Estrogen shields women from COVID-19 complications by reducing ER stress

Shabbir, Sana; Hafeez, Assad; Rafiq, Muhammad; Khan, Muhammad Jadoon

doi:10.1016/j.mehy.2020.110148

Cited by 28 publications

(24 citation statements)

References 33 publications

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“…Correspondingly, they were abolished in Beclin1-deficient cells or CHOP-depleted cells separately, indicating that ORF3 enhances ER apoptotic cell death through excessive ERphagy and ER stress. These findings also support the therapeutic potential of ERphagy and ER stress in COVID-19 treatment, consistent with a hypothesis that ER stress is increased in COVID-19 patients and may benefit treatment 42–44 .…”

Section: Discussionsupporting

confidence: 88%

Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Zhang

Yang

Long

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have resulted in a number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, diseases and therapy remains limited, underlining the urgency of fundamental studies and drug development. Studies have shown that induction of autophagy and hijacking of autophagic machinery are essential for infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3 as an inducer of autophagy and revealed that ORF3 localizes to the ER and induces FAM134B-related ERphagy through the HMGB1-Beclin1 pathway. As a consequence, ORF3 induces ER stress and inflammatory responses through ERphagy and sensitizes cells to ER stress-induced cell death, suggesting that SARS-CoV-2 ORF3 hijacks ERphagy and then harms ER homeostasis to induce inflammatory responses through excessive ER stress. These findings reveal a sequential induction of ERphagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and provide therapeutic potential for ERphagy and ER stress-related drugs for COVID-19 treatment and prevention.ImportanceSARS-CoV-2 infection and replication require autophagosome-like double-membrane vacuoles. Inhibition of autophagy suppresses viral replication, indicating the essential role of autophagy in SARS-CoV-2 infection. However, how SARS-CoV-2 hijacks autophagy and the function of autophagy in the disease progression remain unknown. Here, we reveal that SARS-CoV-2 ORF3 induces ERphagy and consequently induces ER stress to trigger acute inflammatory responses and enhance sensitivity to ER stress-induced apoptosis. Our studies uncover ERphagy-induced inflammatory responses during SARS-CoV-2 infection and provide a promising therapeutic approach for treating SARS-CoV-2 infection and inflammatory responses in COVID-19 by manipulating autophagy and ER stress.

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Section: Discussionsupporting

confidence: 88%

Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Zhang

Yang

Long

et al. 2020

Preprint

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“…Previous studies report lower rates of severe COVID-19 complications amongst women compared to men, and our findings give weight to current hypotheses suggesting that oestrogen may confer a protective effect against COVID-19. [7,8] [4,5] This is consistent with the findings of the COVID Symptom Study which is the largest observational study to date including 152,637 women for menopause status. [7] Their findings across the cohort suggests that higher oestrogen levels may protect against COVID-19.…”

Section: Discussionsupporting

confidence: 78%

“…[18] Higher oestrogen levels may also be able to better promote direct anti-viral activity of T-cells and modulate the uncontrolled immune response (cytokine storm) that has been observed in those with respiratory failure due to COVID-19. [4,5] Immune responses and oestrogen level decrease with age which might explain why previous studies and our results show a greater likelihood of worse outcomes in females with increasing age. [1,7] However, amongst women on HRT with exogenous oestrogen the risk of all-cause mortality are reduced but still do not reach that of younger females presumably related to the direct effect of ageing on the immune system, and the increased number of morbidities acquired with age.…”

Section: Discussionmentioning

confidence: 46%

Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study

Dambha‐Miller

Hinton

Joy

et al. 2021

Preprint

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Objective: To investigate the association between Hormone Replacement Therapy (HRT) or Combined Oral Contraception (COCP) use, and the likelihood of death in women with COVID-19. Design: A cohort study Setting: 465 general practices in England within the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. Population: 1,863,478 women aged over 18 years Methods: We identified a cohort of women with COVID-19 from the computerised medical records of the RCGP RSC database. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use, and all-cause mortality among women with COVID-19 in unadjusted and adjusted models. Results: There were 5451 COVID-19 cases within the cohort. HRT was associated with a significantly lower likelihood of all-cause mortality in COVID-19 (adjusted OR 0.22, 95% CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP. Conclusions: Women on HRT with COVID-19 had a lower likelihood of death. Further work is needed in larger cohorts to examine the association of COCP in COVID-19. Our findings support the current hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

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“…In Italy, the case-fatality rate is higher in men at about 63.9% compared with affected women due to hormonal changes and lifestyle diversity ( 38 ). Shabbir et al's ( 39 ) observational study involved 162,392 Covid-19 patients which showed that 74% of affected patients were men compared to 26% women due to the protective effect of estrogen. Moreover, Garg et al ( 40 ) revealed that the mortality rate was higher in postmenopausal (12.8%) compared with premenopausal women (8.6%), highlighting the protective role of estrogen against Covid-19.…”

Section: Estrogen and Covid-19mentioning

confidence: 99%

“…Thereby, estrogen therapy may have an important step in the management of Covid-19 patients. Shabbir et al ( 39 ) illustrated that estrogen therapy mitigates endoplasmic reticulum stress (ER) induced by SARS-CoV-2 invasion through activation of cellular unfold protein response and regulation of inositol triphosphate (IP3) and phospholipase C. Baran-Gale et al ( 48 ) reported that E2 inhibits type II transmembrane protease serine (TMPRSS2), necessary for trimming and activation of SARS-CoV-2 spike protein to bind ACE2. Indeed, it has been reported that TMPRSS2 inhibitors, such as camostat and nafamostat, block SARS-CoV-2 entry, mainly in lung cells ( 49 ).…”

Section: Estrogen and Renin–angiotensin System In Covid-19mentioning

confidence: 99%

The Looming Effects of Estrogen in Covid-19: A Rocky Rollout

et al. 2021

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In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.

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Estrogen shields women from COVID-19 complications by reducing ER stress

Cited by 28 publications

References 33 publications

Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study

The Looming Effects of Estrogen in Covid-19: A Rocky Rollout

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