Scientific Research News | Research Progress of novel coronavirus Pneumonia (COVID-19) (30)

1. COVID-19 Alert

■ On 2 February, WHO Director-General Tedros Adhanom Ghebreyesus announced in Geneva that the global risk level of COVID had been raised to the highest level "very high". Previously, the global risk level of new coronavirus pneumonia was "high risk". Tedros said that the number of infections continues to increase, and the number of confirmed cases in more countries is worrying, so he decided to raise the global risk level of the new crown pneumonia epidemic.
Tedros said earlier that global epidemic prevention and control has entered a "decisive moment". WHO advocates that every country must be prepared for all eventualities at the same time, and that no country should take any chance that it will not have a case.

Tedros stressed that interconnected outbreaks have emerged in several countries, but most COVID cases can still trace close contacts and clusters of infected people, and there is no evidence of uncontrolled transmission of the virus in the community.

Tedros revealed that there are currently more than 20 new crown pneumonia vaccines under development around the world, and a number of drugs are undergoing clinical trials, and the first clinical trial results are expected to be available within a few weeks.

On the same day, UN Secretary-General António Guterres issued a statement to reporters at UN Headquarters. Guterres pointed out that countries need to be fully prepared, and the biggest enemy now is not the virus, but fear, rumors and discrimination. "It is possible to contain the outbreak, but the window of opportunity is narrowing," Guterres said. "Guterres called on all governments to stand up for global solidarity and full cooperation.

2. Progress in COVID-19 biology research

■ On February 2, Cell magazine published an article online titled "SARS-CoV-28 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically-proven protease inhibitor", which revealed the key proteins needed for the new coronavirus to invade cells. It is also pointed out that a protease inhibitor approved for marketing in Japan has shown inhibitory effects in experiments and is expected to become a potential treatment option.

The researchers used replication-deficient vesicular stomatitis virus (VSV) particles carrying the coronavirus S protein and the SARS virus S protein to infect a series of human and animal cell lines, and found that the expression profiles of the two virus-infected cell lines were consistent, indicating that the receptors selected by the new coronavirus and SARS were consistent. After sequence alignment analysis, it was found that several key amino acids bound by SARS virus to ACE2 receptors also exist conservatively in the new coronavirus. In contrast, some key amino acids in the receptor-binding domain of coronaviruses that do not bind ACE2 are not present in the new coronavirus. This suggests that the new coronavirus, like the SARS virus, uses ACE2 to enter cells.

The researchers then used a cell line called BHK-21, which is insensitive to SARS and coronaviruses, and neither virus is effective at invading BHK-21 cells. The researchers directed BHK-21 cells to express human and bat ACE21, human DPP2 (a receptor used by the MERS virus), and human APN (another receptor bound to a less severe coronavirus), and then infected the SARS virus with the new coronavirus. The results showed that the directed expression of ACE4 in humans and bats allowed the new coronavirus and SARS virus to enter the otherwise insensitive BHK-2 cells driven by their respective S proteins. In addition, the researchers found that serum that inhibits ACE21 can also inhibit the invasion of new coronavirus and SARS virus into BHK-2 cells.

The above results indicate that the new coronavirus invades cells through the ACE2 receptor on the cell surface. After determining that the new coronavirus, like the SARS virus, enters the cell by using the S protein to bind to the ACE2 protein on the surface of human cells, the next question for the researchers is whether the new coronavirus also uses a similar protease like the SARS virus to cut the S protein and invade the cell.

For SARS viruses, the activation of S protein can be promoted by two proteases, CatB/L and TMPRSS2. However, TMPRSS2 is expressed in lung viral target cells, and entry into the TMPRSS2+ cell line is facilitated by TMPRSS2 and is partially CatB/L-independent. To prove whether TMPRSS2 or CatB/L is more critical in the new coronavirus infection, the researchers separately evaluated the role of CatB/L and TMPRSS2. The researchers used ammonium chloride, which raises endosomal pH and thus blocks CatB/L activity. Studies have found that in ammonium chloride-treated cell lines, viral entry into 293T cells (TMPRSS2-) is strongly inhibited, but less efficient in inhibiting viral entry into Caco-2 cells (TMPRSS2+). The researchers point out that the spread of the new coronavirus may also depend on the activity of TMPRSS2, and that a drug that can inhibit TMPRSS2 activity, Camostat mesylate, has been approved for marketing in Japan, although the approved indication is chronic pancreatitis, but has shown antiviral potential in research, and the use of this compound or related compounds to treat patients infected with the new coronavirus can be considered [1].

