Cationic crosslinked carbon dots-adjuvanted intranasal vaccine induces protective immunity against Omicron-included SARS-CoV-2 variants.

Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19.

A recombinant spike‐XBB.1.5 protein vaccine induces broad‐spectrum immune responses against XBB.1.5‐included Omicron variants of SARS‐CoV‐2

The XBB.1.5 subvariant has drawn great attention owing to its exceptionality in immune evasion and transmissibility. Therefore, it is essential to develop a universally protective coronavirus disease 2019 vaccine against various strains of Omicron, especially XBB.1.5. In this study, we evaluated and compared the immune responses induced by six different spike protein vaccines targeting the ancestral or various Omicron strains of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in mice. We found that spike‐wild‐type immunization induced high titers of neutralizing antibodies (NAbs) against ancestral SARS‐CoV‐2. However, its activity in neutralizing Omicron subvariants decreased sharply as the number of mutations in receptor‐binding domain (RBD) of these viruses increased. Spike‐BA.5, spike‐BF.7, and spike‐BQ.1.1 vaccines induced strong NAbs against BA.5, BF.7, BQ.1, and BQ.1.1 viruses but were poor in protecting against XBB and XBB.1.5, which have more RBD mutations. In sharp contrast, spike‐XBB.1.5 vaccination can activate strong and broadly protective immune responses against XBB.1.5 and other common subvariants of Omicron. By performing correlation analysis, we found that the NAbs titers were negatively correlated with the number of RBD mutations in the Omicron subvariants. Vaccines with more RBD mutations can effectively overcome the immune resistance caused by the accumulation of RBD mutations, making spike‐XBB.1.5 the most promising vaccine candidate against universal Omicron variants.

Heterologous vaccination with subunit protein vaccine induces a superior neutralizing capacity against BA.4/5‐included SARS‐CoV‐2 variants than homologous vaccination of mRNA vaccine

BA.4 and BA.5 (BA.4/5), the subvariants of Omicron, are more transmissible than BA.1 with more robust immune evasion capability because of its unique spike protein mutations. In light of such situation, the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is in desperate need of the third booster. It has been reported that heterologous boosters might produce more effective immunity against wild‐type SARS‐CoV‐2 and the variants. Additionally, the third heterologous protein subunit booster should be considered potentially. In the present study, we prepared a Delta full‐length spike protein sequence‐based mRNA vaccine as the "priming” shot and developed a recombinant trimeric receptor‐binding domain (RBD) protein vaccine referred to as RBD–HR/trimer as a third heterologous booster. Compared to the homologous mRNA group, the heterologous group (RBD–HR/trimer vaccine primed with two mRNA vaccines) induced higher neutralizing antibody titers against BA.4/5‐included SARS‐CoV‐2 variants. In addition, heterologous vaccination exhibited stronger cellular immune response and long‐lasting memory response than the homologous mRNA vaccine. In conclusion, a third heterologous boosting with RBD–HR/trimer following two‐dose mRNA priming vaccination should be a superior strategy than a third homologous mRNA vaccine. The RBD–HR/trimer vaccine becomes an appropriate candidate for a booster immune injection. We prepared a Delta full‐length spike protein sequence‐based mRNA vaccine (Figure A, B) and developed a recombinant trimeric receptor‐binding domain (RBD) protein vaccine (Figure C). Later, the mRNA vaccine was injected as the "priming” shot, and the RBD–HR/trimer vaccine was used as a third heterologous booster (Figure D).

The rapid rise of SARS‐CoV‐2 Omicron subvariants with immune evasion properties: XBB.1.5 and BQ.1.1 subvariants

As the fifth variant of concern of the SARS‐CoV‐2 virus, the Omicron variant (B.1.1.529) has quickly become the dominant type among the previous circulating variants worldwide. During the Omicron wave, several subvariants have emerged, with some exhibiting greater infectivity and immune evasion, accounting for their fast spread across many countries. Recently, two Omicron subvariants, BQ.1 and XBB lineages, including BQ.1.1, XBB.1, and XBB.1.5, have become a global public health issue given their ability to escape from therapeutic monoclonal antibodies and herd immunity induced by prior coronavirus disease 2019 (COVID‐19) vaccines, boosters, and infection. In this respect, XBB.1.5, which has been established to harbor a rare mutation F486P, demonstrates superior transmissibility and immune escape ability compared to other subvariants and has emerged as the dominant strain in several countries. This review provides a comprehensive overview of the epidemiological features, spike mutations, and immune evasion of BQ.1 and XBB lineages. We expounded on the mechanisms underlying mutations and immune escape from neutralizing antibodies from vaccinated or convalescent COVID‐19 individuals and therapeutic monoclonal antibodies (mAbs) and proposed strategies for prevention against BQ.1 and XBB sublineages. In the Omicron wave, two emerging subvariants, BQ.1 and XBB, have rapidly become a global public health concern. This diagram illustrates the critical spike mutations in these subvariants, which can lead to immune escape from prior COVID‐19 vaccines, boosters, and therapeutic monoclonal antibodies (mAbs). Notably, XBB.1.5, which carries a rare F486P mutation, has demonstrated significantly higher receptor‐binding domain (RBD)‐ACE2 binding affinity and transmissibility compared to other subvariants, making it the dominant strain in several countries.

