Cells in the nasal passages and upper airways are likely the coronavirus major point of entry into the body


Cells in the nasal passages and upper airways are likely the coronavirus’ major point of entry into the body, according to a study by Stanford Medicine researchers.

The finding further supports the use of masks to prevent viral spread and suggests that nasal sprays or rinses might be effective in blocking infection by the coronavirus.

The study also found that common blood pressure medications are unlikely to increase the risk of contracting COVID-19, countering concerns that hypertension drugs could make it easier for the coronavirus to enter human cells.

“Early in the pandemic, there were concerns that two classes of blood pressure medications may increase the risk for COVID-19,” said Ivan Lee, MD, Ph.D., an instructor of allergy and immunology.

“Our results suggest that this is not the case. Furthermore, face masks should be carefully worn to cover the nose, as the virus binds readily to cells in the nasal passage.”

Lee, research scientist Tsuguhisa Nakayama, MD, Ph.D.; senior scientist Yury Goltsev, Ph.D.; and postdoctoral scholars Chien-Ting Wu, Ph.D., and Sizun Jiang, Ph.D., are co-lead authors of the study, which was published Oct. 28 in Nature Communications. The senior authors are Garry Nolan, Ph.D., the Rachford and Carlota A. Harris Professor and professor of microbiology and immunology; Jayakar Nayak, MD, Ph.D., associate professor of otolaryngology; and Peter Jackson, Ph.D., professor of microbiology and immunology.

Hijacking a defense mechanism

The coronavirus that causes COVID-19 enters human cells by binding to a protein on the cell surface called ACE2.

Lee and his colleagues compared levels of ACE2 in the lungs, kidneys, testes and intestines with ACE2 levels in cells lining the upper and lower airways.

They found high levels of ACE2 in airway cilia—tiny, flexible projections on the respiratory cell surfaces that sweep the airway clean of foreign particles like dust and invading pathogens.

“The virus hijacks this protective feature by binding to ACE2 on cilia and infecting these cells,” Lee said. “Because most people breathe primarily through their nose, this is mostly likely the site of initial viral contact and infection.”

Because hypertension is a risk factor for severe COVID-19, Lee and his colleagues also assessed the levels of ACE2 in sinus tissue samples obtained from hundreds of people with chronic sinusitis. Some of these people were taking common blood pressure medications known as ACE inhibitors or angiotensin receptor blockers; others were not.

“Past studies have found that the use of ACE inhibitors for hypertension increases the expression of ACE2 in the kidney and heart,” Lee said. “But the effect of these medications in the upper airways is more relevant when considering coronavirus infection.”

However, Lee and his colleagues found that ACE2 levels in the upper airways did not vary significantly between those people taking blood pressure medications and those who were not.

“This is the first mechanistic-based evidence that the use of ACE inhibitors and angiotension receptor blockers don’t increase levels of ACE2 in these upper airway cells,” Lee said.

An opening for infection prevention?

The discovery of high levels of ACE2 protein in the airway cells might drive the development of new ways to prevent viral infection at the source, the researchers said.

“We are now examining how airway cilia detect and react to the virus,” Jackson said. “There may be ways to promote rhythmic beating of cilia to increase the flow of mucus and help eliminate the virus.”

“Currently, major efforts are devoted to medications that work systemically through either intravenous or oral delivery,” Lee said. “But if the virus enters the body through the nasal lining, it also makes sense to explore nasally administered drugs and sprays to prevent infection.

The nose is a very favorable location to deliver medications. Our findings also provide strong scientific justification to recommendations made by the health care community to use masks that cover the mouth and nose to prevent coronavirus infection.”

In December 2019, a cluster of atypical pneumonia associated with a novel coronavirus was detected in Wuhan, China1. This coronavirus disease, termed COVID-19, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously termed 2019-nCoV)2.

The virus has since spread worldwide, emerging as a serious global health concern in early 20203,4. Human-to-human transmission of the virus has been reported in several instances5–7 and is thought to have occurred since mid-December 20198. As of early March 2020, there were more than 100,000 confirmed COVID-19 cases4.

