Mathematical Model of SARS-Cov-2 Propagation Versus ACE2 Fits COVID-19 Lethality Across Age and Sex and Predicts That of SARS.

Ugo Bastolla

doi:10.3389/fmolb.2021.706122

Abstract

The fatality rate of Covid-19 escalates with age and is larger in men than women. I show that these variations correlate strongly with the level of the viral receptor protein ACE2 in rat lungs, which is consistent with the still limited data on human ACE2. Surprisingly, lower receptor levels correlate with higher fatality. I propose two possible explanations of this negative correlation: First, a previous mathematical model predicts that the velocity of viral progression in the organism as a function of the receptor level has a maximum and declines for abundant receptor. Secondly, degradation of ACE2 by the virus may cause the runaway inflammatory response that characterizes severe CoViD-19. I present here a mathematical model that predicts the lethality as a function of ACE2 protein level based on the two above hypothesis. The model fits Covid-19 fatality rate across age and sex in three countries with high accuracy () under the hypothesis that the speed of viral progression in the infected organism is a decreasing function of the ACE2 level. Moreover, rescaling the fitted parameters by the ratio of the binding rates of the spike proteins of SARS-CoV and SARS-CoV-2 allows predicting the fatality rate of SARS-CoV across age and sex, thus linking the molecular and epidemiological levels.

Highlights

The Covid-19 pandemics (Zhou et al, 2020) has caused millions fatalities worldwide (Dong et al, 2020), creating a tremendous threat to global health
The level of the Angiotensin converting enzyme 2 (ACE2) protein in rat lungs were quantified across three adult age classes of the two sexes by Xie et al (2006), who found that it strongly decays with age and it is higher in female than male rats, with largest difference in the oldest cohort where the expression is almost double for females
Observations on ACE2 protein in human lungs (Zhang et al, 2021) and ACE2 mRNA in the GTEx database (Chen et al, 2020) suggest that human ACE2 levels across age and sex are qualitatively similar to rodent data, apart for multiplicative factors that may depend on the organ: they decay with age and they are higher in females than in males

Summary

Introduction

The Covid-19 pandemics (Zhou et al, 2020) has caused millions fatalities worldwide (Dong et al, 2020), creating a tremendous threat to global health. It presents a strong gradient of fatalities across age and a sex bias with much higher severity in males than females. I show that the case fatality rate of Covid-19 across age and sex correlates negatively with the level of the protein Angiotensin converting enzyme 2 (ACE2), the cellular receptor both of SARS and SARS-CoV-2 virus (Hamming et al, 2004; Zhou et al, 2020), which belongs to the anti-inflammatory axis of the Renin-Angiotensin-System (RAS) (Paz Ocaranza et al, 2020). The correlation is very strong with membrane-bound ACE2 protein in rat lungs, which decreases with age and is higher in SARS-Cov-2 Propagation Versus ACE2

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Conclusion