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

Bastolla, Ugo

doi:10.3389/fmolb.2021.706122

Cited by 18 publications

(19 citation statements)

References 87 publications

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“…As ACE2 expression is a key factor for SARS-CoV-2 entry into host cells, it is reasonable to assume that low levels of ACE2 would protect against infection, viral amplification, and ultimately a lethal outcome in COVID-19. However, according to a recent model of viral dynamics and gene expression of ACE2 in rats and humans, there is a strong negative correlation between ACE2 and lethality [120]. This hypothesis agrees with research demonstrating that the ACE2 receptor is expressed at lower levels in men than in women, and decreases with age, inflammatory-related comorbidity, and with reduced testosterone and estrogen levels [121].…”

Section: Effects Of Physical Activity and Exercise On Human Biology In View Of Covid-19supporting

confidence: 80%

Potential Physiological and Cellular Mechanisms of Exercise That Decrease the Risk of Severe Complications and Mortality Following SARS-CoV-2 Infection

Jakobsson

Cotgreave

Furberg

et al. 2021

Sports

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unmasked mankind’s vulnerability to biological threats. Although higher age is a major risk factor for disease severity in COVID-19, several predisposing risk factors for mortality are related to low cardiorespiratory and metabolic fitness, including obesity, cardiovascular disease, diabetes, and hypertension. Reaching physical activity (PA) guideline goals contribute to protect against numerous immune and inflammatory disorders, in addition to multi-morbidities and mortality. Elevated levels of cardiorespiratory fitness, being non-obese, and regular PA improves immunological function, mitigating sustained low-grade systemic inflammation and age-related deterioration of the immune system, or immunosenescence. Regular PA and being non-obese also improve the antibody response to vaccination. In this review, we highlight potential physiological, cellular, and molecular mechanisms that are affected by regular PA, increase the host antiviral defense, and may determine the course and outcome of COVID-19. Not only are the immune system and regular PA in relation to COVID-19 discussed, but also the cardiovascular, respiratory, renal, and hormonal systems, as well as skeletal muscle, epigenetics, and mitochondrial function.

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Section: Effects Of Physical Activity and Exercise On Human Biology In View Of Covid-19supporting

confidence: 80%

Potential Physiological and Cellular Mechanisms of Exercise That Decrease the Risk of Severe Complications and Mortality Following SARS-CoV-2 Infection

Jakobsson

Cotgreave

Furberg

et al. 2021

Sports

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“…Mathematical models of virus propagation, tested with experiments with bacteriophages, suggest that there is an optimal receptor density at which the virus propagates fastest, with viral velocity declining both for lower and for higher receptor density (Ortega-Cejas et al, 2004) (see Figure 5). A mathematical model of the dependence of Covid-19 mortality on receptor density fitted to both Covid-19 and SARS 2003 data of lethality across age and sex suggests that both viruses propagate in a regime in which increasing receptor density slows down their propagation (Bastolla, 2021). Thus, the inverse relation between ACE2 expression and Covid-19 severity is not implausible.…”

Section: Effect Of Receptor Level On Viral Propagationmentioning

confidence: 97%

“…As discussed in more detail in Ref. (Bastolla, 2021), this inverse relationship between ACE2 levels and Covid-19 severity might rationalize not only the influence of age and sex but also most of the other known risk factors of Covid-19 examined in the OpenSAFELY study (Williamson et al, 2020), including diabetes, hypertension, obesity, vitamin D deficit (that may explain at least part of the risk factors connected with ethnicity) and perhaps even the curious protecting effect of smoke that increases ACE2 expression (Saheb Sharif-Askari et al, 2020).…”

Section: Comorbidities Support a Negative Relation Between Angiotensi...mentioning

confidence: 99%

Is Covid-19 Severity Associated With ACE2 Degradation?

Bastolla

Chambers

Abia

et al. 2022

Front. Drug Discov.

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Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 by SARS-COV-2, may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the RAS at young age.

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“…Moreover, despite the high transmissibility of SARS-CoV-2, there are highly exposed people who have not acquired the infection. Genetic factors along with other risk factors can determine the susceptibility of each individual to infection, but those are largely unknown ( 13 , 14 ). The goal of our study is to provide some insight into why health care worker (HCW) with reported high-risk exposures to virus and persons cohabiting without protection with infected relatives remained uninfected despite constant contact with the virus.…”

Section: Introductionmentioning

confidence: 99%

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19

et al. 2022

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BackgroundCOVID‐19 can generate a broad spectrum of severity and symptoms. Many studies analysed the determinants of severity but not among some types of symptoms. More importantly, very few studies analysed patients highly exposed to the virus that nonetheless remain uninfected.MethodsWe analysed serum levels of ACE2, Angiotensin II and anti-Spike antibodies in 2 different cohorts at high risk of viral exposure, highly exposed but uninfected subjects, either high risk health care workers or persons cohabiting with infected close relatives and seropositive patients with symptoms. We tested the ability of the sera of these subjects to neutralize lentivirus pseudotyped with the Spike-protein.ResultsWe found that the serum levels of ACE2 are significantly higher in highly exposed but uninfected subjects. Moreover, sera from this seronegative persons can neutralize SARS-CoV-2 infection in cellular assays more strongly that sera from non-exposed negative controls eventhough they do not have anti-CoV-2 IgG antibodies suggesting that high levels of ACE2 in serum may somewhat protect against an active infection without generating a conventional antibody response. Finally, we show that among patients with symptoms, ACE2 levels were significantly higher in infected patients who developed cutaneous as compared with respiratory symptoms and ACE2 was also higher in those with milder symptoms.ConclusionsThese findings suggest that soluble ACE2 could be used as a potential biomarker to predict SARS-CoV-2 infection risk and to discriminate COVID-19 disease subtypes.

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

Cited by 18 publications

References 87 publications

Potential Physiological and Cellular Mechanisms of Exercise That Decrease the Risk of Severe Complications and Mortality Following SARS-CoV-2 Infection

Potential Physiological and Cellular Mechanisms of Exercise That Decrease the Risk of Severe Complications and Mortality Following SARS-CoV-2 Infection

Is Covid-19 Severity Associated With ACE2 Degradation?

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19

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