The role of estradiol in the immune response against COVID-19

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen agent causing coronavirus disease (COVID)-19, which was declared a global pandemic in 2020. The spike protein of this virus and the angiotensin-converter enzyme (ACE)-2 in host cells in humans play a vital role in infection and in COVID-19 pathogenesis. Estradiol is known to modulate the actions of immune cells, and, therefore, the antiviral mechanisms of these cells could also be modified by this hormone stimulus. Even though estradiol is not considered a protective factor, evidence shows that women with high levels of this hormone have a lower risk of developing severe symptoms and an even a lower incidence of death. Understanding the mechanism of action of estradiol with regard to viral infections and COVID-19 is essential for the improvement of therapeutic strategies. This review aims to describe the effects that estradiol exerts on immune cells during viral infections and COVID-19.

Estradiol reduces ACE2 and TMPRSS2 mRNA levels in A549 human lung epithelial cells

“…The 2003 SARS pandemic was caused by a coronavirus which infected lung epithelial cells via their ACE2 receptor, similarly to SARS‐CoV‐2; thus, this observation suggests common pathways which afford women some protection from both SARS‐CoV‐1 and SARS‐CoV‐2. Aside from of its modulatory effects on ACE2 and TMPRRSS2 expression, as observed in our current study with A549 lung epithelial cells, estradiol likely affords partial protection from coronavirus‐mediated diseases by enhancement of immune functions (Dhindsa et al, 2021 ; Khan, 2020 ; Ramírez‐de‐Arellano et al, 2021 ). Notably, “Long Covid,” the persisting neurological symptoms affecting some Covid‐19 patients for many months following their recovery, is most common among premenopausal women, who have higher estradiol levels than either men or postmenopausal women; for such patients, higher endogenous estradiol levels were suggested as the underlying cause (Bai et al, 2021 ; Sigfrid et al, 2021 ).…”

Factors affecting climacteric women with SARS-CoV-2 infection: A multinational Latin America study (REDLINC XI)

“…For example, estrogen could reduce virus receptors on cell surfaces (angiotensinconverting enzyme 2) and can also modulate the immune response, both innate and adaptive, to viral aggression [5]. Furthermore, women would carry genes on the X chromosome involved in the inflammatory response [7]. Therefore, the use of estrogen-only or estrogen/progestogen therapy has even been postulated, both in men and women, to treat and improve the clinical evolution of COVID-19 cases [8,9].…”

Analysis and identification of potential type II helper T cell (Th2)-Related key genes and therapeutic agents for COVID-19

“…Estradiol also inhibits NF-κB mediated macrophage activation via miR-125 b and polarizes Th2 through regulation of B lymphocyte function [ 122 , 126 ]. As such, estrogen may be a potential therapeutic target for promotion of cellular resistance to SARS-CoV-2 [ 127 ]. Estradiol was found to inhibit viral entry by targeting the six-helix (6-HB) fusion core of SARS-CoV-2 S protein [ 128 ].…”