Cellular Responses Downstream of PAMP Recognition

Upon binding to PAMPs, PRRs initiate signal transduction pathways that lead to various cellular responses, including the production of inflammatory mediators, activation of immune cells, and establishment of an antiviral state. Here are some commonly studied signal transduction pathways downstream of PRR activation:

1. Toll-Like Receptor (TLR) Signaling Pathways:
   • TLRs are a family of PRRs located on the cell surface (e.g., TLR1, TLR2, TLR4) or within endosomes (e.g., TLR3, TLR7, TLR9).
   • MyD88-dependent Pathway:
     • Most TLRs signal through MyD88, leading to the activation of NF-κB and the production of pro-inflammatory cytokines.
   • TRIF-dependent Pathway:
     • TLR3 and TLR4 can also signal through TRIF, leading to type I interferon production.
2. NOD-Like Receptor (NLR) Signaling:
   • NLRs are cytoplasmic PRRs that form inflammasomes upon activation.
   • Inflammasome Activation:
     • Inflammasomes, composed of NLRs, ASC, and caspase-1, activate pro-inflammatory cytokines (IL-1β, IL-18) and induce pyroptotic cell death.
3. RIG-I-like Receptor (RLR) Signaling:
   • RLRs, including RIG-I and MDA5, detect viral RNA in the cytoplasm.
   • Activation of MAVS:
     • RLR binding to viral RNA leads to the activation of mitochondrial antiviral signaling protein (MAVS), triggering type I interferon production.
4. C-type Lectin Receptor (CLR) Signaling:
   • CLRs recognize carbohydrates on pathogens.
   • Syk-dependent Pathways:
     • Many CLRs signal through the Syk kinase, activating downstream pathways that induce cytokine production.
5. Cytosolic DNA Sensing:
   • Various sensors detect cytosolic DNA, such as cGAS (cyclic GMP-AMP synthase).
   • STING Pathway:
     • cGAS produces cGAMP, activating the Stimulator of Interferon Genes (STING) pathway, leading to type I interferon production.
6. Downstream Effector Molecules:
   • NF-κB Activation:
     • Common downstream signaling pathway leading to the transcription of pro-inflammatory genes.
   • MAPK Pathways:
     • Activation of mitogen-activated protein kinase (MAPK) pathways, including ERK, JNK, and p38, influencing inflammatory responses.
   • Interferon Regulatory Factor (IRF) Activation:
     • Many PRRs lead to the activation of IRFs, contributing to the induction of interferons.

Understanding these signaling pathways is critical for elucidating the innate immune response and developing targeted therapies for infectious and inflammatory diseases. The crosstalk and regulation within these pathways ensure a finely tuned and coordinated immune response.

Next Topic: Examples of Negative Feedback Mechanisms Following Responses to PAMP Recognition

Source: ChatGPT response prompted and edited by Joel Graff.

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