Research progress in spike mutations of SARS-CoV-2 variants and vaccine development.

The coronavirus disease 2019 (COVID-19) pandemic can hardly end with the emergence of different variants over time. In the past 2 years, several variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), such as the Delta and Omicron variants, have emerged with higher transmissibility, immune evasion and drug resistance, leading to higher morbidity and mortality in the population. The prevalent variants of concern (VOCs) share several mutations on the spike that can affect virus characteristics, including transmissibility, antigenicity, and immune evasion. Increasing evidence has demonstrated that the neutralization capacity of sera from COVID-19 convalescent or vaccinated individuals is decreased against SARS-CoV-2 variants. Moreover, the vaccine effectiveness of current COVID-19 vaccines against SARS-CoV-2 VOCs is not as high as that against wild-type SARS-CoV-2. Therefore, more attention might be paid to how the mutations impact vaccine effectiveness. In this review, we summarized the current studies on the mutations of the SARS-CoV-2 spike, particularly of the receptor binding domain, to elaborate on how the mutations impact the infectivity, transmissibility and immune evasion of the virus. The effects of mutations in the SARS-CoV-2 spike on the current therapeutics were highlighted, and potential strategies for future vaccine development were suggested.

Trimeric protein vaccine based on Beta variant elicits robust immune response against BA.4/5-included SARS-CoV-2 Omicron variants.

The current Coronavirus Disease 2019 (COVID-19) pandemic, induced by newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants, posed great threats to global public health security. There is an urgent need to design effective next­generation vaccines against Omicron lineages. Here, we investigated the immunogenic capacity of the vaccine candidate based on the receptor binding domain (RBD). An RBDß-HR self-assembled trimer vaccine including RBD of Beta variant (containing K417, E484 and N501) and heptad repeat (HR) subunits was developed using an insect cell expression platform. Sera obtained from immunized mice effectively blocked RBD-human angiotensin-converting enzyme 2 (hACE2) binding for different viral variants, showing robust inhibitory activity. In addition, RBDß-HR/trimer vaccine durably exhibited high titers of specific binding antibodies and high levels of cross-protective neutralizing antibodies against newly emerging Omicron lineages, as well as other major variants including Alpha, Beta, and Delta. Consistently, the vaccine also promoted a broad and potent cellular immune response involving the participation of T follicular helper (Tfh) cells, germinal center (GC) B cells, activated T cells, effector memory T cells, and central memory T cells, which are critical facets of protective immunity. These results demonstrated that RBDß-HR/trimer vaccine candidates provided an attractive next-generation vaccine strategy against Omicron variants in the global effort to halt the spread of SARS-CoV-2.

Heterologous vaccination with subunit protein vaccine induces a superior neutralizing capacity against BA.4/5-included SARS-CoV-2 variants than homologous vaccination of mRNA vaccine.

BA.4 and BA.5 (BA.4/5), the subvariants of Omicron, are more transmissible than BA.1 with more robust immune evasion capability because of its unique spike protein mutations. In light of such situation, the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in desperate need of the third booster. It has been reported that heterologous boosters might produce more effective immunity against wild-type SARS-CoV-2 and the variants. Additionally, the third heterologous protein subunit booster should be considered potentially. In the present study, we prepared a Delta full-length spike protein sequence-based mRNA vaccine as the "priming" shot and developed a recombinant trimeric receptor-binding domain (RBD) protein vaccine referred to as RBD-HR/trimer as a third heterologous booster. Compared to the homologous mRNA group, the heterologous group (RBD-HR/trimer vaccine primed with two mRNA vaccines) induced higher neutralizing antibody titers against BA.4/5-included SARS-CoV-2 variants. In addition, heterologous vaccination exhibited stronger cellular immune response and long-lasting memory response than the homologous mRNA vaccine. In conclusion, a third heterologous boosting with RBD-HR/trimer following two-dose mRNA priming vaccination should be a superior strategy than a third homologous mRNA vaccine. The RBD-HR/trimer vaccine becomes an appropriate candidate for a booster immune injection.

