The virome in host health and disease

Abstract

The mammalian virome includes diverse commensal and pathogenic viruses that evoke a broad range of immune responses from the host. Sustained viral immunomodulation is implicated in a variety of inflammatory diseases, but also confers unexpected benefits to the host. These outcomes of viral infections are often dependent on host genotype. Moreover, it is becoming clear that the virome is part of a dynamic network of microorganisms that inhabit the body. Therefore, viruses can be viewed as a component of the microbiome, and interactions with commensal bacteria and other microbial agents influence their behavior. This piece is a review of our current understanding of how the virome, together with other components of the microbiome, affects the function of the host immune system to regulate health and disease.

Figure 1. Categories of viral immunomodulation

The presence of a virus can shift the qualitative and quantitative state of immunity in multiple dimensions, thereby altering susceptibility to inflammatory diseases or subsequent infections. (A) During immunopotentiation, a virus increases the magnitude of a subsequent response or decreases the threshold necessary to evoke a certain immune response. In contrast, immunosuppression occurs when the immune system is compromised and the magnitude of subsequent responses is diminished. (B) In addition to magnitude, the nature of subsequent immune responses can be altered by previous viral infections. In the example shown, the presence of a virus shifts the state of immunity towards a more potent T_H1 response. Another common outcome is sustained increase in type I interferon levels. (C) Viral immunomodulation can change over time, occasionally returning to basal levels, but often not all the way back to the original point. Other dimensions of immunity that are subject to viral immunomodulation include anatomical site and T cell receptor and B cell receptor repertoires.

Figure 2. Types of virome interactions

The virome exists within the microbiome network and interacts with the bacterial microbiome and other organisms that inhabit the host such as fungi (mycobiome), archaea, protozoans, and helminths. The effect of the virome on the host genome represents a subset of the host genome-microbiome interaction. A simple relationship between the virome and host genome is the virus-plus-susceptibility gene interaction, where a phenotypic outcome, such as a disease pathology or symptom, is evoked by the combination of a viral infection and host gene variant (a-i). In addition to this synthetic interaction, another type of virus-plus-susceptibility gene interaction is phenotypic complementation, in which the viral infection masks the effect of a host gene variant (a-ii). Although examples are lacking, a virus could induce benefits in a manner dependent on a host gene variant, or negate the beneficial effect of a gene variant. In situations where the outcome is a complex disease or trait, the virome-genome interaction involves multiple viruses and host genetic variants (b). Some genetic variants exist in non-coding region and may influence gene expression in a manner dependent on viral infection. These interactions are influenced by other members of the microbiome, which regulate the activities of both the host and the virus.

Figure 3. Relationship between murine norovirus and commensal bacteria

The enteric positive-strand RNA virus murine norovirus (MNV) displays similarities with commensal bacteria including the ability to establish long term co-existence with the host without causing disease, promote development of the intestine and associated immune system, protect against chemical and infectious damage to the intestine, and cause pathologies resembling inflammatory bowel disease (IBD) in genetically susceptible hosts (virus-plus-susceptibility gene interaction). MNV also interacts with commensal bacteria, much like bacteria interact with one another. Examples of these interactions include the role of bacteria in promoting MNV persistence through blocking interferon-λ (IFN-λ) activity, the dependence of MNV on bacteria for binding and infecting cells, the ability of MNV to alter the relative abundance of bacterial populations, and immunopotentiation by MNV resulting in increased susceptibility to bacteria that enter circulation. Additionally, MNV exacerbates the intestinal injury response in the genetically susceptible host in a manner dependent on bacteria. This observation provides an example in which MNV interacts with the host together with commensal bacteria.