Differential effects of age, sex and dexamethasone therapy on ACE2/TMPRSS2 expression and susceptibility to SARS-CoV-2 infection

Shahbaz, Shima; Oyegbami, Olaide; Saito, Suguru; Osman, Mohammed; Sligl, Wendy; Elahi, Shokrollah

doi:10.3389/fimmu.2022.1021928

Cited by 7 publications

(5 citation statements)

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“…The radiation-induced changes in ACE and ACE2 expression are similar to findings in a hypertension rat model, where male rats were Frontiers in Physiology frontiersin.org observed to have an imbalance in the relative levels of lung ACE and ACE2 levels pathways favoring activation of the proinflammatory ACE/AngII signaling pathway (Martins et al, 2021). Additionally, in adult mice ACE2 protein expression is significantly upregulated in the lungs of female versus male mice (Shahbaz et al, 2022). Importantly, we observed similar survival in males and females treated with ACE2 agonist DIZE which indicates pharmacologic correction of the radiation-induced ACE/ACE2 imbalance may abrogate sex-differences in radiosensitivity.…”

Section: Discussionsupporting

confidence: 75%

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

et al. 2023

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Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats.Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response.Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors.Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

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Section: Discussionsupporting

confidence: 75%

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

et al. 2023

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“…It remains unclear to which extent the expression level and dynamics of ACE2 contribute to variations in infection susceptibility among individuals and whether the function of ACE2 is affected upon infection by SARS-CoV-2 [5,6]. A hypothetical downregulation of ACE2 upon SARS-CoV-2 infection may lead to increased angiotensin II levels and related symptoms, which are consistent with clinical symptoms observed in severe Covid-19 cases [7][8][9].…”

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2

Wang,

Beyer,

Vaccarin

et al. 2024

Preprint

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Purpose: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics. Methods: Based on computational molecular modeling, the ACE2-binding modes of F-MLN-4760 and F-Aza-MLN-4760 were similar to that of MLN-4760. Co-crystallization of the hACE2/F-MLN-4760 protein complex was performed for confirmation. Displacement experiments using [3H]MLN-4760 enabled the determination of the binding affinities of the synthesized F-MLN-4760 and F-Aza-MLN-4760 to ACE2 expressed in HEK-ACE2 cells. Aryl trimethylstannane-based and pyridine-based radiofluorination precursors were synthesized and used for the preparation of the respective radiotracers. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were evaluated with regard to the uptake in HEK-ACE2 and HEK-ACE cells and in vitro binding to tissue sections of HEK-ACE2 xenografts and normal organs of mice. Biodistribution and PET/CT imaging studies of [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were performed using HEK-ACE2 and HEK-ACE xenografted nude mice. Results: Crystallography data revealed an equal ACE2-binding mode for F-MLN-4760 as previously found for MLN-4760 and indicated that the same would hold true for F-Aza-MLN-4760. The IC50 values were all in the high nM range, but three-fold lower for F-MLN-4760 and seven-fold lower for F-Aza-MLN-4760 than for MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were obtained in 1.4 +/- 0.3 GBq and 0.5 +/- 0.1 GBq activity with >99% radiochemical purity in a 5.3% and 1.2% radiochemical yield, respectively. Uptake in HEK-ACE2 cells was higher for [18F]F-MLN-4760 (67 +/- 9%) than for [18F]F-Aza-MLN-4760 (37 +/- 8%) after 3 h incubation while negligible uptake was seen in HEK-ACE cells (<0.3%). [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 accumulated specifically in HEK-ACE2 xenografts of mice (13 +/- 2% IA/g and 15 +/- 2% IA/g at 1 h p.i.) with almost no uptake observed in HEK-ACE xenografts (<0.3% IA/g). This was confirmed by PET/CT imaging, which also visualized unspecific accumulation in the gall bladder and intestinal tract. Conclusion: Both radiotracers showed specific and selective binding to ACE2 in vitro and in vivo. [18F]F-MLN-4760 was, however, obtained in higher yields and the ACE2-binding affinity was superior over that of [18F]F-Aza-MLN-4760. [18F]F-MLN-4760 would, thus, be the candidate of choice for further developlment to enable PET imaging of ACE2 in patients.

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“…Vero E6 cells were seeded at 100,000 cells/well in culture media in the presence or absence of Gal-3, Gal-8, and Gal-9 (1 µg/mL or 2 µg/mL) in a 24-well flat-bottomed plate for 24 h. Then, cells were washed with warm phosphate-buffered saline (PBS) and exposed to the pseudo-SARS-CoV-2 spike Delta variant green reporter (Montana Molecular, MT, USA) according to the manufacturer’s instruction and our protocol overnight ( 34 ). Then, cells were extensively washed of any extracellular pseudovirus and trypsinized before being subjected to flow cytometry analysis.…”

Section: Methodsmentioning

confidence: 99%

Analysis of SARS-CoV-2 isolates, namely the Wuhan strain, Delta variant, and Omicron variant, identifies differential immune profiles

Shahbaz,

Bozorgmehr,

et al. 2023

Microbiol Spectr

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There is an urgent need to better understand the impact of different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on immune response and disease dynamics to facilitate better intervention strategies. Here, we show that SARS-CoV-2 variants differentially affect host immune responses. The magnitude and quantity of cytokines and chemokines were comparable in those infected with the Wuhan strain and the Delta variant. However, individuals infected with the Omicron variant had significantly lower levels of these mediators. We also found an elevation of plasma galectins (Gal-3, Gal-8, and Gal-9) in infected individuals, in particular, in those with the original strain. Soluble galectins exert a proinflammatory role in COVID-19 pathogenesis. This was illustrated by their correlation with the plasma levels of sCD14, sCD163, enhanced TNF-α/IL-6 secretion, and increased SARS-CoV-2 infectivity in vitro . Moreover, we observed enhanced CD4 + and CD8 + T cell activation in Wuhan strain-infected individuals. Surprisingly, there was a more pronounced T cell activation in those infected with the Omicron in comparison to the Delta variant. In line with T cell activation status, we observed a more pronounced expansion of T cells expressing different co-inhibitory receptors in patients infected with the Wuhan strain, followed by the Omicron and Delta variants. Individuals infected with the Wuhan strain or the Omicron variant had a similar pattern of plasma soluble immune checkpoints. Our results imply that a milder innate immune response might be beneficial and protective in those infected with the Omicron variant. Our results provide a novel insight into the differential impact of SARS-CoV-2 variants on host immunity. IMPORTANCE There is a need to better understand how different SARS-CoV-2 variants influence the immune system and disease dynamics to facilitate the development of better vaccines and therapies. We compared immune responses in 140 SARS-CoV-2-infected individuals with the Wuhan strain, the Delta variant, or the Omicron variant. All these patients were admitted to the intensive care unit and were SARS-CoV-2 vaccination naïve. We found that SARS-CoV-2 variants differentially affect the host immune response. This was done by measuring soluble biomarkers in their plasma and examining different immune cells. Overall, we found that the magnitude of cytokine storm in individuals infected with the Wuhan strain or the Delta variant was greater than in those infected with the Omicron variant. In light of enhanced cytokine release syndrome in individuals infected with the Wuhan strain or the Delta variant, we believe that a milder innate immune response might be beneficial and protective in those infected with the Omicron variant.

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Differential effects of age, sex and dexamethasone therapy on ACE2/TMPRSS2 expression and susceptibility to SARS-CoV-2 infection

Cited by 7 publications

References 62 publications

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2

Analysis of SARS-CoV-2 isolates, namely the Wuhan strain, Delta variant, and Omicron variant, identifies differential immune profiles

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