Myotis bat STING attenuates aging-related inflammation in female mice

Bats,notable as the only flying mammals,serve as natural reservoir hosts for various highly pathogenic viruses in humans(e.g.,SARS-CoV and Ebola virus).Furthermore,bats exhibit an unparalleled longevity among mammals relative to their size,particularly the Myotis bats,which can live up to 40 years.However,the mechanisms underlying these distinctive traits remain incompletely understood.In our prior research,we demonstrated that bats exhibit dampened STING-interferon activation,potentially conferring upon them the capacity to mitigate virus-or aging-induced inflammation.To substantiate this hypothesis,we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING(MdSTING)into the mouse genome.We monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on MdSTING and wild-type mice over a 3-year aging process.Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice,as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines,immunopathology,and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo.These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner.Although the underlying mechanism awaits further study,this research has critical implications for bat longevity research,potentially contributing to our comprehension of healthy aging in humans.

Genomic Epidemiology of Imported Cases of COVID-19 in Guangdong Province,China,October 2020–May 2021

Objective The pandemic of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2) has been engendering enormous hazards to the world. We obtained the complete genome sequences of SARSCo V-2 from imported cases admitted to the Guangzhou Eighth People’s Hospital, which was appointed by the Guangdong provincial government to treat coronavirus disease 2019(COVID-19). The SARS-Co V-2 diversity was analyzed, and the mutation characteristics, time, and regional trend of variant emergence were evaluated.Methods In total, 177 throat swab samples were obtained from COVID-19 patients(from October2020 to May 2021). High-throughput sequencing technology was used to detect the viral sequences of patients infected with SARS-Co V-2. Phylogenetic and molecular evolutionary analyses were used to evaluate the mutation characteristics and the time and regional trends of variants.Results We observed that the imported cases mainly occurred after January 2021, peaking in May2021, with the highest proportion observed from cases originating from the United States. The main lineages were found in Europe, Africa, and North America, and B.1.1.7 and B.1.351 were the two major sublineages. Sublineage B.1.618 was the Asian lineage(Indian) found in this study, and B.1.1.228 was not included in the lineage list of the Pangolin web. A reasonably high homology was observed among all samples. The total frequency of mutations showed that the open reading frame 1 a(ORF1 a) protein had the highest mutation density at the nucleotide level, and the D614 G mutation in the spike protein was the commonest at the amino acid level. Most importantly, we identified some amino acid mutations in positions S, ORF7 b, and ORF9 b, and they have neither been reported on the Global Initiative of Sharing All Influenza Data nor published in Pub Med among all missense mutations.Conclusion These results suggested the diversity of lineages and sublineages and the high homology at the amino acid level among imported cases infected with SARS-Co V-2 in Guangdong Province, China.

Integrating multi-omics data of childhood asthma using a deep association model

Childhood asthma is one of the most common respiratory diseases with rising mortality and morbidity.The multi-omics data is providing a new chance to explore collaborative biomarkers and corresponding diagnostic models of childhood asthma.To capture the nonlinear association of multi-omics data and improve interpretability of diagnostic model,we proposed a novel deep association model(DAM)and corresponding efficient analysis framework.First,the Deep Subspace Reconstruction was used to fuse the omics data and diagnostic information,thereby correcting the distribution of the original omics data and reducing the influence of unnecessary data noises.Second,the Joint Deep Semi-Negative Matrix Factorization was applied to identify different latent sample patterns and extract biomarkers from different omics data levels.Third,our newly proposed Deep Orthogonal Canonical Correlation Analysis can rank features in the collaborative module,which are able to construct the diagnostic model considering nonlinear correlation between different omics data levels.Using DAM,we deeply analyzed the transcriptome and methylation data of childhood asthma.The effectiveness of DAM is verified from the perspectives of algorithm performance and biological significance on the independent test dataset,by ablation experiment and comparison with many baseline methods from clinical and biological studies.The DAM-induced diagnostic model can achieve a prediction AUC of o.912,which is higher than that of many other alternative methods.Meanwhile,relevant pathways and biomarkers of childhood asthma are also recognized to be collectively altered on the gene expression and methylation levels.As an interpretable machine learning approach,DAM simultaneously considers the non-linear associations among samples and those among biological features,which should help explore interpretative biomarker candidates and efficient diagnostic models from multi-omics data analysis for human complexdiseases.

SARS-CoV-2 immunity in animal models

The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has become a worldwide health crisis due to its transmissibility.SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals.These complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDS),and even multiple-organ failure.Animal models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against SARS-CoV-2.Currently,various animal models for SARS-CoV-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been developed.Each model possesses distinctive features and applications.In this review,we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection,as well as the corresponding immune responses and applications of these models.A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients.Finally,we highlighted the current gaps in related research between animal model studies and clinical investigations,underscoring lingering scientific questions that demand further clarification.