■ Guoshuai Cai's team at the University of South Carolina published a paper on the preprint website Preprint.org, in view of the high homology between the new coronavirus and SARS-CoV, the three SARS-CoV-binding receptors in host cells: ACE2, DC-SIGN and L-SIGN, may all be potential receptors for the new coronavirus; DC-SIGN and L-SIGN (genotypes CD209 and CLEC4M) are homologous C-type lectin receptors that recognize the carbon chain structure of viral glycoproteins and play an important role in viral capture, anchoring host cells, and large-scale reproduction in humans.

The researchers found that ACE2 and DC-SIGN expression were higher in the lungs of smokers, especially those who had smoked and quit smoking at present; The cell types expressed by the two were related to smoking history: ACE2 was expressed in goblet cells of smokers, rod-shaped cells of non-smokers, and upregulated in alveolar type II cells of ex-smokers; DC-SIGN is actively expressed only in dendritic cells in smokers, or monocytes in ex-smokers. Current clinical data show that smokers and the elderly have higher mortality rates after new crown pneumonia infection. The researchers speculate that the upregulation of ACE2 in alveolar type II cells of smokers may lead to increased susceptibility to the new coronavirus; The upregulation of DC-SIGN in dendritic cells facilitates the entry of viruses into host cells. At the same time, dendritic cells activated by smoking, activating the immune system, may further lead to the occurrence of cytokine storms in critically ill patients.

The researchers also found that DC-SIGN was expressed in higher amounts in the elderly over 60 years old, and the expression was independent of gender; In addition, the organ and immune system function of the elderly are reduced, and on the basis of susceptibility to the new crown virus, it is also easy to develop severe disease. Taken together, the findings suggest that smokers, especially those who have smoked before, and those over the age of 60 may be at higher risk of contracting 2019-nCoV. The study also suggests a possible pathogenic mechanism of 2019-nCoV in lung infections [2].

■ On February 2, Shandong University and the University of Hong Kong found that coronavirus infection and its induced cytokine storm overregulate the expression of the viral host cell receptor ACE27, so it may further accelerate the infection and spread of the new coronavirus. The study, titled "Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus May Facilitate 2-nCoV Infection," was published in the preprint bioRxiv.[2019]

3. COVID-19 epidemiological studies

■ On February 2, Xu Haibo and Li Yirong of Wuhan University jointly published a research paper entitled "Positive RT-PCR Test Results in Patients Recovered From COVID-27" online in JAMA, which found that there were 19 COVID-4 patients who met the criteria for discharge or isolation quarantine (no clinical symptoms and radiological abnormalities, and 19 negative RT-PCR test results). RT-PCR test results were all positive after 2 to 5 days. These findings suggest that at least a subset of recovered patients may still be carriers of the virus. Although no family members were infected, all reported patients were medical professionals and received intensive care during home isolation. Current criteria for discharge or discontinuation of quarantine and ongoing patient management may need to be reassessed. The study was limited to a small number of patients with mild or moderate infection. Patients who are not healthcare professionals with more severe infections after discharge or isolation should be further studied. Longitudinal studies of larger populations will help to understand the prognosis of the disease [13].

■ On February 2, the team of Professor Hua Shucheng of the First Hospital of Jilin University published a paper entitled "Clinical Data on Hospital Environmental Hygiene Monitoring and Medical Staffs Protection during the Coronavirus Disease 27 Outbreak" on the medical preprint website medRxivThe study collected samples of air, surfaces, door handles and other samples from the isolation ward, fever clinic, guide desk and other places of the First Hospital of Jilin University, as well as samples of medical staff who were in close contact with new crown patients, and used RT-PCR to detect the new coronavirus nucleic acid in the samples. The results showed that the new coronavirus was detected on the surface of the nurse's station in the suspected patient's isolation area, as well as in the air in the intensive care unit. The paper shows that there are certain potential risks of the new coronavirus in the hospital environment, and the results also provide relevant references for hospital control and the protection of medical staff during epidemic disease epidemics [2019].

