Faced with the threat of viruses, how can I improve my own immunity?

Innate immunity is the host's first important line of defense against microbial infections.

In this line of defense, host cells use different types of pattern recognition receptors (PRR) to recognize viral RNA and DNA, and then activate type I interferon (IFN) and inflammatory cytokines through a series of molecular reactions to combat viral infections And coordinate adaptive immunity.

How this antiviral innate immunity is affected by the metabolic state of the host is an interesting question to be studied.

Recently, more and more evidences have shown that cholesterol and glucose metabolism are related to innate immune activation, or can regulate virus immunity.

For example, during a viral infection, cholesterol synthesis is inhibited, which in turn promotes type I IFN-mediated antiviral activity through the STING-TBK1-IRF3 signaling pathway.

In addition, the single-carbon metabolism associated with serine promotes nucleotide synthesis, which in turn promotes cancer and T cell proliferation.

So specifically, is it the serine synthesis pathway (SSP) mediated by phosphoglycerate dehydrogenase (PHGDH), or is exogenous serine involved in the antiviral innate immunity? On April 1, 2021, "Cell Metabolism" magazine published an online study titled "Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation", which was jointly published by Tianjin Medical University's Yu Qiujing team and Wang Ting's team.

This study shows that serine metabolism can inhibit ATP6V0d2-mediated YAP lysosomal degradation, thereby regulating antiviral innate immunity.

DOI: 10.
1016/j.
cmet.
2021.
03.
006 Researchers use RNA virus Sendai virus (SeV) or DNA virus herpes simplex virus (VSV) to infect wild-type and PHGDH conditional knockout mice, and take their peritoneal macrophages (PMs) ) Perform qPCR and WB analysis.

The results showed that in PHGDH-deficient PMs, type I IFN levels were higher, and the phosphorylation levels of TBK1 and IRF3 were higher.

Experiments performed in HEI293T cells verified this result.

At the same time, in vivo animal experiments showed that compared with mice on a homoserine diet, the serum serine concentration was significantly reduced, the expression of IFNB1 was significantly increased, the liver VSV copy number was reduced, lung damage was reduced, and the survival time was longer in mice fed a serine-free diet.
long.

Therefore, the author believes that PHGDH negatively regulates the IFNB signaling pathway by inhibiting the TBK1-IRF3 axis.

Correspondingly, inhibition of serine metabolism can protect mice from viral infections.

PHGDH negatively regulates the IFN-β signaling pathway by inhibiting the TBK1-IRF3 axis.
So, which products of serine metabolism are involved in the suppression of viral innate immunity? Studies have pointed out that the addition of s-adenosylmethionine (SAM) and glutathione (GSH) to the serine-deficient medium can enhance the production of IL-1b in LPS-treated macrophages.

The researchers added SAM to the virus-infected serine-deficient HEK293T cells and found that the activation levels of IFNB1 mRNA and TBK1-IRF3 were significantly reduced, reaching the levels of the control cells after virus infection.

Therefore, the serine metabolite SAM can inhibit the production of IFN-β.

Serine metabolite SAM can inhibit the production of IFN-β.
In order to further clarify the potential mechanism of PHGDH inhibiting antiviral innate immunity, researchers used high-throughput sequencing technology (RNA-seq) to evaluate PHGDH-deficient bone marrow-derived macrophages (BMDMs) And RAW264.
7 macrophage gene expression.

Data analysis shows that PHGDH can reduce the expression of ATP6V0d2.

ATP6V0d2 is a subunit of V-ATPase, which is involved in regulating a variety of biological processes, including protein degradation, promoting influenza A virus fusion and fighting bacterial infections.

At the same time, ATP6V0d2 overexpression significantly enhanced the phosphorylation of IFNB1 mRNA and TBK1 and IRF3 in HEK293T cells.

In other words, PHGDH inhibits the production of TBK1-IRF3 signaling pathway and IFN-β by down-regulating ATP6V0d2.

PHGDH partially inhibits the production of IFN-β by down-regulating ATP6V0d2.
Studies have shown that YAP targets lysosomal degradation through IKK-ε-mediated phosphorylation during viral infection, and can inhibit the activation of TBK1-IRF3 to inhibit IFN-β-mediated The antiviral innate immunity.

Therefore, the researchers assessed whether ATP6V0d2 affects the expression of YAP.

The results show that ATP6V0d2 promotes YAP lysosomal degradation, reduces YAP-mediated blockade of the TBK1-IRF3 axis, thereby increasing the production of IFN-β.

ATP6V0d2 induces the production of IFN-b by promoting YAP lysosomal degradation.
In summary, this study reveals the previously unknown metabolic gene PHGDH and the key immune metabolite serine's viral immunomodulatory effect.

These findings indicate the key function of PHGDH and serine in weakening antiviral innate immunity, and also reveal the therapeutic potential of targeting serine metabolism against viral infections.

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