In vivo evaluation of guide-free Cas9-induced safety risks in a pig model

The CRISPR/Cas9 system has shown great potential for treating human genetic diseases through gene therapy.However,there are concerns about the safety of this system,specifically related to the use of guide-free Cas9.Previous studies have shown that guidefree Cas9 can induce genomic instability in vitro.However,the in vivo safety risks associated with guide-free Cas9 have not been evaluated,which is necessary for the development of gene therapy in clinical settings.In this study,we used doxycycline-inducible Cas9-expressing pigs to evaluate the safety risks of guide-free Cas9 in vivo.Our findings demonstrated that expression of guide-free Cas9 could induce genomic damages and transcriptome changes in vivo.The severity of the genomic damages and transcriptome changes were correlate with the expression levels of Cas9 protein.Moreover,prolonged expression of Cas9 in pigs led to abnormal phenotypes,including a significant decrease in body weight,which may be attributable to genomic damage-induced nutritional absorption and metabolic dysfunction.Furthermore,we observed an increase in whole-genome and tumor driver gene mutations in pigs with long-term Cas9 expression,raising the risk of tumor occurrence.Our in vivo evaluation of guide-free Cas9 in pigs highlights the necessity of considering and monitoring the detrimental effects of Cas9 alone as genome editing via the CRISPR/Cas9 system is implemented in clinical gene therapy.This research emphasizes the importance of further study and implementation of safety measures to ensure the successful and safe application of the CRiSPR/Cas9 system in clinical practice.

Individual virome analysis reveals the general co-infection of mammal-associated viruses with SARS-related coronaviruses in bats

Bats are the natural reservoir hosts for SARS-related coronavirus(SARSr-CoV)and other highly pathogenic microorganisms.Therefore,it is conceivable that an individual bat may harbor multiple microbes.However,there is limited knowledge on the overall co-circulation of microorganisms in bats.Here,we conducted a 16-year monitoring of bat viruses in south and central China and identified 238 SARSr-CoV positive samples across nine bat species from ten provinces or administrative districts.Among these,76 individual samples were selected for further metagenomics analysis.We found a complex microenvironment characterized by the general cocirculation of microbes from two different sources:mammal-associated viruses or environment-associated microbes.The later includes commensal bacteria,enterobacteria-related phages,and insect or fungal viruses of food origin.Results showed that 25%(19/76)of the samples contained at least one another mammal-associated virus,notably alphacoronaviruses(13/76)such as AlphaCoV/YN2012,HKU2-related CoV and AlphaCoV/Rf-HuB2013,along with viruses from other families.Notably,we observed three viruses co-circulating within a single bat,comprising two coronavirus species and one picornavirus.Our analysis also revealed the potential presence of pathogenic bacteria or fungi in bats.Furthermore,we obtained 25 viral genomes from the 76 bat SARSr-CoV positive samples,some of which formed new evolutionary lineages.Collectively,our study reveals the complex microenvironment of bat microbiome,facilitating deeper investigations into their pathogenic potential and the likelihood of cross-species transmission.

The molecular and cellular choreography of early mammalian lung development

Mammalian lung development starts from a specific cluster of endodermal cells situated within the ventral foregut region.With the orchestrating of delicate choreography of transcription factors,signaling pathways,and cell–cell communications,the endodermal diverticulum extends into the surrounding mesenchyme,and builds the cellular and structural basis of the complex respiratory system.This review provides a comprehensive overview of the current molecular insights of mammalian lung development,with a particular focus on the early stage of lung cell fate differentiation and spatial patterning.Furthermore,we explore the implications of several congenital respiratory diseases and the relevance to early organogenesis.Finally,we summarize the unprecedented knowledge concerning lung cell compositions,regulatory networks as well as the promising prospect for gaining an unbiased understanding of lung development and lung malformations through stateof-the-art single-cell omics.

Heterogeneous hybrid immunity against Omicron variant JN.1 at 11 months following breakthrough infection

Dear Editor,Due to the ongoing evolution of SARS-CoV-2 and waning immunity following COVID-19 vaccination,breakthrough infections have become common occurrences.The exposure to viral antigens during different COVID-19 waves and vaccination contribute to the unique"hybrid immunity"-immune protection conferred by the combined vaccination and natural infection in individuals.

