Question

How’s Pathogen Associated Molecular Patterns (PAMPs) associated with coronaviruses? what Pattern Recognition Receptor(s) (PRR) likely recognizes the PAMP?

Answer 1

Coronaviruses (CoVs) are the largest group of known positive‐sense RNA viruses having an extensive range of natural hosts. The innate immune system constitutes the first line of defense against invading microbial pathogens recogonizes a large family of pattern recognition receptors (PRRs), which can identify distinct evolutionarily conserved structures on pathogens, termed as pathogen-associated molecular patterns (PAMPs). In the host, most of the intracellular pattern recognition receptors (PRRs) reside in either the endolysosome or the cytoplasm to detect pathogen-derived RNAs, DNAs or synthetic analogs of double-stranded RNA (dsRNA).

So far, the known PRRs mainly include toll‐like receptor (TLR), RIG‐I‐like receptor (RLR), NOD‐like receptor (NLR), C‐type lectin‐like receptors (CLmin), and free‐molecule receptors in the cytoplasm, such as cGAS, IFI16, STING, DAI, and so on.

Mechanism of infection- Coronaviruses (CoV)

CoV attacks macrophages, and then macrophages present CoV antigens to T cells. This process leads to T cell activation and differentiation, including the production of cytokines associated with the different T cell subsets (ie, Th17), followed by a sudden release of cytokines for immune response amplification. The continued production of these mediators has a negative impact on NK, and CD8 T cell activation. However, CD8 T cells produce effective mediators to kill CoV. CoV gets attached to DPP4R receptor on the host cell through S protein leading to the presence of genomic RNA in the cytoplasm. TLR‐3 sensitized by dsRNA and cascades of signaling pathways (IRFs and NF‐κB activation, respectively) are activated to produce type I IFNs and proinflammatory cytokines. The production of type I IFNs is necessary to enhance the release of antiviral proteins for the protection of uninfected cells. Sometimes, accessory proteins of CoV can interfere with TLR‐3 signaling and bind the dsRNA of CoV during replication to prevent TLR‐3 activation and evade the immune response. TLR‐4 can recognize S protein and lead to the activation of proinflammatory cytokines through the MyD88‐dependent signaling pathway. The secretion of large quantities of chemokines and cytokines (IL‐1, IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1) is promoted in infected cells as a response to CoV infection. Meanwhile these chemokines and cytokines recruit lymphocytes and leukocytes to the site of infection.

Similarly membrane (M) protein of SARS-CoV can directly promote the activation of both beta interferon (IFN-β) and NF-κB through a TLR-related signaling pathway independent of TRAF3. The driving force for M-mediated IFN-β production is most likely generated from inside the cells. SARS-CoV M protein may also function as a cytosolic PAMP to stimulate IFN-β production by activating a TLR-related TRAF3-independent signaling cascade.