Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine

Abstract

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.

Figure 1. The microbiome alters enteric virus infection by both direct and indirect mechanisms

Shown is a schematic representation of major categories of organisms in the intestinal microbiome that, in aggregate, affect enteric infection with the four viral taxa shown. In some cases transkingdom interactions affect enteric viruses directly through physical interactions between viruses and organisms or components of organisms within the intestinal microbiome. In other cases the microbiome regulated viral infection indirectly by altering immunity. Systemic viral infection can also alter intestinal virus infection. Host genes also impact these transkingdom interactions, and the ultimate outcome of virus-triggered disease, as shown on the right portion of the figure.

Figure 2. Transkingdom interactions and mechanisms by which bacteria enhance enteric virus replication and transmission

(A) The intestinal environment includes bacteria (green) and other components of the microbiome, the mucus layer (yellow), host enterocytes (brown), and underlying immune cells (blue and red). Enteric viruses (black) are exposed to bacteria prior to initiating replication in host cells (enterocytes or immune cells, depending on the virus type). Bacteria promote enteric virus replication and transmission by several mechanisms. (B) Poliovirus (PV) binds bacteria, which stabilizes virions and limits premature RNA release to promote transmission. (C) PV and human norovirus (HuNoV) bind bacteria, which increases viral attachment to host cells. (D) Mouse mammary tumor virus (MMTV) binds LPS, which induces host TLR signaling and IL10-mediated immune tolerance. (E) Murine norovirus (MNoV) replication is enhanced by bacteria, likely through regulation of IFNλ responses.