Molecules Inducing Antiviral State in Cells

Pattern Recognition Receptors (PRRs)

PRRs are crucial sensors that detect viral components and initiate antiviral responses (Vitiello et al., 2021)

Toll-Like Receptors (TLRs)

TLRs are membrane-bound PRRs that recognize various viral components:

• TLR2 and TLR4: Respond to viral proteins
• TLR3, TLR7, TLR8, and TLR9: Recognize viral nucleic acids (Vitiello et al., 2021)

RIG-I-Like Receptors (RLRs)

Cytoplasmic RNA sensors that play a crucial role in antiviral responses:

• RIG-I: Recognizes short dsRNA and 5'-triphosphate RNA
• MDA5: Detects longer dsRNA
• LGP2: Regulates RIG-I and MDA5 responses (Vitiello et al., 2021)

DNA Sensors

Cytoplasmic proteins that detect viral DNA:

• cGAS: Recognizes cytosolic DNA and activates STING
• AIM2: Detects DNA and activates the inflammasome (Vitiello et al., 2021)

Signaling Pathways

TLR Signaling

1. MyD88-dependent pathway: Activates NF-κB and AP-1
2. TRIF-dependent pathway: Activates IRF3 and NF-κB (Vitiello et al., 2021)

RLR Signaling

1. RIG-I and MDA5 interact with MAVS
2. MAVS activates TBK1 and IKKε
3. TBK1 and IKKε phosphorylate IRF3 and IRF7 (Ong et al., 2023)

Transcription Factors

NF-κB

Activates pro-inflammatory cytokine genes (e.g., IL-1α, IL-1β, IL-6, TNFα) (Vitiello et al., 2021)

IRF3 and IRF7

Coordinate the expression of type I and type III interferons (Vitiello et al., 2021)

Interferons (IFNs)

Type I IFNs

• IFNα subfamily (13 proteins in humans)
• IFNβ, IFNε, IFNκ, and IFNω

Act through IFNAR1/IFNAR2 receptor complex (Vitiello et al., 2021)

Type III IFNs

• IFN-λ1 (IL-29)
• IFN-λ2 (IL-28A)
• IFN-λ3 (IL-28B)

Act through IFNLR1/IL10R2 receptor complex (Vitiello et al., 2021)

IFN Signaling

1. IFNs bind to their respective receptors
2. Activate JAK-STAT pathway
3. Induce expression of Interferon-Stimulated Genes (ISGs) (Vitiello et al., 2021)

Interferon-Stimulated Genes (ISGs)

MX1

• Cytoplasmic protein
• Inhibits viral transcription and replication
• Retains viral genomes in the cytoplasm (Ong et al., 2023)

IFITM Family

• Interferon-induced transmembrane proteins
• Block early viral entry
• Modify cellular membrane properties (Ong et al., 2023)

RIG-I

• Upregulated by IFN signaling
• Creates a positive feedback loop
• Amplifies antiviral signals (Ong et al., 2023)

Antiviral State

The combined effect of ISGs and other antiviral factors creates an antiviral state in cells, characterized by:

1. Enhanced proteasomal function
2. Increased autophagy
3. Cytostasis and apoptosis of infected cells
4. Improved antigen presentation
5. Restriction of viral replication and spread (Vitiello et al., 2021)

Immune Cell Activation

IFN signaling affects immune cells by:

1. Inducing chemokine production (e.g., CXCL9, CXCL10, CCL2)
2. Enhancing lymphocyte and macrophage recruitment
3. Promoting adaptive immune responses (Vitiello et al., 2021)

Viral Evasion Strategies

Viruses have evolved mechanisms to counteract antiviral responses:

1. Inhibition of PRR signaling
2. Interference with IFN production and signaling
3. Suppression of ISG function

Example: Influenza NS1 protein inhibits RIG-I signaling and blocks transcription of antiviral genes (Ong et al., 2023)