Genetic and genomic technologies, such as nucleic acid-based pathogen detection and genome-wide association studies, have expanded our view of the viruses that can infect our mucosal surfaces, and of human genetic variations that affect host–virus interactions.
These new technologies have revealed a high prevalence of viruses in healthy hosts, indicating that in many cases the presence of a virus is not sufficient to cause disease.
Furthermore, these new technologies have shown that the 'one pathogen–one disease' model may not be applicable for many diseases. In these diseases, the genetics of the host and environmental conditions combine with the presence of a pathogen to determine the outcome of the infection. Mounting evidence indicates that type I diabetes, Crohn's disease and asthma may follow this model.
Mutations in host genes involved in antiviral defence can predispose the host to type 1 diabetes. Changes in a large regulatory network that lead to a heightened immune response have been implicated, by genome-wide association studies, as factors that predispose people to this disease, although no virus has been tied directly to the disease.
Crohn's disease is probably the result of a combination of environmental, genetic and viral factors. Mutations in genes that encode parts of the host innate immune system or autophagy pathway have been shown to sensitize model hosts to particular viruses, leading to Crohn's disease.
In the case of asthma, studies have indicated that viral infections, particularly with human rhinoviruses, are the most common cause of disease exacerbations. Furthermore, a severe response to rhinovirus infection in childhood correlates with subsequent disease development. However, as the majority of the population is repeatedly exposed to rhinoviruses, additional host factors must be required as well.
New technologies have widened our view of 'complex diseases': those with both genetic and environmental risk factors. In this Review, we explore recent genetic and virological evidence implicating host–virus interactions in three diseases: type 1 diabetes, inflammatory bowel disease and asthma. The viruses implicated in these diseases cause mucosal infections that affect most of the population but are asymptomatic or mild in many hosts. These findings place a new emphasis on common viral infections as important environmental factors in the pathogenesis of complex diseases, and they compel the field to pursue a better understanding of host interactions with the human virome.
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This work was supported by awards from the US National Institutes of Health (NIH) (AI054359, AI062428, AI064705, AI083242 and AI081884). A.I. holds an Investigators in Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.
The authors declare no competing financial interests.
- Deep pyrosequencing
A technique for reading thousands to millions of short DNA sequences in parallel from a single sample.
- Index case
The first person to get a disease. Often, this represents the first person in an epidemic or a chain of transmission for the disease.
- Genome-wide association study
A study designed to identify genetic polymorphisms within a population that are associated with a disease phenotype.
- Single-nucleotide polymorphism
A single nucleotide in the human genome sequence that differs from that found in other members of the population (or that found on the other allele in the same individual).
- RIG-I-like receptor
One of a family of pattern recognition receptors, including RIG-I and MDA5, that can detect RNA associated with viral infection, such as the viral RNA genomes and viral replication intermediates.
- Type I interferon
An interferon (IFN) that is produced and secreted in response to cellular stimuli associated with viral infection. Type I IFNs are important mediators of the innate antiviral immune response and include IFNα proteins and IFNβ proteins.
- Interferon regulatory factor 7
A key transcription factor in the antiviral immune response pathway that transmits the signal from pattern recognition receptors to induce transcription of type I interferon genes.
- Toll-like receptor
One of a family of pattern recognition receptors that recognize pathogen-associated molecular patterns, such as bacterial cell wall components or viral nucleic acids.
- Interferon-stimulated gene
A gene that is upregulated by the signalling pathway initiated when type I interferons (IFNs) bind their receptor on the cell surface. Over 300 of these genes have been described, some of which have been shown to play important parts in the antiviral response.
- Odds ratio
The ratio comparing the likelihood of an outcome (for example, a disease) between two groups (for example, cases and controls). It is measured as the ratio of the odds in one group to the odds in the other group and can be calculated as p(1–q) / q(1–p), in which p is the probability of the event occurring for the first group and q, the probability for the second group.
An airborne allergen that can trigger an allergic reaction. Common aeroallergens are pollen and spores.
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Foxman, E., Iwasaki, A. Genome–virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol 9, 254–264 (2011). https://doi.org/10.1038/nrmicro2541