Emerging Microbes & Infections最新文献

ABSTRACTWest Nile Virus (WNV), first identified in Uganda in 1937, remains a significant global health threat, adapting across diverse ecosystems and expanding geographically, particularly into temperate regions of Europe and North America. This review provides a comprehensive exploration of the latest insights and challenges in WNV management, focusing on epidemiological trends, molecular advancements, and public health implications. Recent data highlight WNV's expansion, driven by climate changes such as milder winters and longer warm seasons that increase mosquito activity and enable the virus to overwinter within mosquito populations. This facilitates year-round transmission and challenges current control strategies. Molecularly, advancements in genomic and proteomic technologies have deepened our understanding of WNV's replication and pathogenesis, identifying new therapeutic targets and improving diagnostic methods. However, the absence of an approved human vaccine leaves management dependent on supportive care, particularly for severe neurological cases. Effective vector control remains crucial, with innovative strategies including genetically modified mosquitoes and novel insecticides being pivotal. Furthermore, environmental factors like climate change and urbanization are altering vector behaviors and WNV transmission dynamics, necessitating adaptive public health strategies to manage these evolving threats. The review underscores the need for ongoing research, vaccine and therapeutic development, and enhanced public health infrastructures to better respond to WNV challenges. It stresses the critical role of integrating scientific research, public health policy, and community engagement to effectively address the persistent threat of WNV.

Reassortant highly pathogenic avian influenza A(H5N2) clade 2.3.4.4.b viruses were detected from ducks and environmental samples in Egypt, June 2024. Genomic and phylogenetic analyses revealed a novel genotype produced by the reassortment of an A(H5N1) clade 2.3.3.4b virus with an A(H9N2) G1-like virus. Monitoring the spread of this virus is important.

Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations.Trial registration: ClinicalTrials.gov identifier: NCT04093596.

The nuclear-cytoplasmic trafficking of matrix proteins (M) is essential for henipavirus budding, with M protein ubiquitination playing a pivotal role in this dynamic process. Despite its importance, the intricacies of the M ubiquitination cascade have remained elusive. In this study, we elucidate a novel mechanism by which Nipah virus (NiV), a highly pathogenic henipavirus, utilizes a ubiquitination complex involving the E2 ubiquitin-conjugating enzyme RAD6A and the E3 ubiquitin ligase RAD18 to ubiquitinate the virus's M protein, thereby facilitating its nuclear-cytoplasmic trafficking. We demonstrate that RAD18 interacts with RAD6A, enabling the latter to supply ubiquitins for the RAD18-mediated transfer of ubiquitin to M through RAD18-M interactions. Specifically, M is ubiquitinated by the RAD6A-RAD18 complex at lysine (K) 258 through a K63-linked ubiquitination, a modification crucial for M's function. This ubiquitination drives M's relocation to the cytoplasm, directing it to plasma membranes for effective viral egress. Conversely, disrupting the RAD6A-RAD18-M axis, mutating RAD18's E3 ligase activity, or inhibiting RAD6A activity with TZ9 (a RAD6-ubiquitin thioester formation inhibitor) impairs M ubiquitination, resulting in defective nuclear export and budding of NiV. Significantly, live NiV and Hendra virus infection is attenuated in RAD18 knockout cells or in cells treated with TZ9, highlighting the critical physiological role of RAD6A-RAD18-mediated M ubiquitination in the henipavirus life cycle. Our findings not only reveal how NiV manipulates a nucleus-localized ubiquitination complex to promote virus's M protein ubiquitination and nuclear export, but also suggest that the small molecule inhibitor TZ9 could serve as a potential therapeutic against henipavirus infection.

Neutralizing antibody titres have been shown to correlate with immune protection against COVID-19 and can be used to estimate vaccine effectiveness. Numerous studies have explored the relationship between neutralizing antibodies and protection. However, there remains a lack of quantitative data directly assessing the minimum effective protective neutralizing antibody titre in in vivo. In this study, we utilized eight cohorts of participants with diverse immune backgrounds for evaluation of protective antibody response. To precisely assess the lower threshold of neutralizing antibody titres required for effective protection against SARS-CoV-2 infections, we employed plasma adoptive transfer from different cohorts into mice. This study demonstrated that neutralizing titres in the plasma of recipient mice correlated well with those in human donors, and a positive linear correlation was observed between the human and mouse recipients of transferred plasma neutralizing titre. A pseudotyped virus neutralizing titres greater than 7 was identified as the minimum threshold necessary to reduce viral titres in infected mice, establishing a crucial baseline for effective protection. Furthermore, despite the variability in immune backgrounds, these diverse cohorts' plasma exhibited a similar neutralizing antibody threshold necessary for protection. This finding has significant implications for vaccine design and the assessment of immune competence.

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 characterised 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 hospitalisation. 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.

