2 STTT finally solved the mystery!

Whether and how iNature humoral metabolism regulates the innate antiviral response remains a mystery
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 On April 25, 2022, Shu Hongbing and Hu Mingming of Wuhan University jointly published a research paper entitled "Modulation of innate immune response to viruses including SARS-CoV-2 by progesterone" in Signal Transduction and Targeted Therapy (IF=18).
, which showed that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice
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Progesterone induces downstream antiviral genes and promotes innate antiviral responses in cells and mice, whereas knockout of the progesterone receptor PGR has the opposite effect
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 Mechanistically, progesterone stimulation of PGR activates the tyrosine kinase SRC, which phosphorylates the transcription factor IRF3 at Y107, leading to its activation and induction of antiviral genes
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Patients infected with SARS-CoV-2 have elevated progesterone levels, which are associated with reduced severity of COVID-19
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Taken together, our findings reveal how progesterone modulates host innate antiviral responses and point to progesterone as a potential immunomodulator in infectious and inflammatory diseases
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In addition, on February 14, 2022, Xia Ningshao of Xiamen University, Cheng Tong and Guan Yi of the University of Hong Kong jointly published an online article entitled "Female sex hormone, progesterone, ameliorates the severity of in Signal Transduction and Targeted Therapy (IF=18)" SARS-CoV-2-caused pneumonia in the Syrian hamster model”, which demonstrates the potential use of progesterone for the treatment of COVID-19 in a hamster model of SARS-CoV-2 infection
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Following SARS-CoV-2 infection, 5 consecutive doses of progesterone rescued weight loss, inhibited viral replication, and restored cytokine storm and lung damage
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Combined with previous research, it has been shown that higher endogenous progesterone levels may protect women from progression to severe disease in COVID-19
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In conclusion, progesterone is an important biological factor that can modulate gender bias in SARS-CoV-2 infection and pathogenesis, and may be a potential therapeutic agent for COVID-19 (click to read)
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Innate immunity is the host's first line of defense against viral infection
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Following infection, viral components, especially their genomes or replication intermediates, are sensed by different pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and/or Intracellular DNA sensor
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Sensing of viral nucleic acids by the PRR triggers a signaling cascade that induces the transcription of type I interferons (IFNs), pro-inflammatory cytokines, and other downstream antiviral effector genes
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Downstream cytokines and effectors inhibit viral replication or induce apoptosis in infected cells, resulting in an innate antiviral response
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Different types of viruses are sensed by different PPRs
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Following RNA virus infection, invading cytosolic viral RNA is sensed by the RNA helicases RIG-I or MDA5
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Binding of RIG-1 or MDA5 to viral RNA triggers its recruitment to VISA (also known as MAVS), a mitochondrial-associated adaptor protein
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VISA then recruits the adaptor protein TRAF3, the TBK1 kinase, and the transcription factor IRF3
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During this process, TBK1 phosphorylates IRF3 at multiple sites including S386 and S396, resulting in IRF3 dimerization and translocation into the nucleus, ultimately inducing downstream cytokines and other antiviral effector genes
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Following infection with DNA viruses, invading cytosolic viral DNA is sensed by cyclic GMP-AMP (cGAMP) synthase (cGAS)
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cGAS can also identify mislocalized cellular genomic or mitochondrial DNA
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After sensing DNA, cGAS uses GTP and ATP as substrates to synthesize cGAMP, which binds to the ER-located adaptor protein MITA (also known as STING)
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This triggers the translocation of MITA from the ER through the Golgi to perinuclear punctate structures
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In this process, MITA recruits TBK1 and IRF3, leading to IRF3 activation and induction of downstream antiviral genes
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As a central transcription factor that induces innate antiviral responses, IRF3 needs to be fully activated in the early stage of viral infection and then terminated in a timely manner to avoid excessively harmful innate immune responses
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So far, various post-translational modifications, such as ubiquitination and acetylation, have been reported to inhibit the activity of IRF3
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In contrast, how IRF3 is optimally activated after viral infection is not fully understood
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Viral infection not only triggers an innate antiviral response, but also alters the host's metabolic homeostasis
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For example, viral infection alters the expression levels of rate-limiting enzymes involved in oxidative phosphorylation, sterol biosynthesis, and redox homeostasis, leading to subsequent changes in various metabolic reactions in infected cells
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Virus infection can also cause changes in serum neuroendocrine and other hormone levels, thereby affecting various physiological processes of the host
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In recent years, several studies have revealed mechanisms by which innate antiviral responses are regulated by cellular metabolism such as cholesterol consumption, bile acid synthesis, lactate accumulation, and lipid oxidation
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Until now, how humoral metabolism regulates innate antiviral immunity has been largely unknown
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Article pattern diagram (pictured from Signal Transduction and Targeted Therapy) Progesterone is an important humoral steroid hormone in mammals
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Progesterone has been reported to regulate neural development and T cell differentiation regardless of gender
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Progesterone is biosynthesized in specialized tissues, including the adrenal glands and reproductive organs, and progesterone production is tightly regulated by the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis
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Although progesterone is produced in specialized cells and tissues, it exerts its different biological effects on various types of cells in different tissues and organs
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Progesterone signals through the PGR, a nuclear hormone receptor that directly induces transcription of downstream effector genes
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In addition to its function as a nuclear hormone receptor, PGR can rapidly activate the proto-oncogene tyrosine kinase SRC in breast cancer cytoplasm and mammary epithelial cells upon progesterone stimulation
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In this study, progesterone was identified as the predominantly elevated humoral steroid hormone in virus-infected mice
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The results suggest that progesterone promotes innate antiviral responses in vitro and in vivo
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Mechanistically, the progesterone-PGR axis activates the SRC, which then mediates the phosphorylation of IRF3 at Y107
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This phosphorylation of IRF3 initiates its association and self-association with TBK1, leading to its activation and induction of downstream antiviral genes
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 In addition, the study also showed that patients infected with SARS-CoV-2 had elevated serum progesterone levels, which was inversely related to disease severity
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Our findings shed light on the mechanism of how progesterone metabolism modulates the host's innate antiviral response and point to progesterone as a potential immunomodulator in infectious and inflammatory diseases
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