■ On February 2, the team of Shen Ye from the Department of Ophthalmology of the First Affiliated Hospital of Zhejiang University published a research paper entitled "Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-26 infection" online in the Journal of Medical Virology. Researchers studied the mixture of tears and conjunctival secretions from 2 patients diagnosed in the First Affiliated Hospital of Zhejiang University School of Medicine from January 1 to February 26, and found that one new coronary pneumonia patient had conjunctival inflammation in his left eye, that is, pink eye caused by the new crown, while his right eye did not have this symptom. It is reported that the patient did not have conjunctivitis before admission. Through nucleic acid testing, the researchers found that the left eye with conjunctivitis tested positive for the new coronavirus, while the right eye was negative. To ensure the accuracy of the study, three nucleic acid tests were performed on conjunctival secretions in both eyes, and the results were consistent. At present, the patient has undergone comprehensive antiviral treatment, and in the case of overall cure, conjunctival inflammation has also improved, and the ocular virus has turned negative again [2].

"The conjunctiva is the outermost layer of what we usually call the whites of the eyes, which is the barrier between the eyes and the air, oxygen can be absorbed in the conjunctiva, participate in the barrier function of metabolism, and its normal function can block the invasion of pathogens such as bacteria and viruses." Shen Ye introduced. Through this study, the following conclusions can be drawn: 1. The patient's left eye conjunctivitis is related to the new coronavirus; 2. There is a risk of eye infection with the new coronavirus; 3. The respiratory tract may not be the only way for the new coronavirus to spread.

4. Research progress in COVID-19 pathology

■ On February 2, Professor Wang Huijun of the Forensic Identification Center of the School of Forensic Medicine of Southern Medical University published an article entitled "Review and Prospect of the Pathological Features of Coronavirus Pneumonia" in the Journal of Forensic Science. This paper reviews the pathological characteristics of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and novel coronavirus pneumonia (COVID-28) in autopsy, in order to provide reference for the analysis of pathological changes of COVID-19. The authors found some commonalities between COVID-19 and the pathological changes of the two coronavirus infections. Like SARS and MERS, COVID-19 mainly changes pathology target both lungs, causing diffuse lung damage, edema, hyaline membrane formation after invasion, and viral pneumonia changes characterized by inflammatory cell infiltration and alveolar epithelial damage dominated by monocyte macrophages and lymphocyte exudation. The authors believe that the subsequent improvement of pathological research through systematic autopsy can better explain the clinicopathological connection of COVID-19 and the mechanism of lung injury caused by 19-nCoV, provide a reference for the treatment of patients in Wuhan and even at home and abroad, and help doctors formulate treatment strategies for severely ill patients in a timely manner [2019].

■ On February 2, Professor Liu Liang, Professor Zhou Yiwu and Professor Ren Liang of the Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, published an autopsy report entitled "General Observation Report on the Anatomy of the Novel Coronavirus Pneumonia Death Corpse System" in the Journal of Forensic Science. The results of the "Report" suggest that the new crown pneumonia mainly causes inflammatory reactions characterized by deep airway and alveolar damage, pulmonary fibrosis and consolidation are not as serious as those caused by SARS, and the exudative reaction is more obvious than SARS, and whether there is damage associated with viral infection in the myocardium and epicardium, kidneys, spleen, digestive tract organs, and brain needs to be further studied [28].

Bibliography:

[1] Markus Hoffmann et al., (2020), SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically-proven protease inhibitor, Cell.
[2] Guoshuai Cai, et al. Hint on the COVID-19 Risk: Population Disparities in Gene Expression of Three Receptors of SARS-CoV. Preprint.
[3] Wang P-H. Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection. bioRxiv 2020:2020.02.24.963348.
[4] Lan L, Xu D, Ye G, et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19. JAMA.
[5] Jiang Y, Wang H, Chen Y, et al. Clinical Data on Hospital Environmental Hygiene Monitoring and Medical Staffs Protection during the Coronavirus Disease 2019 Outbreak. medRxiv 2020:2020.02.25.20028043.

[6] Xia J, Tong J, Liu M, Shen Y, Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. Journal of Medical Virology 2020.

[7] WANG Huijun, DU Sihao, YUE Xia, et al. Review and prospect of pathological features of coronavirus pneumonia[J] Journal of Forensic Science, 2020,36(1): 22-25

[8] LIU Qian, WANG Rongshuai, QU Guoqiang, et al. General observation report of autopsy of dead cadaver system of novel coronavirus pneumonia[J] Journal of Forensic Science, 2020,36(1): 19-21

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