Many are epithelial cells, which line the outer surface of organs. The new findings add to an emerging picture of SARS-CoV-2 as a virus that can target cells in many places in the human body, rather than being focused on a particular organ or part of the respiratory tract. By scouring single-cell sequencing records of around 1. The analysis used 16 unpublished datasets of lung and airway cells and 91 published datasets spanning a range of human organs. Overall, the main histological findings in the lungs represents patchy necrosis; hyaline membrane formation and hyperplasia of type II pneumocystis that represent diffuse alveolar damage and injury to the gas-exchange surfaces Anderson et al.
The pathological lung damages in the novel viral disease may be due to either directly viral destruction of alveolar and bronchial epithelial cells or a cytokine storm Xu Z. However, respiratory distress in COVID patients may be due to the viral access to CNS and induced damage in the respiratory centers of the brain, making it more complicated to manage these patients Baig et al. The retrospective studies as well as case reports from different region in the world; indicate that Covid affects CNS in several ways and leads to a broad spectrum of neurological symptoms from a simple headache to more serious encephalitis Sheraton et al.
The new virus may induces nerve damage through the several mechanisms including direct infection or immune injury Wu et al. Coronaviruses are able to reach to the CNS via the synapse connected routes and retrograde transport Perlman et al. In the case of murine models of SARS or MERS-CoVs infection, intranasal infection enables the virus to access the brain via the olfactory nerves and rapidly infect specific brain areas such as the brain stem and thalamus Netland et al.
Since SARS-CoV-2 is mainly spread through the respiratory system, retrograde transport through the olfactory nerve may be the main route for transfer of virus to the central nervous system CNS Mori, ; Desforges et al. The highly specialized functions and limited regenerative capacity of neurons means that chronic and latent CNS SARS-CoV-2 infection may have long-term detrimental consequences Andries and Pensaert, Considering the large number of patients involved globally, the risk of future neurological disorders is worrying and the clinicians should pay more attention to the neurologic symptoms in COVID patients especially in the early phase of infection.
The viral factors include virus type, titer, viability and mutations, whilst the host immune factors including age, gender and genetics such as HLA genes which together determine the duration and severity of the disease Rithanya and Brundha, This long incubation period is due to its ability to escape from host immune detection at the early stages of infection Prompetchara et al. Despite the low viral burden and local propagation of virus, the virus can be detected by nasal swabs by RT-PCR Mason, There is a low immune response at this step.
The virus then replicates and migrates through the conducting airways and a more robust innate immune response is triggered. The innate immune response is the first line of defense against viral infection and has a determinant role in protective or destructive responses upon infection Kindler et al. Upon viral infection, type I interferon IFN responses and its downstream cascade are initiated in order to control viral replication and induce an effective adaptive immune response Prompetchara et al.
This dampening procedure is closely associated with disease severity. Viral proteins actively modulate this pathway. In contrast, a delayed induction of type I IFN compromises the early viral control and drives the influx of hyper-inflammatory neutrophils and monocytes-macrophages which lead to a mass production of pro-inflammatory cytokines and may evoke a cytokine storm Channappanavar and Perlman, A cytokine storm leads to an uncontrolled systemic inflammatory response that may trigger a severe attack on the body by its own immune system.
Furthermore, increased total blood neutrophils and decreased total blood lymphocytes in patients within ICU compared with patients not in ICU care correlated with disease severity and death Prompetchara et al.
In patients with reduced immune fitness whose innate immune system is unable to clear the virus, NLRP3 activation may occur Freeman and Swartz, A sustained and unregulated NLRP3-dependent inflammatory response leads to the severe clinical symptoms including necrosis, fever, release of damage-associated molecular patterns DAMP and severe inflammation van den Berg and Te Velde, Direct activation of NLRP3 induces pyroptosis and cell death in human cells.
Genetic variations in host inflammasome pathways may also influence disease outcome and may be responsible for the heterogeneous response of patients with COVID and the array of clinical severity Freeman and Swartz, In the case of SARS—CoV, infection of lymphocytes has been proposed to play the major role in viral-induced pathogenicity.
SARS-CoV-infected lymphocytes, similar to feline infectious peritonitis virus FIPV -infected macrophages in domestic cats, might transport the virus to distant organs resulting in systemic infection de Groot-Mijnes et al. Upon virus entry, immunogenic peptides are presented to T cells in association with human leukocyte antigen HLA on the surface of antigen presenting cells APC.
