Abstract
Pattern recognition receptors (PRRs) sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis. At the same time, PRR signaling pathways rapidly trigger the innate immune defense against invasive pathogens in the intestine. Intestinal epithelial cells and mononuclear phagocytes in the intestine and the gut-associated lymphoid tissues are critically involved in sensing components of the microbiome and regulating immune responses in the intestine to sustain immune tolerance against harmless antigens and to prevent inflammation. These processes have been mostly investigated in the context of the bacterial components of the microbiome so far. The impact of viruses residing in the intestine and the virus sensors, which are activated by these enteric viruses, on intestinal homeostasis and inflammation is just beginning to be unraveled. In this review, we will summarize recent findings indicating an important role of the enteric virome for intestinal homeostasis as well as pathology when the immune system fails to control the enteric virome. We will provide an overview of the virus sensors and signaling pathways, operative in the intestine and the mononuclear phagocyte subsets, which can sense viruses and shape the intestinal immune response. We will discuss how these might interact with resident enteric viruses directly or in context with the bacterial microbiome to affect intestinal homeostasis.
Highlights
The Enteric Virome in Health and DiseaseThe microbiome comprises all microorganisms inhabiting the human body and is a substantial part of our physiology
Pattern recognition receptors (PRRs) sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis
TLR7/8/9 activation recruits myeloid differentiation primary response 88 (MyD88) and interleukin-1 receptor-associated kinases (IRAK)-1, -2, -4 to form a complex with TRAF6, TRAF3, IRAK1, IKKα, osteopontin and IRF7 leading to phosphorylation and subsequent activation of IRF7 which induces transcription of type I
Summary
The microbiome comprises all microorganisms inhabiting the human body and is a substantial part of our physiology. The availability of new technologies to study complex microbial communities revealed that the microbiome imparts phenotypic differences between individuals similar to gene variants in the host genome [2]. The enteric virome of humans contains viral genes associated with viruses that infect eukaryotic cells, viruses that infect bacteria (bacteriophages) and even viruses that infect plants derived from the diet of the host [8]. An interesting question is if enteric viruses, which have been detected in metagenomic analyses of fecal samples can be truely viewed as “commensal” gut-resident viruses. For bacteriophages this seems to be clear as they infect bacteria which themselves form stable communities in the intestine. Despite low intra-individual variability, the enteric virome is affected by developmental changes in early life, which are influenced by environmental factors such as nutrition [13,14]
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