Susceptibility of the Elderly to SARS-CoV-2 Infection: ACE-2 Overexpression, Shedding, and Antibody-dependent Enhancement (ADE)

Abstract

The world is currently facing a serious SARS-CoV-2 infection pandemic. </mac_aq>This virus is a new isolate of coronavirus, and the current infection crisis has surpassed the SARS and MERS epidemics</mac_aq> that occurred in 2002 and 2013, respectively. SARS-CoV-2 has currently infected more than 142,000 people, causing </mac_aq>5,000 deaths and spreading across more than 130 </mac_aq>countries worldwide. The spreading capacity of the virus clearly demonstrates the potential threat </mac_aq>of respiratory viruses to human health, thereby reiterating to the governments around the world that preventive </mac_aq>health policies and scientific research are pivotal to overcoming the crisis. Coronavirus disease (COVID-19) causes flu-like symptoms in most cases. However, approximately 15% of the patients need hospitalization, and 5% require assisted ventilation, depending on the cohorts studied. What is intriguing, however, is the higher susceptibility of the elderly, especially individuals who are older than 60 years of age, and have comorbidities, including hypertension, diabetes, and heart disease. In fact, the death rate in this group may be up to 10-12%. Interestingly, children are somehow less susceptible and are not considered as a risk group. Therefore, in this review, we discuss some possible molecular and cellular mechanisms by virtue of which the elderly subjects may be more susceptible to severe COVID-19. Toward this, we raise two main </mac_aq>points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 </mac_aq>receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. We believe that these points are pivotal for a better understanding of the pathogenesis of severe COVID-19, and must be carefully addressed by physicians and scientists in the field.

Figure 1

Illustrative scheme of ACE-2 expression in the lungs. Left panel: Normally expressed ACE-2 in the lung tissue interacts with SARS-CoV-2. Middle panel: Increased expression of ACE-2 in lung tissues of hypertensive patients under chronic treatment with AT1R blockers. Right panel: ADAM17 cleaves ACE-2, releasing its soluble form, sACE-2, whose levels are increased in the presence of TNF-α. Illustration was developed by the authors using www.biorender.com.

Figure 2

Illustrative scheme of ADE during SARS-CoV-2 infection. Left panel: First infection and lack of preexisting antibodies allow viral particles to interact with ACE-2. Middle panel: Preexisting low-affinity antibodies or antibodies at sub-optimal concentrations bind to viral particles and facilitate the viral internalization mediated by FcRs expressed on either the epithelial or immune cells. Right panel: Neutralizing IgGs elicited in response to vaccination, or neutralizing IgM that do not mediate enhancement bind to viral particles. Illustration created by the authors using www.biorender.com.