Variant PRC1 subunit RYBP/YAF2 forms condensate with RING1B and promotes H2AK119ub deposition

Dear Editor,Polycomb group(Pc G)proteins represent important roles in repressing gene expression throughout development.The Polycomb repressive complexes(PRCs)have been subdivided into two central protein complexes,PRC1 and PRC2.PRC1 catalyzes H2AK119ub and PRC2catalyzes H3K27me1/2/3(Fursova et al.,2019).PRC1 is further categorized as CBX-containing canonical PRC1(c PRC1)and RYBP/YAF2-containing variant PRC1(v PRC1)(Blackledge and Klose,2021).

Transmission restriction and genomic evolution co-shape the genetic diversity patterns of influenza A virus

Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission.This causes global pandemics and seasonal flu outbreaks,posing sustained threats worldwide.Thus,studying all IAVs'evolutionary patterns and underlying mechanisms is crucial for effective prevention and control.We developed FluTyping to identify IAV genotypes,to explore overall genetic diversity patterns and their restriction factors.FluTyping groups isolates based on genetic distance and phylogenetic relationships using whole genomes,enabling identification of each isolate's genotype.Three distinct genetic diversity patterns were observed:one genotype domination pattern comprising only H1N1 and H3N2 seasonal influenza subtypes,multi-genotypes cocirculation pattern including majority avian influenza subtypes and swine influenza H1N2,and hybrid-circulation pattern involving H7N9 and three H5 subtypes of influenza viruses.Furthermore,the IAVs in multi-genotypes cocirculation pattern showed region-specific dominant genotypes,implying the restriction of virus transmission is a key factor contributing to distinct genetic diversity patterns,and the genomic evolution underlying different patterns was more influenced by host-specific factors.In summary,a comprehensive picture of the evolutionary patterns of overall IAVs is provided by the FluTyping's identified genotypes,offering important theoretical foundations for future prevention and control of these viruses.

Initial COVID-19 severity influenced by SARS-CoV-2-specific T cells imprints T-cell memory and inversely affects reinfection

The immunoprotective components control COVID-19 disease severity,as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity,remain unclarified.Here,we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity.We found that early and robust SARS-CoV-2-specific CD4^(+)and CD8^(+)T cell responses ameliorate disease progression and shortened hospital stay,while delayed and attenuated virus-specific CD8^(+)T cell responses are prominent severe COVID-19 features.Delayed antiviral antibody generation rather than titer level associates with severe outcomes.Conversely,initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity,demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts.Moreover,initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk.Overall,our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection

The angiotensin-converting enzyme 2(ACE2)is a primary cell surface viral binding receptor for SARS-CoV-2,so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19.In the current study,we utilized islet organoids derived from human embryonic stem cells(hESCs),animal models and COVID-19 patients to discover that fibroblast growth factor 7(FGF7)enhances ACE2 expression within the islets,facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion.Using hESC-derived islet organoids,we demonstrated that FGF7 interacts with FGF receptor 2(FGFR2)and FGFR1 to upregulate ACE2 expression predominantly inβcells.This upregulation increases both insulin secretion and susceptibility ofβcells to SARS-CoV-2 infection.Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation,subsequently reducing viral infection and replication in the islets.Furthermore,retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms.Finally,animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels,resulting in a reduction of insulin concentrations in situ.Taken together,our research offers a potential regulatory strategy for ACE2 by controlling FGF7,thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.

Intranasal adenovirus-vectored Omicron vaccine induced nasal immunoglobulin A has superior neutralizing potency than serum antibodies

The upper respiratory tract is the initial site of SARS-CoV-2 infection.Nasal spike-specific secretory immunoglobulin A(slgA)correlates with protection against Omicron breakthrough infection.We report that intranasal vaccination using human adenovirus serotype 5(Ad5)vectored Omicron spike in people who previously vaccinated with ancestral vaccine could induce robust neutralizing slgA in the nasal passage.Nasal slgA was predominantly present in dimeric and multimeric forms and accounted for nearly 40%of total proteins in nasal mucosal lining fluids(NMLFs).A low-level IgG could also be detected in NMLFs but not IgM,IgD,and IgE.After a complete nasal wash,slgA in the nasal passage could be replenished rapidly within a few hours.A comparison of purified paired serum IgA,serum IgG,and nasal slgA from the same individuals showed that slgA was up to 3-logs more potent than serum antibodies in binding to spikes and in neutralizing Omicron subvariants.Serum IgG and IgA failed to neutralize XBB and BA.2.86,while nasal slgA retained potent neutralization against these newly emerged variants.Further analysis showed that slgA Was more effective than IgG or IgA in blocking spike-mediated cell-to-cell transmission and protecting hACE2 mice from XBB challenge.Using a slgA monoclonal antibody as a reference,we estimated that the total nasal slgA contains about 2.6-3.9%spikespecific slgA in NMLFs collected approximately one month after intranasal vaccination.Our study provided insights for developing intranasal vaccines that can induce slgA to build an effective and mutation-resistant first-line immune barrier against constantly emerging variants.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein

