COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies

H uman coronaviruses, along with in- fl uenza virus, human metapneumovirus, respiratory syncytial virus, and rhinovirus, are endemic and cause approximately 15% to 30% of annual respiratory tract infections.Coronavirus infections are generally mild in healthy adults, obviating any urgent need to develop treatments or vaccines.However, outbreaks of acute respiratory distress syndrome (ARDS) due to novel, highly pathogenic strains-severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and now, SARS-CoV-2-have revealed the potency and danger of this expanding family of pathogens that have the capacity to kill many thousands of people around the world if not geographically contained.1 As in severe SARS and MERS disease, the mortality rate is disproportionately high in the elderly and patients with preexisting comorbidities such as heart disease, diabetes mellitus, hypertension, and renal disease. 2 Higher morbidity in the elderly may partly be attributed to muted interferon antiviral responses (although the suggestive study has not yet been peer-reviewed) 3 as well as overall lower adaptive immunity, 2 resulting, paradoxically, in longer courses of hyperactivity of the innate immune system ("cytokine storm"). ■ A ZOONOTIC INFECTIONBats have been implicated as the likely source of SARS-CoV-2, as both SARS-CoV and MERS-CoV are genetically similar to viruses recovered from bats, and bat coronaviruses can use human receptors for cell entry.4 How-ever, phylogenetic studies, looking at sequencebased virus evolution, suggest that the virus is not transmitted directly from bats to humans but rather fi rst infects intermediate animal hosts in close contact with humans.In the case of SARS-CoV, these can be civets or raccoon dogs sold at crowded markets; for MERS-CoV, they can be domesticated dromedary camels.4 Transmission from bats to intermediate hosts and then to humans, as well as from human to human, all involve viral adaptation, slight changes in viral sequence to improve fi tness in the new host.This is not unique to coronaviruses, as endemics and pandemics also occur when novel infl uenza A virus strains emerge in the human population from an animal host.5 Similar to introduction of Ebolavirus and human immunodefi ciency virus 1 by mammals, many other viruses circulating in wild animals have the potential for zoonotic transmission.6 SARS-CoV-2, the causative agent for the pandemic corona virus disease of 2019 (CO-VID-19) outbreak, was fi rst found in Wuhan, China, and initial analysis of viral RNA obtained from patients hospitalized in late 2019 revealed it was 96% identical at the whole-genome level to a bat SARS-like coronavirus.7 Uniquely, SARS-CoV-2 can be transmitted by people who are infected but have no symptoms, not just by symptomatic patients.Concern about potential spread of SARS-CoV-2 to household cats has emerged from a news report of infection in a tiger in the Bronx Zoo.Ferrets can be infected, with intraspecies transmission, 8 and cats can also be infected and transmit the virus to other cats, while dogs have low susceptibility.However, it is unknown if any of these animals can transmit the virus to humans.9