This would markedly diminish T cell activation in response to the virus Shokri et al. During viral infection, antigen presentation triggers both humeral and cellular immunity mediated by virus-specific B and T cells. Specific B and T cells epitopes are commonly mapped against the structural S and N proteins Berry et al. Indeed, long lasting specific IgG was detected up to 2 years post infection Li et al. In one patient, serology reports showed the peak of specific IgM at day 9 after the onset of the disease and switching to IgG by week 2 Zhou P.
Furthermore, all sera from patients were able to neutralize SARS-CoV-2 in an in vitro plaque assay, suggesting a possible successful mounting of the humoral responses Zhou P et al. In a recent study of patients with mild to severe disease, In addition, Antibody titers in the severe group were higher than those with milder disease.
This highlights the importance of serological testing as a complement to the RT-PCR test in surveying for asymptomatic patients in close contact with other Liu et al. During viral infection, T helper Th cells play an important role in the adaptive immunity.
The cytokine microenvironment generated by antigen presenting cells directs T cell responses. In contrast, memory T cells promote antigen-specific immune responses.
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections as well as during persistent viral infections Wherry, It seems that the cytokine storm may promote apoptosis or necrosis of T cells and thereby reduce their numbers Xi-zhi and Thomas, Interestingly, the concentrations of these cytokines were negatively correlated with total T cell counts Diao et al.
Inhibition of IL also reduced the degree of T cell exhaustion in animal models of chronic infection Ejrnaes et al. IL-6 contributes to host defense by stimulating acute phase responses or immune reactions in response to infections and tissue injury. Deregulated and continual synthesis of IL-6 plays a pathological role in chronic inflammation and infection Jones and Jenkins, The level of IL-6 in severe patients continue to increase over time and is higher in non-survivors Zhou F et al.
It is suggested that the different mortality rates in COVID patients is due to the difference in the response to infection Bienvenu et al. Furthermore, it is reported that male patients had higher plasma levels of innate immune cytokines including IL-8 and IL along with activated non-classical monocytes. A poor T cell response may be responsible for the worse outcome in male patients, while in female patients, higher levels of innate immune cytokines were associated with worse disease Takahashi et al.
Another question regarding this new disease is that whether the infection induces persistent immune memory that could protect the recovered individual against reinfection. The durability of protective antibodies induced by SARS-CoV-2 or the antibody titers that will protect against reinfection is still unclear.
It is reported that antibodies disappear rapidly after recovery particularly in patients with mild disease. However; even in the absence of specific serum antibodies, the presence of memory B and T cells may be maintained Cox and Brokstad, This longitudinal study assessed the immune response in patients who recovered from mild symptomatic COVID These recovered individuals developed SARS-CoVspecific IgG antibody and neutralizing plasma in addition to virus-specific memory B and T cells that had ability to expand over three months following the onset of symptoms Rodda et al.
Studies of patients infected with SARS-CoV in suggested that the infection induced durable T cell responses lasting for up to 6 years but no prolonged memory B cells. It is hypothesized that this might be due to immunity to common cold coronaviruses that could influence COVID disease severity Sette and Crotty, Currently, broad-spectrum antiviral drugs like nucleoside analogues and HIV-protease inhibitors are being used to attenuate viral infection Lu, Other treatment regimens include a combination of oral oseltamivir, lopinavir and ritonavir and intravenous administration of ganciclovir for 3—14 days Chen N.
Although the antivirals remdesivir and chloroquine controlled SARS-CoV-2 infection in vitro , these have shown variable results in the clinic Wang et al. EIDD is a new drug used to control and treat seasonal and pandemic influenza virus infections.
It has high therapeutic efficacy in humans and may be considered as a potential drug for the treatment of COVID infection Toots et al. Data from cohort and cross sectional studies in patients with heart failure or cardiovascular disease showed that the effect of these inhibitors on ACE2 is not uniform even in response to a given drug class Shearer et al. Angiotensin receptor 1 AT1R blockers, such as losartan, have also been suggested as a therapeutic approach for reducing the severity and mortality of SARS-CoV-2 infections Gurwitz, The central role of cytokine dysregulation in the pathogenicity of seriously ill COVID patients has indicated the potential of cytokine-targeted therapy in managing disease progression Rahmati M.
Tocilizumab Actemra is a humanized anti-IL-6 receptor antibody that was successful in the treatment of rheumatoid arthritis RA and juvenile idiopathic arthritis Burmester et al. Anakinra is a recombinant interleukin-1 IL-1 receptor antagonist that has anti-inflammatory and immunomodulatory effect used to treat of inflammatory arthritides Furst, Remdesivir an antiviral compound that was firstly introduced for Ebola virus Wang et al.
