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).