Biology and Life Cycle of Coronaviruses
Coronaviruses are enveloped, single-stranded positive sense RNA viruses that infect a wide variety of animal species and cause respiratory, gastrointestinal, and central nervous system diseases (Li et al., 2006; Perlman and Netland, 2009; Fehr and Perlman, 2015; Li, 2015). Coronaviruses have been subdivided into four genera based upon genetic clustering and antigenicity: alpha, beta, gamma, and delta coronaviruses (Dhama et al., 2014; Coleman et al., 2014). Common human coronaviruses include the 229E and NL63 alpha coronaviruses and the OC43 and HKU-1 beta coronaviruses. In infected humans, they are associated with a range of cold-like symptoms as well as severe respiratory tract infections (Fielding, 2011). Other more symptomatically severe human coronaviruses that have been transmitted from animals include MERS-CoV, a beta coronavirus that causes Middle East Respiratory Syndrome (MERS); SARS-CoV, a beta coronavirus that causes severe acute respiratory syndrome (SARS); and SARS-CoV-2, a beta coronavirus that causes coronavirus disease 2019 (COVID-19).
Features that are in common among these groups of coronaviruses are their large RNA genomes (26-35 kb), a highly conserved genomic organization with a large replicase gene that precedes the structural and accessory genes, expression of non-structural genes by ribosomal frameshifting, unique enzymatic activities encoded within the replicase polyprotein, and expression of downstream genes by synthesis of 3’ nested mRNAs (Fehr and Perlman, 2015)
SARS-CoV-2 and Interspecies Transmission
Evidence of SARS-CoV-2 transmission to and between other animals has been discovered in cats, lions, tigers, minks, dogs, hamsters and ferrets (Halfmann et al., 2020; Sit et al., 2020; American Veterinary Medical Association, 2020). Cats have presented with mild symptoms or as asymptomatic in discovered cases and can show signs of gastrointestinal and respiratory disease when infected. Mink have shown low mortality rates and have also presented with gastrointestinal and respiratory symptoms (often as a cough). The sample size for domestic animals confirmed to have COVID-19 disease is small, but this may also point to fundamentally low rates of transmission of the disease from humans to pets (American Veterinary Medical Association, 2020). There is thus far no evidence of transmission from domesticated animals back to humans, and pets are not considered a cause for concern when it comes to further spread of SARS-CoV-2.
The presence of the disease in the lungs and gastrointestinal tract in pets mirrors infection patterns in humans, and it is likely that it is also infecting animal host epithelial cells by binding to ACE2. The ACE2 receptor has high conservation across common domestic and wild mammals, and moderate conservation across other classes including birds (Sun et al., 2020; BLAST, 2020). ACE2 has greater than 80% sequence identity with the same receptor found in many mammals ranging from 86% in cats to decreasing percentages in dogs (85%), rats (84%), ferrets (83%), chinchillas (84%), polar bears (83%), and orcas (81%). In birds, human ACE2 has 72% sequence identity in crows, 71% in parakeets, and 68% in pigeons.
In humans, SARS-CoV-2 gains entry to the host cell when the spike glycoprotein binds ACE2 via its S1 subunit RBD (receptor binding domain). It is known to engage the ACE2 receptor alpha-1 helix at residues H34, D30, and Q24; interact with M82 via van der Waals forces; and also utilize the alpha-2 helix and the beta-3 and beta-4 linker by forming H-bonds with residues Y41, Q42, K353, and R357 (Yan et al., 2020). Notably, Y41, Q42, K353, and R357 are conserved across human, feline, and canine ACE2. A study by Luan et al. (2020) predicted that dog, cat, pangolin, and hamster ACE2 would potentially bind the SARS-CoV-2 spike protein RBD based on sequence and structural similarity, and the virus has already been shown to infect these animals. They also concluded that rat and mouse ACE2 receptors were unlikely to bind the protein. The SARS-CoV-2 spike protein may have similar or slightly diminished binding affinity and modality compared to the ACE2 receptor expressed in non-human hosts. However, further studies are necessary to detail the exact mechanisms of SARS-CoV-2 infection in various animals
Clinical and Pathologic Features of COVID-19
As with SARS-CoV, MERS-CoV, and influenza viruses, the primary route of disease transmission in humans is via respiratory droplets and direct contact (Guo et al., 2020; Morawaska and Cao, 2020). After a mean incubation period of 4 days, patients develop symptoms including fever, non-productive cough, sore throat, shortness of breath, headache, myalgias, and fatigue (Guan et al., 2020; Huang C et al., 2020). Unlike respiratory viruses that primarily affect the upper respiratory tree, SARS-CoV-2 infects the lower respiratory tract and alveoli, resulting in bilateral pneumonia with ground-glass opacity and patchy bilateral shadowing on computed tomography in half of patients at the time of diagnosis (Guan et al., 2020; Xu Z et al., 2020).