There are ongoing clinical trials in a number of countries for remdesivir as a potential treatment for COVID Currently, the drug is given intravenously through daily infusions in the hospital. However, an inhaled formulation given through a nebulizer, may potentially allow for easier administration outside the hospital at earlier stages of the disease. These approaches would be valuable to investigate for COVID and open a window for finding new ways to protect against and treat this deadly epidemic.
These include numerous pharmacological and biological approaches and the use of natural products. Despite the high rate of mortality and morbidity, no medication or vaccine has been consistently shown to be effective.
The rapid spread, induction of severe infection, cross-species transmission and unpredicted behavior of coronaviruses result in them being a continuous threat to human health. This is important due to the existence of many animal reservoirs for CoVs and the lack of an approved treatment. There is an imperative need to design and develop effective therapeutic and preventive strategies.
Techniques such as single cell sequencing and cellular indexing of transcriptomes and epitopes by sequencing CITE-seq will tremendously increase our understanding of disease pathology and enable knowledge-based decisions for the adoption of new therapeutic immune modalities. SA wrote first draft. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ades P. Artery Dis. Aggarwal S. PubMed Abstract Google Scholar. Al-Obaidi M. Disruption of the blood brain barrier is vital property of neurotropic viral infection of the central nervous system. Acta Virol. Andersen K. Anderson D. AIDS 24 2 , — Andries K. Immunofluorescence studies on the pathogenesis of hemagglutinating encephalomyelitis virus infection in pigs after oronasal inoculation.
Atal S. Ayala-Nunez N. Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells. Babaha F. Badae N. Is the cardioprotective effect of the ACE2 activator diminazene aceturate more potent than the ACE inhibitor enalapril on acute myocardial infarction in rats?
Baig A. ACS Chem. Bansal M. Beigel J. Remdesivir for the Treatment of Covid - Preliminary Report. Belouzard S. Mechanisms of coronavirus cell entry mediated by the viral spike protein. ACE2 is distributed mainly in the lung, intestine, heart, and kidney, and alveolar epithelial type II cells are the major expressing cells [ 36 ].
Luan et al. Viral fusion refers to fusion of the viral membrane and host cell membrane, resulting in the release of the viral genome into the host cell. The S protein is cleaved into two parts, the S1 subunit and S2 subunit, by host proteases, and the subunits exist in a noncovalent form until viral fusion occurs [ 40 ]. SARS-CoV-2 S has multiple furin cleavage sites, which increases the probability of being cleaved by furin-like proteases and thereby enhances its infectivity [ 43 , 44 ].
The furin-like cleavage domain is also present in highly pathogenic influenza virus and is related to its pathogenicity, as observed in the avian influenza outbreak in Hong Kong in [ 45 , 46 ]. Another host cell protease that has been proven to cleave viral S protein is trypsin [ 49 ].
The formation of 6-HB is essential for viral fusion. Under the action of some special ligands, the fusion protein undergoes a conformational change and then inserts into the host cell membrane Fig.
The distance between the viral membrane and host cell membrane is shortened, and the HR1 domain of the S protein is in close proximity to the host cell membrane, whereas the HR2 domain is closer to the viral membrane side.
Then, HR2 folds back to HR1, the two HR domains form a six-helix structure in an antiparallel format of the fusion core, the viral membrane is pulled toward the host cell membrane and tightly binds to it, and the two membranes fuse [ 52 ]. The fundamental role of the S protein in viral infection indicates that it is a potential target for vaccine development, antibody-blocking therapy, and small molecule inhibitors. Unlike other functional proteins of SAS-CoV-2, it is responsible for inducing the host immune response, and nAbs targeting the S protein can induce protective immunity against viral infection.
The mapping of multiple S sequences of the subgenus Sarbecovirus underscores that the S2 fusion region is more conserved than the S1 subunit and that the S1 subunit is more exposed at the viral surface [ 16 ]. Viracept is the first reported small molecule fusion inhibitor in addition to peptide fusion inhibitors. This discovery makes possible clinical applications of anti-SARS-CoV-2 therapeutics, especially in the early stage of infection. There are currently five clinical trials registered to evaluate the efficacy of camostat mesilate ClinicalTrials.
Phosphatidylinositol 3-phosphate 5-kinase PIKfyve is the main enzyme synthesizing PI 3,5 P2 in early endosomes [ 71 ]. Furin proprotein convertase PC subtilisin kexin 3, PCSK3 , as a member of the PC family, catalyzes the hydrolysis of peptide and protein substrates at paired basic residues [ 74 ]. The SARS-CoV-2 S protein binds to the host cell receptor and induces virus—cell membrane fusion, which plays a vital role in the process of virus invasion.
