Toll-like Receptor Family
As in the case of SARS-CoV, angiotensin-converting enzyme 2 (ACE2) has been identified as main host cell receptor of SARS-CoV-26. The ACE2 receptor was detected on cells from various human organs including lung alveolar epithelial cells and enterocytes of the small intestine. Interestingly, virus-activation of ACE2 can promote signaling and activation of NF-κB similar to that mediated by the TLRs7,8.
TLRs also play important roles with respect to the outcome of viral infection. TLRs play a central role in promoting innate immune responses via their interactions with PAMPs as pattern-recognition receptors (PRRs) both at the plasma membrane and within endosomes. Downstream signaling pathways of TLRs result in the activation of nuclear factor kappa B (NF-κB)5 mainly via signals transmitted through myeloid differentiation factor 88 (MyD88)9, 10, 11, 12. Other factors involved in TLRs-mediated modulation of NF-κB are endosomal acidification13; activation of this pathway results in the production of proinflammatory cytokines and type I interferons. TLRs have been identified on B-lymphocytes, NK cells, dendritic cells, and macrophages, as well as on non-immune cells, including fibroblasts, epithelial cells and endothelial cells14, 15. TLR3 may play a critical role in detecting RNA viruses and altering the pathogenesis of acute virus infection. Activation of this pathway may result in damage to alveolar and bronchial epithelial cells, as well as in various immune cells such as macrophages16. Bronchial epithelial cells and alveolar cells of lower respiratory tract express increasing amounts of TLR4 in response to inflammatory cell infiltration observed in response to coronavirus and other virus infections11, 17. All TLR signaling pathways result in the activation NF-κB which is the master regulator of inflammatory cytokine expression5.