The rapid rise of SARS-CoV-2 Omicron subvariants with immune evasion properties: XBB.1.5 and BQ.1.1 subvariants.

As the fifth variant of concern of the SARS-CoV-2 virus, the Omicron variant (B.1.1.529) has quickly become the dominant type among the previous circulating variants worldwide. During the Omicron wave, several subvariants have emerged, with some exhibiting greater infectivity and immune evasion, accounting for their fast spread across many countries. Recently, two Omicron subvariants, BQ.1 and XBB lineages, including BQ.1.1, XBB.1, and XBB.1.5, have become a global public health issue given their ability to escape from therapeutic monoclonal antibodies and herd immunity induced by prior coronavirus disease 2019 (COVID-19) vaccines, boosters, and infection. In this respect, XBB.1.5, which has been established to harbor a rare mutation F486P, demonstrates superior transmissibility and immune escape ability compared to other subvariants and has emerged as the dominant strain in several countries. This review provides a comprehensive overview of the epidemiological features, spike mutations, and immune evasion of BQ.1 and XBB lineages. We expounded on the mechanisms underlying mutations and immune escape from neutralizing antibodies from vaccinated or convalescent COVID-19 individuals and therapeutic monoclonal antibodies (mAbs) and proposed strategies for prevention against BQ.1 and XBB sublineages.

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.

Molecular mechanisms and therapeutic target of NETosis in diseases.

Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web-like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: "suicidal" NETosis and "vital" NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell-free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small-vessel vasculitis, inflammatory bowel disease, cancer, COVID-19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll-like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis-induced diseases, and NETosis-targeted therapy.

A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant.

The recently emerged Omicron (B.1.1.529) variant has rapidly surpassed Delta to become the predominant circulating SARS-CoV-2 variant, given the higher transmissibility rate and immune escape ability, resulting in breakthrough infections in vaccinated individuals. A new generation of SARS-CoV-2 vaccines targeting the Omicron variant are urgently needed. Here, we developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of RBD derived from the Delta variant (containing L452R and T478K) and HR1 and HR2 in SARS-CoV-2 S2 subunit in a tandem manner, which can self-assemble into a trimer. In multiple animal models, vaccination of RBD-HR/trimer formulated with MF59-like oil-in-water adjuvant elicited sustained humoral immune response with high levels of broad-spectrum neutralizing antibodies against Omicron variants, also inducing a strong T cell immune response in vivo. In addition, our RBD-HR/trimer vaccine showed a strong boosting effect against Omicron variants after two doses of mRNA vaccines, featuring its capacity to be used in a prime-boost regimen. In mice and non-human primates, RBD-HR/trimer vaccination could confer a complete protection against live virus challenge of Omicron and Delta variants. The results qualified RBD-HR/trimer vaccine as a promising next-generation vaccine candidate for prevention of SARS-CoV-2, which deserved further evaluation in clinical trials.

Molecular mechanisms and therapeutic target of NETosis in diseases

Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web‐like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: “suicidal” NETosis and “vital” NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell‐free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small‐vessel vasculitis, inflammatory bowel disease, cancer, COVID‐19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll‐like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis‐induced diseases, and NETosis‐targeted therapy. NETs are involved in the pathogenesis and progression of various diseases, such as sepsis, SLE, RA, SVV, IBD, cancer, and COVID‐19. Components of NETs may act as autoantigens, leading to inflammation and autoimmune diseases. In addition, some diseases aggravate NETosis and cause a vicious circle.

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 ACE2-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 generate a mouse model of COVID-19 under a general laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) observed in humans. Briefly, human ACE2-transgenic (hACE2) mice were intratracheally instilled 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-1ß, 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.

SARS-CoV-2 Omicron variant: Characteristics and prevention.

Coronavirus disease 2019 (COVID-19) has brought about a great threat to global public health. Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 has been reported in South Africa and induced a rapid increase in COVID-19 cases. On November 24, 2021, B.1.1.529 named Omicron was designated as a variant under monitoring (VUM) by World Health Organization (WHO). Two days later, the Omicron variant was classified as a variant of concern (VOC). This variant harbors a high number of mutations, including 15 mutations in the receptor-binding domain (RBD) of spike. The Omicron variant also shares several mutations with the previous VOC Alpha, Beta, and Gamma variants, which immediately raised global concerns about viral transmissibility, pathogenicity, and immune evasion. Here we described the discovery and characteristics of the Omicron variant, compared the mutations of the spike in the five VOCs, and further raised possible strategies to prevent and overcome the prevalence of the Omicron variant.