Further understanding of the structure and function of SARS-CoV-2 S will allow for additional information regarding invasion and pathogenesis of the virus, which will support the discovery of antiviral therapeutics and precision vaccine design.
Structural information will also assist in evaluating mutations of the SARS-CoV-2 S protein and will help in determining whether these residues have surface exposure and map to known antibody epitopes of S proteins from other coronaviruses.
In addition, structural knowledge ensures that the proteins produced by constructs are homogeneous and participate in the prefusion conformation, which should maintain the most neutralization-sensitive epitopes when used as a candidate vaccine or B-cell probe for isolating neutralizing human mAbs. Furthermore, atomic-level details will enable the design and screening of small molecules that inhibit fusion.
Similarly, focusing on high expression of the S protein or its receptor binding region is also of great significance for the development of vaccines. Therefore, the development of antibodies targeting this functional motif may cross-bind and neutralize these two viruses and related CoVs.
Antiviral peptides prevent SARS-CoV-2 membrane fusion and can potentially be used for the prevention and treatment of infection. More importantly, EK1C4 can be used as a nasal drop, which increases its medicinal properties, it possesses a high genetic barrier to resistance, and does not easily induce drug-resistant mutations. On the other hand, peptide fusion inhibitors may not be widely used clinically and have low bioavailability. Therefore, the development of oral small molecule fusion inhibitors is a major direction.
In the course of virus epidemics, the ability to adapt to external pressure is an important factor affecting the spread of the virus. Regarding the envelope S protein, recombination or mutation in the gene of its RBD can occur to promote transmission between different hosts and lead to a higher fatality rate [ 81 ]. Mutation of the aspartate D at position to glycine G results in a more pathogenic strain of SARS-CoV-2 [ 82 ], which makes it more difficult to develop antibodies or vaccines that target nonconservative regions.
To effectively prevent disease, combinations of different mAbs that identify different epitopes on the SARS-CoV-2 S surface can be assessed to neutralize a wide range of isolates, including escape mutants [ 83 ].
Clinical trials of the vaccine are expected in the coming months. A novel coronavirus from patients with pneumonia in China, N Engl J Med. Acta Pharm Sin B. Research and development on therapeutic agents and vaccines for COVID and related human coronavirus diseases.
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The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol. Fusion mechanism of nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cell Mol Immunol. Coronavirus membrane fusion mechanism offers a potential target for antiviral development. However, the ability of these cells to protect from future infection remains to be determined. These studies were done in small numbers of patients and need verification.
Potential for long-term immunity Early research suggests that the antibodies in people infected with SARS-CoV-2 dropped significantly within 2 to 3 months [ 21 , 22 ], causing concern that humoral immunity against the virus may decline rapidly.
However, it is a normal part of the immune response that antibody levels fall after an infection has resolved [ 23 ].
For example, in seasonal coronavirus infections, antibodies start to decline at about a week after infection and typically only last for about a year [ 24 ].
It should also be noted that memory T and B cells are formed after infection [ 25 , 26 ]; these can be reactivated when another infection with the same virus occurs and could provide long-lasting immunity. A preliminary study that has not yet undergone peer review has shown that memory T and B cells were found in patients with mild COVID symptoms who had recovered and that these cells persisted, suggesting the potential for longer-term immunity [ 27 ].
SARS-CoVspecific memory T cells have also been detected in exposed seronegative healthy individuals relatives of confirmed cases , which may indicate asymptomatic infection. Asymptomatic infections may therefore be more common, and antibody testing alone may underestimate the true prevalence of the infection or population immunity. SARS-CoVspecific T cells were found in most of the convalescent patients in this study, which is a promising sign that infection may give rise to immunity [ 29 ].
Potential therapeutic interventions Interleukin 7 IL-7 , a cytokine that is essential for lymphocyte survival and expansion, may provide a promising therapeutic strategy and when given to patients can increase circulating and tissue lymphocytes [ 30 ]. However, randomized controlled trials are required to assess the safety and efficacy of IL-7 as a treatment, and some are currently underway [ 31 ].
Questions remain around the use of immune checkpoint inhibitors, for example, in cancer therapy, and their role in COVID infection. It could theoretically either mitigate or exacerbate COVID severity [ 37 ], depending on the stage of the disease. Trials are required to evaluate these interventions in COVID; one trial evaluating pembrolizumab as part of a study assessing checkpoint blockade interventions in COVID is currently underway [ 38 ] and several trials are registered planning to assess nivolumab safety and efficacy in patients with COVID [ 39 ].
Acknowledgements: The authors would like to thank Dr. Griseri for helpful discussions. Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement, and the sources cited should be checked.
The views are not a substitute for professional medical advice. Navigate this website. Box 1.
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