Fifteen percent of patients present or develop severe acute respiratory disease, and of those patients, a quarter expire despite mechanical ventilation and intensive therapy for an overall case-fatality rate that ranged from 3-15% depending upon the age of the patient and the presence of existing co-morbid conditions. The cause of death is most commonly severe acute respiratory distress syndrome (ARDS), a result of direct viral pulmonary damage and the cytokine release syndrome, an uncontrolled inflammatory response resulting from the release of large amounts of pro-inflammatory cytokines and chemokines by immune cells reacting to cellular damage caused by the viral infection. Patients also commonly presented with lymphopenia, thrombocytopenia, or leukopenia at onset of disease. The severity of the lymphopenia was predictive of poor prognosis (Huang I, 2020). Lymphocyte depletion, which is also a feature of SARS and MERS, is hypothesized to be due to a combination of factors: direct viral infection due to the presence of the ACE2 receptor on lymphocytes, release of proinflammatory cytokines such as IL-6, and lymphocyte sequestration (Li et al., 2004; Huang I, 2020; Lin et al., 2020). A subset of patients also present with diarrhea, vomiting, and abdominal pain, since the ACE2 receptor is prominently located on enterocytes of the entire gastrointestinal tract, from duodenum to small intestine to the colon (Hamming et al., 2004; D’Amico et al., 2020; Wong et al., 2020). Gastrointestinal symptoms and diarrhea were also frequently observed in patients with SARS as well as MERS (Leung et al., 2003; Chan et al., 2015). Fecal-oral transmission has been implicated because SARS-CoV-2 RNA has been consistently found in biopsies of gastrointestinal tissue as well as fecal samples from infected patients (D’Amico et al., 2020; Hindson, 2020; Wong et al., 2020; Xiao et al., 2020; Xu Y et al., 2020). The virus has also been found in the semen of infected and recovering patients (Li et al., 2020) in rectal epithelia and the oral mucosa, as well as in saliva, suggesting that the virus may also be transmitted sexually (Patri et al., 2020; Peng et al., 2020; Xu H et al., 2020). Patients have also been reported with liver injury as detected by the presence of elevated liver enzymes, including abnormal levels of alanine and aspartate aminotransferases (ALT and AST), elevated levels of gamma-glutamyl transferase (GGT), and mild elevations in serum bilirubin. Although most of the cases had mild liver injury, the level of liver damage was proportional to the severity of COVID-19 disease (Wong et al., 2020; Zhang et al., 2020). Neurologic manifestations have been reported in 36% of patients and were more common in patients with severe disease (Mao et al., 2020). Loss of taste (ageusia) and sense of smell (anosmia) have also been reported to be early findings in a significant percentage of patients during the early stage of COVID-19 disease (Menni et al., 2020; Speth et al., 2020; Vaira et al., 2020). Headache, dizziness, confusion, memory problems, impaired consciousness, and cases of intracerebral bleeding, viral encephalitis, and necrotizing encephalopathy have all been reported in COVID-19 patients (Cardona et al., 2020; Li YC et al., 2020; Li Z et al., 2020; reviewed by Baig, 2020). The neuroinvasive and neurotrophic properties of SARS-CoV-2 are similar to studies with other betacoronaviruses, including SARS-CoV and MERS-CoV (Li YC et al., 2020). Pediatric patients with COVID-19 have been reported to develop a multisystem inflammatory syndrome resembling Kawasaki’s disease, with features of macrophage activation syndrome, a form of cytokine storm (Cheung et al., 2020; Verdoni et al., 2020; Whittaker et al., 2020). The patients presented with symptoms and signs such as fever, abdominal pain, conjunctivitis, rash, erythema of hands and feet, lymphadenopathy, mucous membrane changes, myocardial injury and arrhythmias, mild bilateral pneumonia, diarrhea, acute renal injury, and toxic shock. The patients tested positive for SARS-CoV-2, suggesting that coronaviruses may be responsible for other cases of Kawasaki’s disease (Verdoni et al.,2020). Acute kidney damage has been reported in as many as 36% COVID-19 patients (Chen et al., 2020; Cheng et al., 2020; Diao et al., 2020; Guan et al., 2020; Hirsch et al., 2020; Huang C et al., 2020; Wang et al., 2020; Zhou et al., 2020). Acute kidney injury was primarily observed in patients with respiratory failure (90%), suggesting that the etiology was due to ischemic acute tubular necrosis (Hirsch et al., 2020).
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