This transient deficiency in IFN-I benefits the host as it does not lower resistance to common secondary bacterial infections (Fig. 1). In support of this hypothesis, IFN-I exhaustion is most likely to be evolutionarily as it

appears to be a consequence of all primary viral infections. We and others have shown this to be the case for adenoviruses, alphaviruses, orthomyxoviruses, murine cytomegalovirus and lymphocytic choriomeningitis virus [16, 21]. From an evolutionary perspective, there must have been a strong selective advantage to transiently exhaust IFN-I responses after primary viral infections selleck kinase inhibitor to occur. Thus, it is reasonable to speculate the evolutionary advantage of negative feedback regulation to suppress virus-induced immune responses that are detrimental against secondary bacterial infections. It has been shown previously, exploring influenza virus/S. pneumoniae co-infection models, that secondary challenges, with either virus or bacteria, at the peak or during the IFN-I response, are highly lethal and the increased lethality is attributable to IFN-I [34-36]. It would be interesting

to find out whether the outcome of such co-infection experiments would differ if mice undergoing a primary virus infection were challenged with bacterial pathogens at the time of IFN-I exhaustion, 5–9 days post-infection. Thus, to provide evidence for the above-outlined hypothesis, all that find more would be required is to establish correlates of strength of IFN-I response and exhaustion with severity of secondary bacterial challenges. A time course of bacterial infections after primary virus infection and/or poly I:C treatment would provide an answer to this question. Poly I:C, a synthetic analogue of double-stranded RNA, mimics RNA viral infections, but would eliminate potential unrelated viral-induced pathologies affecting secondary bacterial pathologies. It has been shown that poly I:C-treated mice mount IFN-I responses that render the host transiently more susceptible to bacterial infections [41, 46]. Evaluation of the severity of bacterial growth, morbidity and mortality should establish whether IFN-I exhaustion ameliorates secondary bacterial pathology.

Poly I:C-treated experimental groups will eliminate potential unknown viral-induced complications. It is somewhat surprising that the by now widely known phenomenon, that of an Terminal deoxynucleotidyl transferase IFN-I refractory period after a viral infection, has as yet not been investigated as to its consequences for the host’s susceptibility to bacterial infections, given its potential clinical implications. The known detrimental consequences of the refractory period to secondary viral infections, namely heightened susceptibility, are somewhat hard to understand in evolutionary terms unless there exists an overriding host–benefit rationale. This may well turn out to be protection from potentially lethal bacterial infection, which can be controlled in the absence of IFN-I.