The challenges of COVID‐19 Delta variant: Prevention and vaccine development

Several SARS‐CoV‐2 variants have emerged since the pandemic, bringing about a renewed threat to the public. Delta variant (B.1.617.2) was first detected in October 2020 in India and was characterized as variants of concern (VOC) by WHO on May 11, 2021. Delta variant rapidly outcompeted other variants to become the dominant circulating lineages due to its clear competitive advantage. There is emerging evidence of enhanced transmissibility and reduced vaccine effectiveness (VE) against Delta variant. Therefore, it is crucial to understand the features and phenotypic effects of this variant. Herein, we comprehensively described the evaluation and features of Delta variant, summarized the effects of mutations in spike on the infectivity, transmission ability, immune evasion, and provided a perspective on efficient approaches for preventing and overcoming COVID‐19. SARS‐CoV Delta (B.1.617.2) variant has been classified as variants of concern (VOC) by World Health Organization (WHO). The reproductive number (R0) of SARS‐CoV‐2 wild type and Delta variant is 2.3‐5.7 and 5‐8, respectively. Patients infected by Delta variant exhibit shorter mean generation time and mean serial interval, higher virus load and hospitalization rate compared to those infected by wild‐type SARS‐CoV‐2.

Animal models for SARS‐CoV‐2 infection and pathology

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the etiology of coronavirus disease 2019 (COVID‐19) pandemic. Current variants including Alpha, Beta, Gamma, Delta, and Lambda increase the capacity of infection and transmission of SARS‐CoV‐2, which might disable the in‐used therapies and vaccines. The COVID‐19 has now put an enormous strain on health care system all over the world. Therefore, the development of animal models that can capture characteristics and immune responses observed in COVID‐19 patients is urgently needed. Appropriate models could accelerate the testing of therapeutic drugs and vaccines against SARS‐CoV‐2. In this review, we aim to summarize the current animal models for SARS‐CoV‐2 infection, including mice, hamsters, nonhuman primates, and ferrets, and discuss the details of transmission, pathology, and immunology induced by SARS‐CoV‐2 in these animal models. We hope this could throw light to the increased usefulness in fundamental studies of COVID‐19 and the preclinical analysis of vaccines and therapeutic agents. Animal models that recapitulate characteristics and immune responses observed in COVID‐19 patients are urgently needed. These animal models such as mouse, hamster, nonhuman primate, and ferret, have provided robust platforms for studying the transmission, pathogenesis, and immunology induced by SARS‐CoV‐2, and for evaluating the immunomodulatory and antiviral drugs and vaccines against COVID‐19.

Pulmonary vascular system: A vulnerable target for COVID‐19

The number of coronavirus disease 2019 (COVID‐19) cases has been increasing significantly, and the disease has evolved into a global pandemic, posing an unprecedented challenge to the healthcare community. Angiotensin‐converting enzyme 2, the binding and entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in hosts, is also expressed on pulmonary vascular endothelium;thus, pulmonary vasculature is a potential target in COVID‐19. Indeed, pulmonary vascular thickening is observed by early clinical imaging, implying a tropism of SARS‐CoV‐2 for pulmonary vasculature. Recent studies reported that COVID‐19 is associated with vascular endothelial damage and dysfunction along with inflammation, coagulopathy, and microthrombosis;all of these pathologic changes are the hallmarks of pulmonary vascular diseases. Notwithstanding the not fully elucidated effects of COVID‐19 on pulmonary vasculature, the vascular endotheliopathy that occurs after infection is attributed to direct infection and indirect damage mainly caused by renin‐angiotensin‐aldosterone system imbalance, coagulation cascade, oxidative stress, immune dysregulation, and intussusceptive angiogenesis. Degradation of endothelial glycocalyx exposes endothelial cell (EC) surface receptors to the vascular lumen, which renders pulmonary ECs more susceptible to SARS‐CoV‐2 infection. The present article reviews the potential pulmonary vascular pathophysiology and clinical presentations in COVID‐19 to provide a basis for clinicians and scientists, providing insights into the development of therapeutic strategies targeting pulmonary vasculature. SARS‐CoV‐2 infection‐induced pulmonary vascular injury and potential treatments target the pulmonary vascular system.

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-Barré syndrome, 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.