Researchers at Duke and Mt. Sinai have identified a molecular mechanism that prevents a viral infection during a mother’s pregnancy from harming her unborn baby.
When a person becomes infected by a virus, their immune system sends out a chemical signal called type I interferon, which tells surrounding cells to increase their anti-viral defenses, including making more inflammation.
This response helps to prevent the virus from copying itself and gives the adaptive immune system more time to learn about the new invader and begin to hunt it down.
A pregnant woman who encounters a virus generates these same signals to protect herself, but if those signaling molecules and the resulting inflammation were able to cross the placenta and reach the fetus, they would lead to serious developmental abnormalities and even fetal death.
But this generally doesn’t happen, except for the Zika virus and a handful of other viruses known to replicate inside the fetus and harm it. (Despite almost 100 million reported cases of COVID-19 to date around the world, there is no strong evidence that the virus which causes the disease, SARS-CoV-2, poses a threat to fetuses.)
The research team found a mechanism that protects the fetus from the harm the mother’s immune response to a virus could cause.
In a paper appearing Jan. 15 in Science, they identify a key player in this pathway as a cell-surface estrogen receptor called GPER1 that is especially abundant in the placenta and fetal tissues.
“This likely explains why many maternal infections during pregnancy don’t hurt the fetus,” said study leader Nicholas Heaton, an assistant professor of Molecular Genetics and Microbiology in the Duke School of Medicine.
Having arrived at GPER1 as a possible candidate for this effect by a series of screens, the researchers found GPER1 receptors concentrated in the placenta, where the mother’s blood supply passes oxygen and nutrients over to the fetus.
Estrogen levels are much higher during pregnancy, making the GPER1 receptor even better able to suppress interferon signaling in the placenta and developing fetus.
The researchers tried blocking this particular estrogen receptor in pregnant mice with a compound called G15. They found changes in the placenta during influenza A virus infection or G15 treatment, which led to slightly smaller mouse pups. But with both G15 and influenza virus present, the pups were dramatically smaller and many were stillborn.
They also tested mouse pregnancies with Zika and influenza B virus infections and saw that the addition of the G15 treatment again led to many more fetal defects.
“If we disable the GPER1 pathway, even normally benign maternal infections (like flu) will now cause major fetal developmental issues,” Heaton said.
Heaton calls it a pathway because his team doesn’t yet understand how GPER1 provides this protection. They suspect the receptor triggers other downstream mechanisms that come into play.
Heaton said the beauty of this system being concentrated around the baby is that it protects the fetus from inflammation, while leaving the rest of the mother’s tissues more able to use interferon to fight the virus.
The researchers are next going to pursue tests of whether “hyperactivating” the GPER1 pathway would be a way to protect fetal development when a mother becomes virally infected.
Role of the “Cytokine Storm” in COVID-19
The previous severe acute respiratory syndromes caused by SARS-CoV and MERS-CoV were often associated with rapid viral replication, huge infiltration of inflammatory cells, and excessive production of proinflammatory cytokines (cytokine storm syndrome), leading to lung injury and respiratory distress syndrome (Channappanavar and Perlman, 2017).
Notably, accumulating evidence demonstrates that cytokine storm syndrome is involved also in the most severe cases of COVID-19 (Mehta et al., 2020). These patients rapidly develop respiratory distress syndrome, lung edema and failure (often associated with hepatic, myocardial, and renal injury, hemostasis alteration).
Elevated levels of proinflammatory cytokines are observed in these patients. In particular, compared with non-intensive care patients, intensive care patients have higher levels of IL-2, IL-7, and TNF. Many cytokines detected in these patients belong to the Th17 type response (as previously observed in MERS-CoV and SARS-CoV patients).
The consequent IL-17-related pathway promotes broad pro-inflammatory effects by induction of specific cytokines, such as IL-1b, IL-6, TNF (responsible for systemic inflammatory symptoms), chemokines and matrix metalloproteinases (responsible for tissue damage and remodeling) (Wu and Yang, 2020).
Moreover, pro-inflammatory cytokines, including IL-1b and IL-6, are directly induced by SARS-CoV-2 by interaction between viral components (probably nucleocapsid proteins) and toll like receptors of the host cells. Besides Th17 responses, patients diagnosed with COVID-19 showed marked rise of the Th1 subset (inflammatory cytokines IL-1β, IL-6, and IL-12) for more than 2 weeks after the infection onset (Russell et al., 2020).
In turn, IL-6 induced by SARS-CoV-2 in the lung seems to promote/amplify Th17 responses that may worsen the severe lung pathology in susceptible hosts (Hotez et al., 2020). In fact, IL-6 plays a crucial pathogenetic role in pulmonary injury induced by COVID-19.
