Loss-of-function mutations in genes encoding immunologically relevant molecules can often result in an unexpected variation in disease penetrance. In eLife, Virgin and colleagues investigate the cause of this variation by using mice with genetic deficiency in a variety of molecules involved in the positive regulation of inflammatory responses, including HOIL-1, caspase-1 or IL-6 alone or caspase-1 plus caspase-11. These mutant mice are highly susceptible to certain bacterial infections (such as listeria) yet in some cases (HOIL-1 deficiency) are resistant to others (such as mycobacterium). This susceptibility is dependent mainly on a dysfunctional innate immune response and diminished production of inflammatory cytokines. Chronic infection with the herpesvirus MHV-68 rescues the mutant mice from listerial infection at least in part by normalizing the production of inflammatory cytokines. These findings suggest how the host virome might complement otherwise deficient immune responses and offer insight into the environmental basis of disease penetrance.

eLife (20 January 2015) doi:10.7554/eLife.04494