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An enteric virus can replace the beneficial function of commensal bacteria.

Kernbauer E, Ding Y, Cadwell K - Nature (2014)

Bottom Line: Intestinal microbial communities have profound effects on host physiology.Consistent with this observation, the IFN-α receptor was essential for the ability of MNV to compensate for bacterial depletion.Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: 1] Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA [2] Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Intestinal microbial communities have profound effects on host physiology. Whereas the symbiotic contribution of commensal bacteria is well established, the role of eukaryotic viruses that are present in the gastrointestinal tract under homeostatic conditions is undefined. Here we demonstrate that a common enteric RNA virus can replace the beneficial function of commensal bacteria in the intestine. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice restored intestinal morphology and lymphocyte function without inducing overt inflammation and disease. The presence of MNV also suppressed an expansion of group 2 innate lymphoid cells observed in the absence of bacteria, and induced transcriptional changes in the intestine associated with immune development and type I interferon (IFN) signalling. Consistent with this observation, the IFN-α receptor was essential for the ability of MNV to compensate for bacterial depletion. Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection. These data indicate that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similarly to commensal bacteria.

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MNV infection of adult germfree mice has similar effects as mono-association of germfree mice from birth6-8 week old adult GF mice were infected with MNV.CR6 for 10 days and examined for reversal of intestinal abnormalities. (a,b) Quantification of villi width (a) and granules per Paneth cell (b) in H&E-stained small intestinal sections. N = 5 mice/group. (c) Quantification of the number of CD3+ T cells in the SI LP by flow cytometric analysis. N = 6 mice/group. (d, e) Quantification of IFN-γ producing CD3+CD4+ (d) and CD3+CD8+ (e) T cells by flow cytometry. (f) Quantification of small intestinal IgA by ELISA. N = 6 mice/group. *p<0.05. All graphs display means ± SEM from at least two independent experiments.
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Figure 8: MNV infection of adult germfree mice has similar effects as mono-association of germfree mice from birth6-8 week old adult GF mice were infected with MNV.CR6 for 10 days and examined for reversal of intestinal abnormalities. (a,b) Quantification of villi width (a) and granules per Paneth cell (b) in H&E-stained small intestinal sections. N = 5 mice/group. (c) Quantification of the number of CD3+ T cells in the SI LP by flow cytometric analysis. N = 6 mice/group. (d, e) Quantification of IFN-γ producing CD3+CD4+ (d) and CD3+CD8+ (e) T cells by flow cytometry. (f) Quantification of small intestinal IgA by ELISA. N = 6 mice/group. *p<0.05. All graphs display means ± SEM from at least two independent experiments.

Mentions: While GF mice had thin villi containing few CD3+ T cells and narrow crypts, the general appearance of the small intestine (SI) in GF+MNV mice resembled that of conventional mice (Fig. 1a-f). The presence of virus in GF mice also partially restored the number of granules and lysozyme expression in Paneth cells (Extended data Fig. 2a-d). These changes in appearance due to MNV.CR6 were associated with a significant increase in the overall cellularity of the lamina propria (LP) and mesenteric lymph nodes (MLNs) (Fig. 1g, h). Consistent with the ability of certain bacterial species to promote lymphocyte differentiation1, GF mice had reductions in the numbers of CD4+ T cells in the LP and MLNs, CD8+ T cells in MLNs, interferon (IFN)-γ expression by these cells, and mucosal and serum antibody production (Extended data Fig. 2e-p). In contrast, GF+MNV mice displayed increases in these factors, in some cases to an extent similar to or in excess of conventional mice (Extended data Fig. 2e-p). These effects of the virus were not dependent on neonatal infection since reversal of abnormalities was observed when adult GF mice were infected with MNV.CR6 for 10 days (Extended data Fig. 3). Also, the effects of MNV.CR6 cannot be explained by uncontrolled viral replication because GF mice harbor less virus compared to conventional mice upon infection (Extended data Fig. 1b), as seen with other intestinal viruses17, 18. Importantly, these changes in response to MNV.CR6 are specific to conditions in which bacteria are absent. MNV.CR6 had little or no effect on the appearance of the intestine and lymphocytes in conventional mice (Extended data Fig. 4). Therefore, there is significant overlap in responses to MNV and commensal bacteria.


An enteric virus can replace the beneficial function of commensal bacteria.

