However, since the viral pneumonia was resolved within 2 weeks in Syrian hamsters and antibodies that react to hamster molecules in order to examine immune responses are not available, another model is required to examine the pathogenicity of severe COVID-19. in the elimination of SARS-CoV-2. Thus, because of similar symptoms to approximately 80% of patients, cynomolgus macaques are appropriate to extrapolate the efficacy of vaccines and antiviral drugs for humans. Keywords: SARS-CoV-2, Nonhuman primate, Pneumonia, Thrombus, Neutralizing antibody, Th1 response 1.?Introduction Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19) has been spreading around the world since late 2019 (Zhu et al., 2020), and WHO declared a pandemic on March 11, 2020. Accumulating reports indicate varying degrees of illness including asymptomatic patients, patients with mild respiratory symptoms, and patients with acute respiratory distress syndrome (ARDS) requiring admission to an intensive care unit (ICU) (Huang et al., 2020; Guan et al., 2020; Z Xu et al., 2020). In addition to the development of vaccines and antiviral drugs specific for SARS-CoV-2, determination of the pathogenicity in patients with severe clinical signs of disease and development of therapeutics for severe cases are urgent issues. For the development of prophylactics and therapeutics for SARS-CoV-2 infection, not only studies but also studies are required for evaluation of their efficacy, especially estimation of efficacy, for which assessments with challenge infection are difficult in clinical trials. Therefore, animal models that show pathogenicity similar to that in humans are necessary for research and development of vaccines and antiviral drugs (Cleary et al., 2020). The results of several studies on experimental infection of SARS-CoV-2 in animals have been reported. In a mouse model, SARS-CoV-2 propagated in the lungs of human angiotensin-converting enzyme Jujuboside A 2 (ACE2) Jujuboside A transgenic mice but not in the lungs of wild-type mice, and the virus caused interstitial pneumonia in the ACE2 transgenic mice (Bao et al., 2020). However, co-expression of human ACE2 and endogenous mouse ACE2 may change the disease progression to recapitulate COVID-19. Wild-type Syrian hamsters are sensitive to SARS-CoV-2, which propagated in the lungs to cause viral pneumonia, indicating a useful small animal model (Chan et al., 2020; Imai et al., 2020). However, since the viral pneumonia was resolved within 2 weeks in Syrian hamsters and antibodies that react to hamster molecules in order to examine immune responses are not available, another model is required to examine the pathogenicity of severe COVID-19. SARS-CoV-2 also propagated and caused lung inflammation and pneumonia in rhesus and cynomolgus macaques (Yu et al., 2020; Williamson et al., 2020; Rockx et al., 2020; Munster et al., 2020; Deng et al., 2020). The pathogenicity in macaques was examined until 21 days after virus infection in all of the studies except for one study (Deng et al., 2020), in which the reason for the prolonged detection of viral genes in patients and virus antigen specific-T-lymphocyte responses were not revealed. Therefore, in the present study, we observed cynomolgus macaques infected with SARS-CoV-2 for 4 weeks and examined T-lymphocyte responses specific for SARS-CoV-2 antigen Jujuboside A peptides. The macaque model, of which immune responses and metabolism resemble those of humans, Jujuboside A is useful to extrapolate the efficacy of vaccines and antiviral drugs in humans against SARS-CoV-2. In our previous studies on influenza virus infection, various influenza viruses including pandemic and avian influenza viruses propagated in cynomolgus macaques that showed clinical signs of disease similar to human symptoms (Itoh et al., 2009; Muramoto et al., 2014). In addition, we detected influenza viruses that were less sensitive to neuraminidase inhibitors in treated macaques, indicating a useful model for predicting the emergence of a drug-resistant virus (Itoh et al., 2015; Suzuki et al., 2020). Therefore, we have used the cynomolgus macaque model to evaluate the efficacy of vaccines and antiviral drugs in influenza virus infection (Arikata et al., 2012, 2019; Nakayama et al., 2013; Kitano et al., 2014; Nguyen et al., 2020). In the present study, we expanded our experimental Rabbit Polyclonal to SRPK3 system to establish a SARS-CoV-2 infection model in cynomolgus macaques for preclinical studies. We revealed the pathogenicity of SARS-CoV-2 in the cynomolgus macaques. SARS-CoV-2 propagated in respiratory tissues and caused body temperature rises in all of the macaques. However, viral pneumonia in X-ray radiographs was confirmed in one macaque, in which a neutralizing antibody against SARS-CoV-2 in plasma was detected. We also found a thrombus in the lung of a macaque infected with SARS-CoV-2 as reported in human cases (Wichmann et al., 2020). These results Jujuboside A are similar to observations in human patients with COVID-19 (Zhu et al., 2020). Compared to influenza virus infection, the rate of detection of a neutralizing antibody was low in macaques infected with SARS-CoV-2 (Arikata et al., 2012;Wang et al., 2020a). In addition,.