Wong, S.-Y. | bioRxiv Science

bioRxiv2020

Enteric viruses evoke broad host immune responses resembling bacterial microbiome

Contributions of the viral component of the microbiome, the virome, to the development of innate and adaptive immunity are largely unknown. Here, we systematically defined the host response in mice to a panel of eukaryotic enteric viruses representing six different families. Most of these viruses asymptomatically infected the mice, the magnitude and duration of which was dependent on the microbiota. Flow cytometric and transcriptional profiling of mice mono-associated with these viruses unveiled general adaptations by the host, such as lymphocyte differentiation and IL-22 signatures in the intestine as well as numerous viral strain-specific responses that persist. Comparison with a dataset derived from analogous bacterial mono-association mice identified bacterial species that evoke an immune response comparable to the viruses we examined. These results expand an understanding of the immune space occupied by the enteric virome and underscore the importance of viral exposure events.

microbiology↗

bioRxiv2018

B cell defects observed in Nod2 knockout mice are a consequence of a Dock2 mutation frequently found in inbred strains

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments, and contribute to challenges with reproducibility across institutions. Notably, C57BL/6NHsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2. Here, we demonstrate the presence of this Dock2 variant in the widely used Nod2-/- mice. NOD2 is a cytosolic innate immune receptor that has been the subject of intense investigation due to its association with inflammatory bowel disease (IBD) susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2-/- mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells and B1a cells. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2-/- mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2-/- mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2-/- mice. Our findings highlight the effects of confounding mutations from widely-used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.

immunology↗