Kernbauer E, Ding Y, Cadwell K - Nature (2014)

MNV infection of adult germfree mice has similar effects as mono-association of germfree mice from birth6-8 week old adult GF mice were infected with MNV.CR6 for 10 days and examined for reversal of intestinal abnormalities. (a,b) Quantification of villi width (a) and granules per Paneth cell (b) in H&E-stained small intestinal sections. N = 5 mice/group. (c) Quantification of the number of CD3+ T cells in the SI LP by flow cytometric analysis. N = 6 mice/group. (d, e) Quantification of IFN-γ producing CD3+CD4+ (d) and CD3+CD8+ (e) T cells by flow cytometry. (f) Quantification of small intestinal IgA by ELISA. N = 6 mice/group. *p<0.05. All graphs display means ± SEM from at least two independent experiments.
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getmorefigures.php?uid=PMC4257755&req=5

Figure 8: MNV infection of adult germfree mice has similar effects as mono-association of germfree mice from birth6-8 week old adult GF mice were infected with MNV.CR6 for 10 days and examined for reversal of intestinal abnormalities. (a,b) Quantification of villi width (a) and granules per Paneth cell (b) in H&E-stained small intestinal sections. N = 5 mice/group. (c) Quantification of the number of CD3+ T cells in the SI LP by flow cytometric analysis. N = 6 mice/group. (d, e) Quantification of IFN-γ producing CD3+CD4+ (d) and CD3+CD8+ (e) T cells by flow cytometry. (f) Quantification of small intestinal IgA by ELISA. N = 6 mice/group. *p<0.05. All graphs display means ± SEM from at least two independent experiments.
Mentions: While GF mice had thin villi containing few CD3+ T cells and narrow crypts, the general appearance of the small intestine (SI) in GF+MNV mice resembled that of conventional mice (Fig. 1a-f). The presence of virus in GF mice also partially restored the number of granules and lysozyme expression in Paneth cells (Extended data Fig. 2a-d). These changes in appearance due to MNV.CR6 were associated with a significant increase in the overall cellularity of the lamina propria (LP) and mesenteric lymph nodes (MLNs) (Fig. 1g, h). Consistent with the ability of certain bacterial species to promote lymphocyte differentiation1, GF mice had reductions in the numbers of CD4+ T cells in the LP and MLNs, CD8+ T cells in MLNs, interferon (IFN)-γ expression by these cells, and mucosal and serum antibody production (Extended data Fig. 2e-p). In contrast, GF+MNV mice displayed increases in these factors, in some cases to an extent similar to or in excess of conventional mice (Extended data Fig. 2e-p). These effects of the virus were not dependent on neonatal infection since reversal of abnormalities was observed when adult GF mice were infected with MNV.CR6 for 10 days (Extended data Fig. 3). Also, the effects of MNV.CR6 cannot be explained by uncontrolled viral replication because GF mice harbor less virus compared to conventional mice upon infection (Extended data Fig. 1b), as seen with other intestinal viruses17, 18. Importantly, these changes in response to MNV.CR6 are specific to conditions in which bacteria are absent. MNV.CR6 had little or no effect on the appearance of the intestine and lymphocytes in conventional mice (Extended data Fig. 4). Therefore, there is significant overlap in responses to MNV and commensal bacteria.

Bottom Line: Intestinal microbial communities have profound effects on host physiology.Consistent with this observation, the IFN-α receptor was essential for the ability of MNV to compensate for bacterial depletion.Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: 1] Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA [2] Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Intestinal microbial communities have profound effects on host physiology. Whereas the symbiotic contribution of commensal bacteria is well established, the role of eukaryotic viruses that are present in the gastrointestinal tract under homeostatic conditions is undefined. Here we demonstrate that a common enteric RNA virus can replace the beneficial function of commensal bacteria in the intestine. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice restored intestinal morphology and lymphocyte function without inducing overt inflammation and disease. The presence of MNV also suppressed an expansion of group 2 innate lymphoid cells observed in the absence of bacteria, and induced transcriptional changes in the intestine associated with immune development and type I interferon (IFN) signalling. Consistent with this observation, the IFN-α receptor was essential for the ability of MNV to compensate for bacterial depletion. Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection. These data indicate that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similarly to commensal bacteria.

Show MeSH
Related in: MedlinePlus