemic infection mouse model showed that MDR and ECR C. parapsilosis isolates had comparable fungal burden in most organs relative to susceptible isolates. Overall, we observed a notable increase in the genotypic diversity and frequency of MDR isolates and identified MDR and ECR isolates potentially capable of causing persistent outbreaks in the future.

Dengue is often misclassified and underreported in Africa due to inaccurate differential diagnoses of nonspecific febrile illnesses such as malaria, sparsity of diagnostic testing and poor clinical and genomic surveillance. There are limited reports on the seroprevalence and genetic diversity of dengue virus (DENV) in humans and vectors in Nigeria. In this study, we investigated the epidemiology and genetic diversity of dengue in the rainforest region of Nigeria. We screened 515 febrile patients who tested negative for malaria and typhoid fever in three hospitals in Oyo and Ekiti States in southern Nigeria with a combination of anti-dengue IgG/IgM/NS1 rapid test kits and metagenomic sequencing. We found that approximately 28% of screened patients had previous DENV exposure, with the highest prevalence in persons over sixty. Approximately 8% of the patients showed evidence of recent or current infection, and 2.7% had acute infection. Following sequencing of sixty samples, we assembled twenty DENV-1 genomes (3 complete and 17 partial). We found that all assembled genomes belonged to DENV-1 genotype III. Our phylogenetic analyses showed evidence of prolonged cryptic circulation of divergent DENV lineages in Oyo state. We were unable to resolve the source of DENV in Nigeria owing to limited sequencing data from the region. However, our sequences clustered closely with sequences in Tanzania and sequences reported in Chinese with travel history to Tanzania in 2019. This may reflect the wider unsampled bidirectional transmission of DENV-1 in Africa, which strongly emphasizes the importance of genomic surveillance in monitoring ongoing DENV transmission in Africa.

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T-cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signalling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T-cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC)₅₀/MIC₉₀ values for AMXT-1501 in the range of 3.13-12.5 μM (2.24-8.93 μg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis. Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.