Respiratory syncytial virus(RSV)is the major cause of bronchiolitis and pneumonia in young children and the elderly.There are currently no approved RSV-specific therapeutic small molecules available.Using high-throughput antiviral screening,we identified an oral drug,the prenylation inhibitor lonafarnib,which showed potent inhibition of the RSV fusion process.Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells(HBEC).Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry,but has farnesyltransferase-independent antiviral efficacy.Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation.Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab.Furthermore,lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice.Collectively,lonafarnib could be a potential fusion inhibitor for RSV infection.

Artificial intelligence system for outcome evaluations of human in vitro fertilization-derived embryos

Background:In vitro fertilization(IVF)has emerged as a transformative solution for infertility.However,achieving favorable live-birth outcomes remains challenging.Current clinical IVF practices in IVF involve the collection of heterogeneous embryo data through diverse methods,including static images and temporal videos.However,traditional embryo selection methods,primarily reliant on visual inspection of morphology,exhibit variability and are contingent on the experience of practitioners.Therefore,an automated system that can evaluate heterogeneous embryo data to predict the final outcomes of live births is highly desirable.Methods:We employed artificial intelligence(AI)for embryo morphological grading,blastocyst embryo selection,aneuploidy prediction,and final live-birth outcome prediction.We developed and validated the AI models using multitask learning for embryo morphological assessment,including pronucleus type on day 1 and the number of blastomeres,asymmetry,and fragmentation of blastomeres on day 3,using 19,201 embryo photographs from 8271 patients.A neural network was trained on embryo and clinical metadata to identify good-quality embryos for implantation on day 3 or day 5,and predict live-birth outcomes.Additionally,a 3D convolutional neural network was trained on 418 time-lapse videos of preimplantation genetic testing(PGT)-based ploidy outcomes for the prediction of aneuploidy and consequent live-birth outcomes.Results:These two approaches enabled us to automatically assess the implantation potential.By combining embryo and maternal metrics in an ensemble AI model,we evaluated live-birth outcomes in a prospective cohort that achieved higher accuracy than experienced embryologists(46.1%vs.30.7%on day 3,55.0%vs.40.7%on day 5).Our results demonstrate the potential for AI-based selection of embryos based on characteristics beyond the observational abilities of human clinicians(area under the curve:0.769,95%confidence interval:0.709-0.820).These findings could potentially provide a noninvasive,high-throughput,and low-cost screening tool to facilitate embryo selection and achieve better outcomes.Conclusions:Our study underscores the AI model’s ability to provide interpretable evidence for clinicians in assisted reproduction,highlighting its potential as a noninvasive,efficient,and cost-effective tool for improved embryo selection and enhanced IVF outcomes.The convergence of cutting-edge technology and reproductive medicine has opened new avenues for addressing infertility challenges and optimizing IVF success rates.

Characterization of humoral immune responses against SARS-CoV-2 accessory proteins in infected patients and mouse model

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of COVID-19,encodes several accessory proteins that have been shown to play crucial roles in regulating the innate immune response.However,their expressions in infected cells and immunogenicity in infected humans and mice are still not fully understood.This study utilized various techniques such as luciferase immunoprecipitation system(LIPS),immunofluorescence assay(IFA),and western blot(WB)to detect accessory protein-specific antibodies in sera of COVID-19 patients.Specific antibodies to proteins 3a,3b,7b,8 and 9c can be detected by LIPS,but only protein 3a antibody was detected by IFA or WB.Antibodies against proteins 3a and 7b were only detected in ICU patients,which may serve as a marker for predicting disease progression.Further,we investigated the expression of accessory proteins in SARS-CoV-2-infected cells and identified the expressions of proteins 3a,6,7a,8,and 9b.We also analyzed their ability to induce antibodies in immunized mice and found that only proteins 3a,6,7a,8,9b and 9c were able to induce measurable antibody productions,but these antibodies lacked neutralizing activities and did not protect mice from SARS-CoV-2 infection.Our findings validate the expression of SARS-CoV-2 accessory proteins and elucidate their humoral immune response,providing a basis for protein detection assays and their role in pathogenesis.

