The lack of a consistent role for individual TLRs in protection
from viral infection should not come as a surprise
given the more restricted distribution of these receptors
compared to the RLR family, the possibility of redundancy
among distinct TLRs, and the overlap between the endosomal
and cytosolic pathways (Figure 2). However, the latter
might be a lot less redundant: Preliminary evidence indicates
that RIG-I-deficient mice are highly susceptible to
infection with JEV, whereas mice lacking MDA5 succumb
to EMCV as early as those lacking IFNAR (Kato et al.,
2006). Similarly, LGP2-deficient mice show enhanced
susceptibility to EMCV (Venkataraman et al., 2007).
The experimental infection of mice is a highly contrived
situation that does not mimic exposure to natural inoculating
routes and virus doses and is markedly affected by genetic
background, including the absence of certain antiviral
pathways in most inbred mouse strains (Pichlmair et al.,
2004). In contrast, analysis of primary immunodeficiencies
in patients is more informative in determining the relative
importance of innate recognition pathways in human populations
naturally exposed to the repertoire of human
viruses. So far, patients lacking IRAK4 have been found
to possess normal resistance to viruses even though
they cannot couple TLR7 and 9 recognition to IFN-a and
-b or IFN-l induction (Yang et al., 2005). Similarly, patients
with an autosomal recessive defect in UNC93B are resistant
to most viral infections, although they suffer from
sporadic HSV encephalitis (Casrouge et al., 2006). Thus,
the TLR pathway might be dispensable for responses to
many viruses in human populations. Patients with defects
in the cytosolic pathway have not been reported.