Risk Factors for Severe COVID-19 and Hepatitis C Infections: The Dual Role of Apolipoprotein E4

Lima, Felipe Barbosa; Bezerra, Karine C; Nascimento, José Carlos Rodrigues; Meneses, Gdayllon Cavalcante; Oriá, Reinaldo B.

doi:10.3389/fimmu.2022.721793

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…Shi and colleagues reported that human-induced pluripotent stem cell (hiPSC)-derived ApoE4-expressing neurons and astrocytes are more susceptible to SARS-CoV-2 infection, and ApoE4 astrocytes exhibit a more severe response (13). The association between the ApoE4 genotype and the risk and severity of COVID-19 disease has also been reported by several other genetic studies (14)(15)(16), but the molecular mechanisms that are responsible for this isoform-dependent association remain poorly understood. Considering the strong effect of ApoE4 on COVID-19 severity and the high prevalence of the ε4 allele among individuals (the ε4 allele has a worldwide frequency of 13.7%), it is of great importance to explore the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 92%

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

Chen

et al. 2022

Preprint

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The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); host cell entry by this virus relies on the interaction between the receptor-binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor on cell membranes. In addition to serving as a receptor for SARS-CoV-2, ACE2 was originally discovered as a protective factor in the renin-angiotensin system (RAS) that catalyses the degradation of angiotensin II (Ang II) to Ang 1-7, which is involved in multiple organ pathology. Recent genetic and clinical studies reported that ApoE4 expression is associated with increased susceptibility to SARS-CoV-2 infection and the development of severe COVID-19, but the underlying mechanism is currently unclear. In the present study, by using immunofluorescence staining, molecular dynamics simulations, proximity ligation assay (PLA) and coimmunoprecipitation (Co-IP) combined with a biolayer interferometry (BLI) assay, we found that ApoE interacts with both the spike protein and ACE2 but does not show obvious isoform-dependent binding effects. These data suggest that ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Importantly, further immunoblotting and immunofluorescence staining results showed that ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7, which could worsen tissue lesions; these findings provide a possible explain by which ApoE4 exacerbates COVID-19 disease.

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Section: Introductionmentioning

confidence: 92%

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

Chen

et al. 2022

Preprint

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“… 58 , 59 Some researchers speculate that the higher binding affinity between ApoE4 and HSPGs may promote viral infection, bridging the virus to the ACE2 receptor on the cell membrane and facilitating coronavirus spread through tissues. 60 In addition, ApoE4 has been reported to be associated with the incidence of neurodegenerative diseases, 43 diabetes, 44 and cardiovascular diseases. 44 The incidence and progression of COVID-19 may be impacted by these pre-existing comorbidities.…”

Section: Apoe4 Is a Major Genetic Risk Factor For Sars-cov-2...mentioning

confidence: 99%

Apolipoprotein E and viral infection: Risks and Mechanisms

Chen¹,

Ke²,

Wei³

et al. 2023

Molecular Therapy - Nucleic Acids

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“…Shi and colleagues observed that human-induced pluripotent stem cell (hiPSC)-derived ApoE4-expressing neurons and astrocytes are more susceptible to SARS-CoV-2 infection, and ApoE4 astrocytes exhibit a more severe response [10]. The association between the ApoE4 genotype and the risk and severity of COVID-19 disease has also been reported by numerous other genetic studies and yielded inconsistent results [11][12][13][14]. Therefore, a meta-analysis is necessary to con rm the association of ApoE polymorphism with the risk and severity of COVID-19, and to further explore the potential underlying mechanism.…”

Section: Introductionmentioning

confidence: 96%

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

Chen

et al. 2022

Preprint

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Background Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism may associate with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. Methods A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and spike protein and between ApoE and also the SARS-CoV-2 primary receptor ACE2. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. Results ApoE gene polymorphism (ε4 carries genotypes VS non-ε4 carries genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI: 1.18–1.76) and progression (P < 0.00001, OR = 1.85, 95% CI: 1.50–2.28) of COVID-19. ApoE interacts with both the spike protein and ACE2 but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7. Conclusions ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

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Risk Factors for Severe COVID-19 and Hepatitis C Infections: The Dual Role of Apolipoprotein E4

Cited by 5 publications

References 46 publications

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

Apolipoprotein E and viral infection: Risks and Mechanisms

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

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