Accurate prediction of myopic progression and high myopia by machine learning

Background Myopia is a leading cause of visual impairment in Asia and worldwide.However,accurately predicting the progression of myopia and the high risk of myopia remains a challenge.This study aims to develop a predictive model for the development of myopia.Methods We first retrospectively gathered 612530 medical records from five independent cohorts,encompassing 227543 patients ranging from infants to young adults.Subsequently,we developed a multivariate linear regression algorithm model to predict the progression of myopia and the risk of high myopia.Result The model to predict the progression of myopia achieved an R^(2) value of 0.964 vs a mean absolute error(MAE)of 0.119D[95%confidence interval(CI):0.119,1.146]in the internal validation set.It demonstrated strong generalizability,maintaining consistent performance across external validation sets:R^(2)=0.950 vs MAE=0.119D(95%CI:0.119,1.136)in validation study 1,R^(2)=0.950 vs MAE=0.121D(95%CI:0.121,1.144)in validation study 2,and R^(2)=0.806 vs MAE=−0.066D(95%CI:−0.066,0.569)in the Shanghai Children Myopia Study.In the Beijing Children Eye Study,the model achieved an R^(2) of 0.749 vs a MAE of 0.178D(95%CI:0.178,1.557).The model to predict the risk of high myopia achieved an area under the curve(AUC)of 0.99 in the internal validation set and consistently high area under the curve values of 0.99,0.99,0.96 and 0.99 in the respective external validation sets.Conclusion Our study demonstrates accurate prediction of myopia progression and risk of high myopia providing valuable insights for tailoring strategies to personalize and optimize the clinical management of myopia in children.

AI for organic and polymer synthesis

Recent years have witnessed the transformative impact from the integration of artificial intelligence with organic and polymer synthesis. This synergy offers innovative and intelligent solutions to a range of classic problems in synthetic chemistry. These exciting advancements include the prediction of molecular property, multi-step retrosynthetic pathway planning, elucidation of the structure-performance relationship of single-step transformation, establishment of the quantitative linkage between polymer structures and their functions, design and optimization of polymerization process, prediction of the structure and sequence of biological macromolecules, as well as automated and intelligent synthesis platforms. Chemists can now explore synthetic chemistry with unprecedented precision and efficiency, creating novel reactions, catalysts, and polymer materials under the datadriven paradigm. Despite these thrilling developments, the field of artificial intelligence(AI) synthetic chemistry is still in its infancy, facing challenges and limitations in terms of data openness, model interpretability, as well as software and hardware support. This review aims to provide an overview of the current progress, key challenges, and future development suggestions in the interdisciplinary field between AI and synthetic chemistry. It is hoped that this overview will offer readers a comprehensive understanding of this emerging field, inspiring and promoting further scientific research and development.

Brainstem opioid peptidergic neurons regulate cough reflexes in mice

Cough is a vital defensive reflex for expelling harmful substances from the airway.The sensory afferents for the cough reflex have been intensively studied.However,the brain mechanisms underlying the cough reflex remain poorly understood.Here,we developed a paradigm to quantitatively measure cough-like reflexes in mice.Using this paradigm,we found that prodynorphin-expressing(Pdyn+)neurons in the nucleus of the solitary tract(NTS)are critical for capsaicin-induced cough-like reflexes.These neurons receive cough-related neural signals from Trpv1+vagal sensory neurons.The activation of Pdyn+NTS neurons triggered respiratory responses resembling cough-like reflexes.Among the divergent projections of Pdyn+NTS neurons,a glutamatergic pathway projecting to the caudal ventral respiratory group(cVRG),the canonical cough center,was necessary and sufficient for capsaicin-induced cough-like reflexes.These results reveal that Pdyn+NTS neurons,as a key neuronal population at the entry point of the vagus nerve to the brainstem,initiate cough-like reflexes in mice.

Nasal mucosal secretory immunoglobulin A but not serum antibodies is resistant to Omicron evasion

Intramuscular vaccines against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)can effectively alleviate the severity of SARS-CoV-2-caused disease and reduce mortality.However,they cannot effectively prevent SARS-CoV-2 infection and transmission due to the failure to elicit protective viral-specific mucosal secretory immunoglobulin A(sIgA)[1,2].Unlike intramuscular immunization,natural infection,irrespective of prior vaccination,can induce neutralizing mucosal sIgA in the upper respiratory tract,the first site where SARS-CoV-2 infection establishes,replicates,and persists until the final viral clearance[3].The local presence of viral antigens in the respiratory tract is essential for generating mucosal immunity,which guards against subsequent infection.Several studies showed that the Omicron breakthrough infection rate is lower in people with a higher spike-specific mucosal sIgA level[4–6].