Figure 4. A model for the role of common infections in complex disease.

Converging evidence suggests that variations in the host antiviral response are important features of complex disease pathogenesis, in the context of a constant-albeit-changing virome of common infections. In this model, all hosts are exposed to certain highly prevalent viruses. Those with a non-susceptible antiviral response do not get the disease. Those with an altered antiviral response get the disease, but only if certain other key environmental factors are present. Avoiding these key environmental factors offers one avenue for circumventing complex diseases. This model also suggests a new mode for intervention in complex disease pathogenesis. If we understood the mechanisms whereby the altered antiviral response led to disease, we could potentially design interventions to shift this response to that of a non-predisposed host. Such interventions might include vaccines, well-timed virus exposures, or other immune modulating therapeutics. This model suggests that to tackle complex diseases, it is critical to learn more about the human virome and factors that influence host-virome interactions.