SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Sungnak, Waradon; Huang, Ni; Bécavin, Christophe; Berg, Marijn; Queen, Rachel; Litviňuková, Monika; Talavera-López, Carlos; Maatz, Henrike; Reichart, Daniel; Sampaziotis, Fotios; Worlock, Kaylee B; Yoshida, Masahiro; Barnes, Josephine

doi:10.1038/s41591-020-0868-6

Cited by 2,435 publications

(2,752 citation statements)

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“…Recent literature also indicated the potential role of other proteases like cathepsin B/L that can functionally replace TMPRSS2, need to be evaluated extensively. [2] All these hypotheses warrant further in-silico analyses with better computational resources, as well as experimental study designs and for these we are open to seek collaborations.…”

Section: Dynamics and Binding Analysis Of Ace2 With Sars Cov-2 Rbd Inmentioning

confidence: 99%

“…It has been established that Human ACE2 mediates SARS-CoV-2 entry into cells through its Spike (S) Protein an primarily makes entry to host body through respiratory tract with recent reporting of nasal epithelial cells as potential initial infection site. [2] Angiotensin-converting enzyme 2 (ACE2) is functional receptor on human cells for this newly originated coronavirus [3] with higher affinity then severe acute respiratory syndrome coronavirus (SARS-CoV) originated in 2002. [4].…”

Section: Introductionmentioning

confidence: 99%

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ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

Sharma

Singh

Haider

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S protein priming by host cell serine protease TMPRSS2. Recently COVID19 has been declared pandemic by World Health Organization yet high differences in disease outcomes across countries have been seen. We provide evidences based on analyses of existing public datasets and by using various insilico approaches to explain some of these as factors that may explain population level differences. One of the key factors might be entry of virus in host cells due to differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that higher expression of ACE2 facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs) and with different frequencies in different populations, results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2 and becomes more difficult in presence of broad neutral amino acid transporter, B0AT1 (coded by SLC6A19), that usually does not express in Lungs. We also propose that the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of Virus in host cells. In addition, we suggest some other potential key host genes like ADAM17, RPS6, HNRNPA1, SUMO1, NACA,

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Section: Dynamics and Binding Analysis Of Ace2 With Sars Cov-2 Rbd Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

Sharma

Singh

Haider

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The novel SARS-CoV-2 virus infection is mainly transmitted by micro-droplets generated in the airway of an infected person and ejected during cough, sneeze and ordinary talk [16,17]. The droplets, containing virions, can enter a host through the epithelial cells of the upper respiratory tract and conjunctiva [18]. The clinical and epidemiological importance of aerosol transmission remains under investigation [19].…”

Section: The Sars-cov-2 Virus Its Transmission and Entry Pointsmentioning

confidence: 99%

“…The virus uses a double-domain glycoprotein on its surface (S1), which has a high affinity to angiotensin-converting enzyme type 2 (ACE2) receptors, to invade cells [2,3,21]. Viral entry is enabled through the promotion of S1 by hosts transmembrane protease serine 2 (TMPRSS2) and endosomal cysteine proteases cathepsin B and L [18,22]. Expression of the ACE2 gene may differ between populations, thus explaining some geographical differences in COVID-19 severity [23].…”

Section: The Sars-cov-2 Virus Its Transmission and Entry Pointsmentioning

confidence: 99%

“…Given the vast representation of the receptors as mentioned above in human tissues, the virus itself has a broad capacity to infect various human cell types and induce different pathogenic chains of events that correspond with a variety of clinical pictures of COVID-19 [14,24,25]. Viral replication begins in the ciliated epithelium of the nasal cavity with the highest expression of its receptors in the goblet/secretory cells and the highest virus yield found in nasal swabs [18,24]. Down the airway, the next target of the virus and the site of its replication with critical pathogenic implications is the lower respiratory tract and pneumocytes [7].…”

Section: The Sars-cov-2 Virus Its Transmission and Entry Pointsmentioning

confidence: 99%

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COVID-19 — Toward a comprehensive understanding of the disease

et al. 2020

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The evidence on the pathophysiology of the novel coronavirus SARS-CoV-2 infection is rapidly growing. Elucidating why some patients suffering from COVID-19 are getting so sick, while others are not, has become an informal imperative for researchers and clinicians around the globe. The answer to this question would allow rationalizing the fear surrounding this pandemic. Understanding of the pathophysiology of COVID-19 relies on unraveling of interplaying mechanisms, including SARS-CoV-2 virulence, human immune response, and complex inflammatory reactions with coagulation playing a major role. An interplay with bacterial co-infections, as well as the vascular system and microcirculation affected throughout the body should also be examined. More importantly, a comprehensive understanding of pathological mechanisms of COVID-19 will increase the efficacy of therapy and decrease mortality. Herewith, the authors present a combined viewpoint based on the current state of knowledge on COVID-19: beginning from the virus, its transmission, and mechanisms of entry into the human body, through the pathological effects on the cellular level, up to immunological reaction, systemic and organ presentation. Last but not least, currently available and possible future therapeutic and diagnostic options are briefly commented on. (Cardiol J 2020; 27, 2: 99-114)

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Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19)

Wiersinga

Rhodes

Cheng

et al. 2020

JAMA

4,454

4,322

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IMPORTANCEThe coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.OBSERVATIONS SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies.CONCLUSIONS AND RELEVANCE As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

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SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Cited by 2,435 publications

References 40 publications

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

COVID-19 — Toward a comprehensive understanding of the disease

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19)

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