How does SARS-CoV-2 infection cause pathology?
Based on published data for both SARS viruses, we propose a pathophysiologic chain of events for COVID-19 (Figure 1 ). Central to this mechanism is angiotensin (ANG II) signaling, which we elaborate in sections below.
SARS-CoV-2 infection typically begins in the upper respiratory tract by exposure to the virus in aerosolized droplets or from fomites (Bar-On et al., 2020). Oral epithelial cells and other respiratory tract areas have substantial expression of ACE2, explaining their susceptibility to viral entry (Xu et al., 2020a; Zhou et al., 2020a). The virus spreads into the lower respiratory tract (the lungs) where epithelial cells, in particular type-2 pneumocytes, express ACE2 (Hamming et al., 2004; Mossel et al., 2008; Tian et al., 2020; Zhang et al, 2020). Infection in the lungs, and especially damage to the alveolae, is a primary cause of morbidity in COVID-19 (He et al., 2020; Zhou et al., 2020a; Zhou et al., 2020b). In susceptible patients, lesions from viral infection and entry of fluid into alveolar spaces induce respiratory distress. Pulmonary lesions appear to be a hallmark and diagnostic feature of COVID-19 (Pan et al., 2020). Certain patients have severe inflammation and cytokine storm, with overwhelming immune activation that attacks the host (Qin et al., 2020). These events can produce respiratory failure and death, especially if critical care support and mechanical ventilation are unavailable and may ultimately be associated with multiple organ failure and death (Du et al, 2020). The pulmonary pathobiology in COVID-19 is akin to what occurred with SARS-1 infection (Channappanavar & Perlman, 2017).
In addition to pulmonary injury, COVID-19 can cause cardiac complications. Most notable is myocarditis from viral infection of the myocardium, perhaps facilitated by ACE2 on cardiac myocytes (Sun et al., 2020; Chen et al., 2020). Myocardial infection, myocarditis and cardiomyopathy occurred with SARS-1 infection (Oudit et al., 2009) but data for their frequency in COVID-19 are still emerging. Cardiac injury in COVID-19 patients likely occurs from at least two mechanisms: a) cytokine release (“storm”) associated with inflammation in the lung (Pedersen & Ho, 2020) that affects the heart and b) infection of the myocardium, most likely via viremia (Huang et al., 2020; Kam et al., 2020). In SARS-1, a strong association was noted between circulating viral loads and disease severity (Hung et al., 2004). This finding suggests that viremia results from alveolar damage and access of the virus to the capillary network in the lung, which can occur in more severe cases. The stage of illness during which viremia occurs in COVID-19 and if viremia correlates with severity/injury are not as-yet well-defined.
SARS-1 and COVID-19 can affect other tissues. A symptom of COVID-19 is gastric distress, which can occur prior to pulmonary symptoms (Rothan & Byrareddy, 2020; Gu et al., 2020). Fecal transmission of SARS-CoV-2 has also been documented (Gu et al., 2020), which confirms the presence of the virus in the gastrointestinal (GI) tract, a site in which ACE2 is expressed (Hamming et al., 2004). The spread of infection to the GI tract may result from viremia or from the mouth and upper respiratory tract, suggesting that the virus survives passage through the stomach. COVID-19 can involve other ACE2-expressing tissues, including the kidneys (Naicker et al., 2020).