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.