Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals.

Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide "353-KGDFR-357 (H. sapiens ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.

Effect by mRNA based COVID-19 vaccination on efficiency of therapy with anti-PD-1 blockade

Immune checkpoint inhibitors are drugs that keep the immune system strong enough to attack cancer cells. To date, cancer immunotherapy using immune checkpoint inhibitors has been shown to be effective against various types of cancer. During the coronavirus infectious disease-2019 (COVID-19) pandemic, concern is raised whether clinical treatment with immune checkpoint inhibitors can interfere with COVID-19 vaccination in patients with several malignancies. Recent report shows significantly improved anti-tumor efficacy of the combination of anti-programmed cell death protein-1 (anti-PD-1) therapy and chemotherapy in patients with advanced nasopharyngeal cancer (NPC) who received COVID-19 vaccination, however, the incidence of severe immune-related adverse events was similar. However, our results revealed that there is no medical evidence stating that COVID-19 vaccination significantly improved the efficacy of the combination of anti-PD-1 therapy and chemotherapy in patients with advanced NPC. Clinical studies with large cohorts of large numbers of patients are required to clarify the impact of COVID-19 vaccines on the efficacy of cancer immunotherapy with immune checkpoint inhibitors.

Pathological Evidence for Residual SARS-CoV-2 in the Micrometastatic Niche of a Patient with Ovarian Cancer.

In previous clinical studies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients has a high risk of aggravation and mortality than in healthy infected individuals. Inoculation with coronavirus disease 2019 (COVID-19) vaccine reduces the risk of SARS-CoV-2 infection and COVID-19 severity. However, vaccination-induced anti-SARS-CoV-2 antibody production is said to be lower in cancer patients than in healthy individuals. In addition, the rationale for why the condition of patients with cancer worsens with COVID-19 is not well understood. Therefore, we examined the infection status of SARS-CoV-2 in the primary tumor and micrometastasis tissues of the patient with cancer and COVID-19. In this study, the expression of angiotensin-converting enzyme 2 (ACE2) was observed, and SARS-CoV-2 particles was detected in ovarian tissue cells in contact with the micrometastatic niche of the patient with high-grade serous ovarian cancer. We believe that the severity of COVID-19 in patients with cancer can be attributed to these pathological features. Therefore, the pathological findings of patients with advanced and recurrent ovarian cancer infected with SARS-CoV-2 may help decrease COVID-19 severity in patients with other cancer types.

Highly conserved binding region of ACE2 as a receptor for SARS‐CoV‐2 between humans and Hippopotamus

Background Several cases of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS‐CoV‐2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. Mother and daughter of Hippopotamus amphibius (Hippo) at the Antwerp Zoo in Belgium have been reported infected with SARS‐CoV‐2. SARS‐CoV‐2 is believed to have been infected by the hippo caretaker. Objective These reports have influenced us to perform a comparative analysis among angiotensin‐converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide “353‐KGDFR‐357 (H.sapiens ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS‐CoV‐2 spike receptor binding domain (RBD). Methods/Results ACE2 works as a receptor for the SARS‐CoV‐2 spike glycoprotein between humans, dogs, cats, tigers, Hippo, and other animals, except for snakes. The three‐dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS‐CoV‐2 spike RBD of the Hippo ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (805 residues of the Hippo ACE2 available sequence vs 805 residues of the human ACE2) (Figure). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353‐KGDFR‐357 with humans, dogs, cats, tigers, Hippo, and other animals, except for snakes. Conclusion Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS‐CoV‐2 transmission from animals to humans.

Spontaneous Myocarditis in Mice Predisposed to Autoimmune Disease: Including Vaccination-Induced Onset.

Nonobese diabetic (NOD)/ShiLtJ mice, such as biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with moderate glycosuria and nonfasting hyperglycemia. Previously, in NOD/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of nuclear factor-kappa B1 (NF-κB1) (also known as p50) in the development of type 1 diabetes was investigated. In response to these arguments, NOD mice with inconsistent NF-κB1 expression were established. Surprisingly, the majority of NOD Nfκb1 homozygote mice were found to die by the eighth week of life because of severe myocarditis. The incidence of spontaneous myocarditis in mice was slightly higher in males than in females. Furthermore, insulitis was observed in all NOD Nfκb1 heterozygote mice as early as 4 months of age. Additionally, in NOD Nfκb1 heterozygote mice, myocarditis with an increase in cTnT levels due to influenza or hepatitis B virus vaccination was observed with no significant gender difference. However, myocarditis was not observed with the two types of human papillomavirus vaccination. The results of immunological assays and histopathological examinations indicated that vaccination could induce myocarditis in genetically modified mice. In this study, we report that NOD Nfκb1 heterozygote mice can be used for investigating the risk of myocarditis development after vaccination.

Possibility of SARS-CoV-2 Infection in the Metastatic Microenvironment of Cancer.

According to a report from the World Health Organization (WHO), the mortality and disease severity induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly higher in cancer patients than those of individuals with no known condition. Common and cancer-specific risk factors might be involved in the mortality and severity rates observed in the coronavirus disease 2019 (COVID-19). Similarly, various factors might contribute to the aggravation of COVID-19 in patients with cancer. However, the factors involved in the aggravation of COVID-19 in cancer patients have not been fully investigated so far. The formation of metastases in other organs is common in cancer patients. Therefore, the present study investigated the association between lung metastatic lesion formation and SARS-CoV-2 infectivity. In the pulmonary micrometastatic niche of patients with ovarian cancer, alveolar epithelial stem-like cells were found adjacent to ovarian cancer. Moreover, angiotensin-converting enzyme 2, a host-side receptor for SARS-CoV-2, was expressed in these alveolar epithelial stem-like cells. Furthermore, the spike glycoprotein receptor-binding domain (RBD) of SARS-CoV-2 was bound to alveolar epithelial stem-like cells. Altogether, these data suggested that patients with cancer and pulmonary micrometastases are more susceptible to SARS-CoV-2. The prevention of de novo niche formation in metastatic diseases might constitute a new strategy for the clinical treatment of COVID-19 for patients with cancer.