Accordingly, elevated levels of IL-6, produced by monocytes, lung interstitial fibroblasts, and alveolar macrophages, are observed in critical patients (Sun et al., 2020). Such a crucial role of IL-6 provided the rational basis for considering anti-IL-6 monoclonal antibodies (i.e. tocilizumab) as promising drugs for COVID-19 (Hotez et al., 2020).
Estrogens in Cytokine Regulation
The complex pathways of cytokine regulation may pave the way to new pharmacological approaches aimed at limiting IL-6 expression and cytokine storm. As reported above, COVID-19 outcomes show clear gender-related differences; notably, gonadal hormones deeply influence the immune response.
Indeed, estrogen receptors (ERs) regulate the expression of IL-6 gene through inhibition of transcription factors NF-IL6 and NF-κB, and through disruption of NF-κB transactivation (Luo and Zheng, 2016). As well, estradiol (and probably progesterone) inhibits Th17 cell differentiation (Chen et al., 2015). ERα activation in immune cells reduces Th1 and Th17 responses and skews cytokine production towards a Th2 type, with enhanced antibody response.
ER modulation has been proposed in a murine experimental model of pulmonary inflammation as a useful pharmacological strategy. In particular, ERα are expressed in resident and infiltrated inflammatory cells of the lungs and activation of these receptors by estradiol markedly reduces the histological and biochemical markers of inflammation.
Notably, these effects were observed in both male and female animals (Vegeto et al., 2010). Protective effects of ER mediators were also observed in murine models of pulmonary inflammation induced by influenza virus infection (Vermillion et al., 2018). Consistently, estradiol (Zhang and Liu, 2020) and other estrogen hormones (such as the horse estrogen equilin) has been presently reviewed as an alternative option for the treatment of COVID‐19 (Suba, 2020).
SERMs as Possible “Adjuvant Drugs” in COVID-19
Noteworthy, the protective effects evoked by endogenous estrogens are also promoted by drugs belonging to the class of SERMs (selective estrogen receptor modulators) (Polari et al., 2018). These drugs exhibit a complex profile of mixed agonist/antagonist modulators of the ER subtypes and their effects on immune system and immune-mediated inflammatory responses have been described (Behjati and Frank, 2009).
Indeed, many preclinical and clinical studies demonstrated that SERMs evoke significant anti-inflammatory responses and inhibit the expression of many proinflammatory cytokines, in different conditions of systemic or local inflammation (Suuronen et al., 2005; Nalbandian et al., 2005; Cerciat et al., 2010; Azizian et al., 2018).
Concerning coronavirus infections, a single preclinical study investigated the role of sex hormones in shaping gender-related vulnerability to SARS-CoV. In this study, male and female mice were infected with murine-adapted SARS-CoV (Channappanavar et al., 2017). Male mice were more vulnerable to SARS-CoV infection compared to female mice.
Such a higher susceptibility of male mice to SARS-CoV was associated with higher viral titers, enhanced vascular leakage, and alveolar edema. These changes were also associated with elevated levels of inflammatory cytokines in lungs of male mice. Ovariectomy or treatment of female mice with an ER antagonist increased mortality, indicating a protective effect for ER signaling in mice infected with SARS-CoV. In contrast, treatment of female mice with SERMs (i.e. tamoxifen) led to increased levels of protection.
Moreover, beyond the effects of SERMs on ERs, these drugs seem to present useful ancillary properties. Besides their potential effects on proinflammatory cytokine expression (mediated by ERs), some SERMs seem to play broader roles in inhibiting viral replication by ER-independent mechanisms.
Indeed, in vitro studies on established cell lines reported that some drugs of the SERM class interfere with processes of viral entry into the host cell and inhibit different viral infections, including MERS-CoV, SARSCoV, and Ebola virus. These effects may be due to potential interaction with viral glycoproteins and with host proteins involved in the viral infection (Zhou et al., 2020).
The hypothesized mechanisms of the potential effect of SERMs are summarized in Figure 1.
Hypothesized mechanisms accounting for the potential effects of SERMs. (A) ERs regulate the expression of proinflammatory cytokines, such as IL-6, by inhibition of the transcription factors NF-IL6 and NF-κB, and disruption of NFκB transactivation. (B) in experimental studies on established cell lines, some SERMs have been reported to interfere with the processes of viral entry into the host cell and to inhibit different viral infections, including MERS-CoV, SARSCoV, and Ebola. Potential interactions with viral glycoproteins and with host proteins involved in the viral infection have been hypothesized.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381128/
More information: Alfred T. Harding et al. GPER1 is required to protect fetal health from maternal inflammation, Science (2021). DOI: 10.1126/science.aba9001