Patients with suspected COVID-19 have been treated in the Wuhan Jin Yintan Hospital since Dec 31st, 20199. In a meta-analysis of 50,466 hospitalized patients with COVID-19 from 10 studies, most patients were from China and the average age in the included studies ranged from 41 to 56 years old10.

The prevalence rates of fever, cough, and muscle soreness or fatigue were 89.1%, 72.2%, and 42.5%. Critical illness requiring admission to an intensive care unit occurred in 18.1% of patients, and 14.8% developed acute respiratory distress syndrome (ARDS)10. Acute renal injury and septic shock have been observed in 4% and 5% of patients hospitalized with COVID-19, respectively1,9.

Chest imaging demonstrated bilateral pneumonia involvement in more than 80% of cases1,9,11. Ground-glass opacities were the most common radiologic finding on chest computed tomography (CT)11,12. Abnormalities on CT were also observed preceding symptom onset in patients exposed to infected individuals, with an incidence of 93%10,11.

Pathological evaluation of a patient who died of severe disease revealed diffuse alveolar damage consistent with ARDS13. Currently, the estimated mortality rate is 3.4%14. These clinical data underscore the severity of this infection. The involvement of both lungs in most of the cases suggests viral dissemination after initial infection.

Viral RNA was detected in the upper airways from symptomatic patients, with higher viral loads observed in nasal swabs compared to those obtained from the throat15. Similar viral loads were observed in an asymptomatic patient15, indicating that the nasal epithelium is an important portal for initial infection, and may serve as a key reservoir for viral spread across the respiratory mucosa and an important locus mediating viral transmission. Identification of the cells hosting viral entry and permitting viral replication as well as those contributing to inflammation and disease pathology is essential to improve diagnostic and therapeutic interventions.

Cellular entry of coronaviruses depends on the binding of the spike (S) protein to a specific cellular receptor and subsequent S protein priming by cellular proteases. Similar to severe acute respiratory syndrome-associated coronavirus (SARS-CoV)16,17, the SARS-CoV-2 employs angiotensin-converting enzyme-2 (ACE2) as a receptor for cellular entry.

In addition, studies have shown that the serine protease TMPRSS2 can prime S protein15,18 although other proteases like cathepsin B/L can also be involved18. For SARS, the binding affinity between the S protein and the ACE2 receptor was found to be a major determinant of viral replication rates and disease severity19. The SARS-CoV-2 has been shown to infect and replicate in Vero cells, a Cercopithecus aethiops (old world monkey) kidney epithelial cell line, and huh7 cells, a human hepatocarcinoma cell line15.

The BHK21 cell line has been shown to facilitate viral entry by the SARS-CoV-2 S protein only when engineered to express the ACE2 receptor ectopically18. In addition, viral entry was found to depend on TMPRSS2 activity, although cathepsin B/L activity might substitute for the loss of TMPRSS218. The in vivo expression of ACE2 and TMPRSS2 (as well as other candidate proteases) by cells of the upper and lower airways and alveoli must be defined.

Previously, gene expression of ACE2 and TMPRSS2 has been reported to occur largely in type-2 alveolar (AT-2) epithelial cells15, which are central to SARS-CoV pathogenesis. A study reported that ACE2 expression is absent from the upper airways20. The rapid spread of the SARS-CoV-2 suggests efficient human-to-human transmission which would, in turn, seem to supersede the odds of dependency on alveolar epithelial cells as the primary point of entry and viral replication8,21,22.

Indeed, protein expression, based on immunohistochemistry, of ACE2 and TMPRSS2 has been reported in both nasal and bronchial epithelium23. To clarify the expression patterns of ACE2 and TMPRSS2 and analyze the expression of the other potential genes associated with SARS-CoV-2 pathogens at cellular resolution, we interrogated single-cell transcriptome expression data from published scRNA-seq datasets from healthy donors generated by the Human Cell Atlas consortium24.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280877/

More information: Ivan T. Lee et al. ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs, Nature Communications (2020). DOI: 10.1038/s41467-020-19145-6


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