Estrogen Hormone Is an Essential Sex Factor Inhibiting Inflammation and Immune Response in COVID-19.
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ABSTRACT:
SUBMITTER: Li F
PROVIDER: S-EPMC8491851 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although vaccines have been evaluated and approved for SARS-CoV-2 infection prevention, there remains a lack of effective treatments to reduce the mortality of COVID-19 patients already infected with SARS-CoV-2. The global data on COVID-19 showed that men have a higher mortality rate than women. We further observed that the proportion of mortality of females increases starting from around the age of 55 significantly. Thus, sex is an essential factor associated with COVID-19 mortality, and sex related genetic factors could be interesting mechanisms and targets for COVID-19 treatment. However, the associated sex factors and signaling pathways remain unclear. Here, we propose to uncover the potential sex associated factors using systematic and integrative network analysis. The unique results indicated that estrogens, e.g., estrone and estriol, (1) interacting with ESR1/2 receptors, (2) can inhibit SARS-CoV-2 caused inflammation and immune response signaling in host cells; and (3) estrogens are associated with the distinct fatality rates between male and female COVID-19 patients. Specifically, a high level of estradiol protects young female COVID-19 patients, and estrogens drop to an extremely low level in females after about 55 years of age causing the increased fatality rate of women. In conclusion, estrogen, interacting with ESR1/2 receptors, is an essential sex factor that protects COVID-19 patients from death by inhibiting inflammation and immune response caused by SARS-CoV-2 infection. Moreover, medications boosting the down-stream signaling of ESR1/ESR2, or inhibiting the inflammation and immune-associated targets on the signaling network can be potentially effective or synergistic combined with other existing drugs for COVID-19 treatment.
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Project description:The current COVID-19 pandemic began in December 2019 in Wuhan (China) and rapidly extended to become a global sanitary and economic emergency. Its etiological agent is the coronavirus SARS-CoV-2. COVID-19 presents a wide spectrum of clinical manifestations, which ranges from an asymptomatic infection to a severe pneumonia accompanied by multisystemic failure that can lead to a patient's death. The immune response to SARS-CoV-2 is known to involve all the components of the immune system that together appear responsible for viral elimination and recovery from the infection. Nonetheless, such immune responses are implicated in the disease's progression to a more severe and lethal process. This review describes the general aspects of both COVID-19 and its etiological agent SARS-CoV-2, stressing the similarities with other severe coronavirus infections, such as SARS and MERS, but more importantly, pointing toward the evidence supporting the hypothesis that the clinical spectrum of COVID-19 is a consequence of the corresponding variable spectrum of the immune responses to the virus. The critical point where progression of the disease ensues appears to center on loss of the immune regulation between protective and altered responses due to exacerbation of the inflammatory components. Finally, it appears possible to delineate certain major challenges deserving of exhaustive investigation to further understand COVID-19 immunopathogenesis, thus helping to design more effective diagnostic, therapeutic, and prophylactic strategies.
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Project description:The preoptic area (POA) is one of the most evolutionarily conserved regions of the vertebrate brain and contains subsets of neuropeptide-expressing neurons. Here we found in the teleost medaka that two neuropeptides belonging to the secretin family, pituitary adenylate cyclase-activating polypeptide (Pacap) and vasoactive intestinal peptide (Vip), exhibit opposite patterns of sexually dimorphic expression in the same population of POA neurons that project to the anterior pituitary: Pacap is male-biased, whereas Vip is female-biased. Estrogen secreted by the ovary in adulthood was found to attenuate Pacap expression and, conversely, stimulate Vip expression in the female POA, thereby establishing and maintaining their opposite sexual dimorphism. Pituitary organ culture experiments demonstrated that both Pacap and Vip can markedly alter the expression of various anterior pituitary hormones. Collectively, these findings show that males and females use alternative preoptic neuropeptides to regulate anterior pituitary hormones as a result of their different estrogen milieu.
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Project description:Coronavirus disease-2019 (COVID-19) is a novel respiratory disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It remains poorly understood how the host immune system responds to the infection during disease progression. We applied microarray analysis of the whole genome transcriptome to peripheral blood mononuclear cells (PBMCs) taken from severe and mild COVID-19 patients as well as healthy controls. Functional enrichment analysis of genes associated with COVID-19 severity indicated that disease progression is featured by overactivation of myeloid cells and deficient T cell function. The upregulation of TLR6 and MMP9, which promote the neutrophils-mediated inflammatory response, and the downregulation of SKAP1 and LAG3, which regulate T cells function, were associated with disease severity. Importantly, the regulation of these four genes was absent in patients with influenza A (H1N1). And compared with stimulation with hemagglutinin (HA) of H1N1 virus, the regulation pattern of these genes was unique in PBMCs response to Spike protein of SARS-CoV-2 ex vivo. Our data also suggested that severe SARS-CoV-2 infection largely silenced the response of type I interferons (IFNs) and altered the proportion of immune cells, providing a potential mechanism for the hypercytokinemia. This study indicates that SARS-CoV-2 infection impairs inflammatory and immune signatures in patients, especially those at severe stage. The potential mechanisms underpinning severe COVID-19 progression include overactive myeloid cells, impaired function of T cells, and inadequate induction of type I IFNs signaling.
