Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.

SARS-CoV-2 variants,immune escape,COVID-19 vaccine,and therapeutic strategies

The global pandemic of coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus2(SARS-CoV-2) has brought considerable challenges to worldwide public health and the economy. Over 535 million confirmed cases and 6.3 million deaths of COVID-19 were reported as of June 17, 2022(https://covid19.who.int/).

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies available.Novel variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains crucial.Here,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe COVID-19.By using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was conducted.Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment.TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

Neurological complications and infection mechanism of SARS-CoV-2

Currently,SARS-CoV-2 has caused a global pandemic and threatened many lives.Although SARS-CoV-2 mainly causes respiratory diseases,growing data indicate that SARS-CoV-2 can also invade the central nervous system(CNS)and peripheral nervous system(PNS)causing multiple neurological diseases,such as encephalitis,encephalopathy,Guillain-Barrésyndrome,meningitis,and skeletal muscular symptoms.Despite the increasing incidences of clinical neurological complications of SARS-CoV-2,the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established.In this review,we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence.Finally,we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion.These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Inactivated SARS-CoV-2 induces acute respiratory distress syndrome in human A CE2-transgenic mice

The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.