National Natural Science Fund Hotspot | Antiviral Innate Immunity
Antiviral innate immunity is a rapid defense mechanism activated by the body at the initial stage of viral infection and serves as the first line of defense of the immune system. It does not rely on pre-existing immune memory for specific pathogens, but instead responds quickly by recognizing pathogen-associated molecular patterns (PAMPs) that are common to viruses.
Recognition Mechanisms of Innate Immunity
Innate immune cells recognize viral pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs). Common PRRs include:
Toll-like receptors (TLRs): These are primarily located on the cell surface or endosomal membranes and can recognize viral nucleic acids or proteins. For example, TLR3 recognizes double-stranded RNA viruses, while TLR7 and TLR8 recognize single-stranded RNA viruses.
RIG-I-like receptors (RLRs): These mainly function in the cytoplasm, with RIG-I and MDA5 being the representative members. They can recognize viral RNA.
DNA sensors: For example, the cGAS-STING pathway can recognize viral DNA in the cytoplasm.
Signal Pathways of Antiviral Innate Immunity
After PRRs recognize viral PAMPs, a series of signaling pathways are activated, ultimately leading to the production of antiviral effector molecules:
Production of Type I Interferons (IFN-α/β): This is the core response of innate immunity. After viral infection of cells, RIG-I or MDA5 recognizes viral RNA, which activates the MAVS protein. This subsequently activates the transcription factors IRF3 and IRF7, inducing the expression of Type I interferons.
Production of Inflammatory Cytokines: Such as TNF-α and IL-6, these factors promote inflammatory responses and recruit immune cells to the site of infection.
Release of Cytokines and Chemokines: Such as CXCL10 and CCL5, which attract natural killer cells (NK cells) and dendritic cells (DCs).
Effect Mechanisms of Innate Immunity
Antiviral innate immunity inhibits viral replication and spread through multiple mechanisms:
Interferon Function: Type I interferons, by binding to their receptors, activate the JAK-STAT signaling pathway, inducing cells to express antiviral proteins (such as OAS, RNase L, and MX proteins), which directly inhibit viral replication.
Natural Killer Cells (NK Cells): NK cells can recognize and kill virus-infected cells. Their killing mechanisms include the release of perforin and granzymes.
Macrophages and Dendritic Cells: These cells clear viral particles through phagocytosis and present viral antigens to adaptive immune cells.
Regulation of Innate Immunity
Innate immune responses require precise regulation to prevent excessive activation that could cause self-damage:
Negative Regulatory Factors: Such as SOCS proteins and DUBs (deubiquitinating enzymes), which inhibit the overproduction of Type I interferons.
Inflammation Resolution Mechanisms: Through the secretion of anti-inflammatory cytokines (such as IL-10) or the activation of regulatory immune cells (such as Tregs), the inflammatory response is limited.
Synergy Between Innate and Adaptive Immunity
Innate immunity is the initiator of adaptive immunity, activating it through the following mechanisms:
Activation of Dendritic Cells: After being activated in innate immunity, dendritic cells present viral antigens to T cells, initiating adaptive immunity.
Function of Type I Interferons: Type I interferons promote antibody production by B cells and activation of T cells.
Research Progress
Dual Functions of PCSK9 in Antiviral Innate Immunity Against RNA Viruses
Atypical Antiviral Innate Immunity Signaling Pathway Mediated by IRF1
Regulatory Mechanisms of the cGAS-STING Pathway
Ubiquitination Regulation Mechanisms of MAVS
Translocation and Activation Mechanisms of STING
References
H Fang, M Shi, C Wang. PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS.
Zhou H, Tang YD, Zheng C. Revisiting IRF1-mediated antiviral innate immunity. Cytokine Growth Factor Rev. 2022 Apr.
Zhang Z, Zhang C. Regulation of cGAS-STING signaling and its diversity of cellular outcomes. Nat Rev Immunol. 2025 Jan.
Liu F, Zhuang W. MAVS-loaded unanchored Lys63-linked polyubiquitin chains activate the RIG-I-MAVS signaling cascade. Cell Mol Immunol. 2023 Oct.
Fang R, Jiang Q, Jia X, Jiang Z. ARMH3-mediated recruitment of PI4KB directs Golgi-to-endosome trafficking and activation of the antiviral effector STING. Immunity. 2023 Mar.
Antiviral innate immunity is the first line of defense against viral infections. It rapidly recognizes viruses, activates signaling pathways, produces effector molecules, and regulates immune responses, thereby supporting the initiation of adaptive immunity. Recent research has continuously uncovered its complex regulatory mechanisms, providing new ideas for the development of novel antiviral drugs and vaccines.
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