Transkingdom control of viral infection and immunity in the mammalian intestine

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Science  15 Jan 2016:
Vol. 351, Issue 6270, aad5872
DOI: 10.1126/science.aad5872

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Microbial villages shape viral infections

Viruses infecting the intestinal tract, such as noroviruses and rotaviruses, are major human pathogens. Despite facing an extreme environment within their hosts, which includes pH gradients, digestive enzymes, and the billions of microbes that inhabit human guts, these viruses somehow manage to survive and often thrive. Pfeiffer and Virgin review the complex microbial encounters that occur between enteric viruses and gut microbiota. Trans-kingdom interactions (that is, between viruses, bacteria, archaea, helminthes, fungi, and phage) are particularly important in shaping the course of a viral infection and the ensuing host immune response.

Science, this issue p. 10.1126/science.aad5872

Structured Abstract


Viruses that infect the mammalian gastrointestinal tract have intimate relationships with the host, as well as members of the complex community of microbes that inhabit the intestine. The mammalian intestine contains the highest density of microbes in the body. These microbes, collectively referred to as the intestinal microbiota, include bacteria, archaea, fungi, viruses, and eukaryotes. Emerging data indicate that enteric viruses regulate, and are regulated by, these other microbes through a series of processes termed “transkingdom interactions.” Recent advances have shed light on the nature and importance of these transkingdom interactions for enteric virus replication, transmission, and disease.


The study of enteric virus pathogenesis has traditionally focused on viral virulence genes of classical pathogens and host immunity to these agents. Recent analysis of the viruses present in the intestine has revealed a dynamic and diverse taxonomic intestinal viral world (the enteric virome) featuring, in addition to recognized enteric viral pathogens, many new viruses and new relationships between known viral types and disease. We now know that enteric viral infection must be considered in light of the fact that viruses are part of a complex milieu of microbes and microbial products that directly and indirectly regulate viral pathogenesis. Thus, interactions of enteric viruses with other microbes are increasingly recognized as critical to viral infectivity, disease, and control. Studies leveraging the simple paradigm of examining enteric viruses in the intestine after natural oral infection have driven the field forward. It is now clear that members of the intestinal microbiome promote replication and transmission of enteric viruses from four different families: noroviruses, picornaviruses, retroviruses, and reoviruses. Therefore, the standard reductionist approach of understanding the pathogenesis of, and immunity to, viral infection in the context of a single virus interacting with a single host is too limited to capture the full range of relevant pathogenic mechanisms. This simple concept has broad implications for prevention and therapy of viral infections of great medical importance.


Despite recent rapid advances, there are still major gaps in our understanding of transkingdom control of enteric virus replication, pathogenesis, and transmission. Recognition of the important impact of the bacterial microbiota has advanced more rapidly than for any other component of the intestinal microbiota. A particular challenge for studies to comprehensively identify viruses within the enteric virome is their diversity and extreme sequence variability. A key direction for the field is to identify functional relationships governing transkingdom interactions in the intestine, including the dynamic coevolved relationship between the intestinal microbiota and innate and adaptive immunity. The field is now poised to define, in structural and biochemical terms, specific molecular mechanisms responsible for such transkingdom interactions. Future studies on the mammalian virome and transkingdom factors that influence viral infection may inspire new therapeutic approaches. In this Review, we explore the interplay between viruses, the microbiota, and host immune responses. We highlight how transkingdom interactions influence infection with mammalian enteric viruses, including pathogens.

Intestinal microbiota promote enteric virus replication.

Enteric viruses can interact with bacteria before initiating replication in the mammalian intestine. This illustration shows norovirus interacting with bacteria. Through these interactions, and/or through microbiota-mediated alteration of host immune responses, intestinal microbiota facilitate enteric virus replication in the gut.

[Credit: K. Sutliff/Science]


Viruses that infect the intestine include major human pathogens (retroviruses, noroviruses, rotaviruses, astroviruses, picornaviruses, adenoviruses, herpesviruses) that constitute a serious public health problem worldwide. These viral pathogens are members of a large, complex viral community inhabiting the intestine termed “the enteric virome.” Enteric viruses have intimate functional and genetic relationships with both the host and other microbial constituents that inhabit the intestine, such as the bacterial microbiota, their associated phages, helminthes, and fungi, which together constitute the microbiome. Emerging data indicate that enteric viruses regulate, and are in turn regulated by, these other microbes through a series of processes termed “transkingdom interactions.” This represents a changing paradigm in intestinal immunity to viral infection. Here we review recent advances in the field and propose new ways in which to conceptualize this important area.

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