Congenital Zika virus (ZIKV) infection significantly affects neurological development in infants and subsequently induces neurodevelopmental abnormality symptoms; however, the potential mechanism is still unknown. Therefore, in order to effectively intervene in neurodevelopmental abnormalities in infected infants, it is necessary to identify the main brain regions affected by congenital infection. In this study, we constructed a congenital ZIKV-infected murine model using immunocompetent human STAT2 knock-in mice, which presented long-term neurodevelopmental abnormalities with abnormal neurodevelopmental symptoms. We found that the hippocampus, which regulates cognitive behavior and processes spatial information and navigation, was the main brain region affected by congenital infection and that hippocampal cells were more prone to autophagy during the growth period of these mice at the transcriptional and pathological levels. These findings highlighted that congenital ZIKV infection could interrupt hippocampal function by activating autophagy, thus providing a theoretical basis for the clinical treatment of congenital ZIKV-infected infants.

AbstractIn 2018, a single detection of a novel reassortant swine influenza A virus (swIAV) was made in Denmark. The hemagglutinin (HA) of the virus was from the H1N1 pandemic 2009 (H1N1pdm09) lineage and the neuraminidase (NA) from the H1N1 Eurasian avian-like swine lineage (H1N1av). By 2022, the novel reassortant virus (H1pdm09N1av) constituted 27% of swIAVs identified through the Danish passive swIAV surveillance program. Sequencing detected two H1pdm09N1av genotypes; Genotype 1 contained an entire internal gene cassette of H1N1pdm09 origin, Genotype 2 differed by carrying an NS gene segment of H1N1av origin. The internal gene cassette of Genotype 2 became increasingly dominant, not only in the H1pdm09N1av population, but also in other Danish enzootic swIAV subtypes. Phylogenetic analysis of the HA genes from H1pdm09N1av viruses revealed a monophyletic source, a higher substitution rate compared to other H1N1pdm09 viruses and genetic differences with human seasonal and other swine adapted H1N1pdm09 viruses. Correspondingly, H1pdm09N1av viruses were antigenically distinct from human H1N1pdm09 vaccine viruses. Both H1pdm09N1av genotypes transmitted between ferrets by direct contact, but only Genotype 1 was capable of efficient aerosol transmission. The rapid spread of H1pdm09N1av viruses in Danish swine herds is concerning for swine and human health. Their zoonotic threat is highlighted by the limited pre-existing immunity observed in the human population, aerosol transmission in ferrets and the finding that the internal gene cassette of Genotype 2 was present in the first two zoonotic infections ever detected in Denmark.

Yersinia pestis, the etiological agent of the devastating plague, has caused three pandemics in human history. While known for its fatality, it has long been intriguing that biovar microtus strains are highly attenuated to humans. The survival and replication within macrophages are critical in the early stages of the Y. pestis lifestyle within warm-blooded hosts. Here, we demonstrate that a frameshift truncation of gppA, a gene encoding the phosphohydrolase GppA that responsible for the conversion of stringent response alarmone pppGpp to ppGpp, significantly promotes Y. pestis to survive inside human macrophages. This frameshift mutation of gppA is present in all the evolutionary branches formed by the modern Y. pestis strains responsible for the plague pandemics, while the relative ancient microtus strains express a functional GppA showing high activity in catalyzing pppGpp to ppGpp conversion. This adaptive evolution potentially explains why microtus Y. pestis strains exhibit attenuated virulence in humans in contrast to the lethal pathogenicity of non-microtus strains. Transcriptome analysis suggests that the disturbed balance of the ratio of ppGpp to pppGpp caused by GppA inactivation results in an upregulation of genes involved in the synthesis of branched-chain amino acids, which are essential for bacterial growth. This enhanced survival ability within macrophages could be a key factor for the virulence of Y. pestis towards humans. Our work sheds light on the molecular mechanisms behind Y. pestis host-specific pathogenicity, offering a glimpse into the transformative journey of a seemingly harmless bacterium into a formidable foe in humans. This understanding holds significant implications for enhancing our ability to predict and counteract the emergence of new infectious diseases.

Background: Scrub typhus, caused by Orientia tsutsugamushi, often involves multiple organs, but its cardiovascular (CV) sequelae in survivors remain under-researched.

Method: This retrospective cohort study analyzed data from the National Health Insurance Research Database (NHIRD) spanning 2010-2015 to assess CV risks among scrub typhus survivors. Excluding those with prior CV events, we focused on outcomes such as acute myocardial infarction (AMI), heart failure hospitalization (HFH), strokes, new-onset atrial fibrillation (AF), aortic aneurysm or dissection, venous thromboembolism (VTE), and CV death.

Result: From 2,269 scrub typhus patients without previous CV events (mean age 47.8±16.1; 38.0% female), and a matched control group (n=2,264), we observed a higher incidence of HFH, new-onset AF, and total CV events in the scrub typhus cohort. Adjusted hazard ratios (aHRs) were 1.97 (95% CI: 1.13-3.42) for HFH, 2.48 (95% CI: 1.23-5.0) for new-onset AF, and 1.43 (95% CI: 1.08-1.91) for total CV events. Other outcomes did not significantly differ.

Conclusion: Scrub typhus survivors exhibit an increased risk of CV events, particularly HFH and new-onset AF, underscoring the importance of heightened physician awareness and post-infection cardiac surveillance.