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Project description:ObjectivesSepsis is a clinical disease that is typically treated in the intensive care unit, and the complex pathophysiology under this disease has not been thoroughly understood. While ferroptosis is involved in inflammation and infection, its effect in sepsis is still unknown. The study aimed to identify ferroptosis-related genes in sepsis, providing translational potential therapeutic targets.MethodsThe dataset GSE65682 was used to download the sample source from the Gene Expression Omnibus (GEO) database. Consensus weighted gene co-expression network analysis (WGCNA) was performed to find suspected modules of sepsis. The differentially expressed genes (DEGs) most significantly associated with mortality were intersected with those altered by lipopolysaccharide (LPS) treatment and were further analyzed for the identification of main pathways of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The related pathway markers were further verified by qPCR.ResultsA total of 802 blood samples with sepsis were included for WGCNA, which identified 21 modules. Intersected with ferroptosis databases and LPS treatment groups, we identified two ferroptosis-related genes: PEBP1 and LPIN1. Only LPIN1 contributes to a poor outcome. Then, 205 DEGs were further identified according to the high or low LPIN1 expression. Among them, we constructed a gene regulatory network with several transcriptional factors using the NetworkAnalyst online tool and identified that these genes mostly correlate with inflammation and immune response. The immune infiltration analysis showed that lower expression of LPIN1 was related to macrophage infiltration and could be an independent predictor factor of the survival status in sepsis patients. Meanwhile, the multivariate Cox analysis showed that LPIN1 had a significant correlation with survival that was further verified by in vitro and in vivo experiments.ConclusionIn conclusion, LPIN1 could become a reliable biomarker for patient survival in sepsis, which is associated with immune and inflammation status.
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Project description:BackgroundSex differences in COVID-19 are increasingly recognized globally. Although infection rates are similar between the sexes, men have more severe illness. The mechanism underlying these sex differences is unknown, but a differential immune response to COVID-19 has been implicated in several recent studies. However, how sex differences shape the immune response to COVID-19 remains understudied.MethodsWe collected demographics and blood samples from over 600 hospitalized patients diagnosed with COVID-19 from May 24th 2020 to April 28th, 2021. These patients were divided into two cohorts: Cohort 1 was further classified into three groups based on the severity of the disease (mild, moderate and severe); Cohort 2 patients were longitudinally followed at three time points from hospital admission (1 day, 7 days, and 14 days). MultiPlex and conventional ELISA were used to examine inflammatory mediator levels in the plasma in both cohorts. Flow cytometry was conducted to examine leukocyte responses in Cohort 2.ResultsThere were more COVID+ males in the total cohort, and the mortality rate was higher in males vs. females. More male patients were seen in most age groups (in 10-year increments), and in most ethnic groups. Males with severe disease had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) than females; levels of IL-8, GRO, sCD40L, MIP-1β, MCP-1 were also significantly higher in severe vs. mild or control patients in males but not in females. Females had significantly higher anti-inflammatory cytokine IL-10 levels at 14 days compared to males, and the level of IL-10 significantly increased in moderate vs. the control group in females but not in males. At 7 days and 14 days, males had significantly more circulating neutrophils and monocytes than females; however, B cell numbers were significantly higher in females vs. males.ConclusionSex differences exist in hospitalized patients with acute COVID-19 respiratory tract infection. Exacerbated inflammatory responses were seen in male vs. female patients, even when matched for disease severity. Males appear to have a more robust innate immune response, and females mount a stronger adaptive immune response to COVID-19 respiratory tract infection.
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Project description:Sex hormones are significant regulators of stress reactivity, however, little is known about how genetic variation in hormone receptors contributes to this process. Here we report interactions between biological sex and repeat polymorphisms in genes encoding sex hormone receptors, and their effects on salivary cortisol reactivity in a sample of 100 participants (47 men & 53 women; 24.7?±?3.23?years). Three genes were investigated: estrogen receptors alpha (ESR1) and beta (ESR2), and the androgen receptor (AR). Participants were classified as carrying 'Short' or 'Long' alleles based on median splits of the repeat distribution for each gene. Measures of physiological reactivity were collected before and after exposure to a canonical laboratory stressor and converted to traditional summary measures for analyses. Overall, men exhibited greater cortisol (p?=?0.001) and mean arterial pressure reactivity (p?=?0.002), while women displayed elevated heart rate throughout the session (p?=?0.02). The effect of polymorphisms on salivary cortisol was sex sensitive. ESR1 was associated with differential reactivity in men (p?=?0.04), but not women (p?=?0.24). ESR2 genotype interacted with sex such that each additional 'Long' allele was associated with a 6.4% decrease in salivary cortisol in men, but a 9.5% increase in the levels of women (p?=?0.02 for interaction). For the X-linked AR, the 'Long' allele was associated with decreased cortisol levels in men (p?=?0.047), but in women had no effect (p?=?0.75). Together, these results provide evidence for the saliency of genetic variation in sex hormone receptors on stress reactivity in humans and highlight their important role as mediators of hormonal activity.
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Project description:Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women.
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