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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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Type I interferon induction by Poly(I:C) changes small intestinal architecture without affecting the T cell compartment(a) qRT-PCR quantification of the type I interferon (IFN-I) inducible gene MX2 in small intestinal tissue of untreated GF mice, GF mice injected for 10 days with Poly(I:C), MNV.CR6 mono-associated GF mice (GF+MNV), and conv mice indicate that the poly(I:C) injection procedure induces an IFN-I response. Values represent fold induction of MX2 compared to untreated GF mice after normalizing to Gapdh. (b-d) Quantification of the villi width (b), granules (c) and CD3+ cells in the small intestine of same mice of H&E stained small intestinal sections. (e-h) Percentages of CD4+TCRβ+ (e), CD8+TCRβ+ cells (g), and IFN-γ producing CD4+ (f) and CD8+ (h) T cells from the SI LP. N = 6 mice/group. ns = not significant, ***p<0.001, and ****p<0.0001. All graphs display means ± SEM from at least two independent experiments.
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Figure 13: Type I interferon induction by Poly(I:C) changes small intestinal architecture without affecting the T cell compartment(a) qRT-PCR quantification of the type I interferon (IFN-I) inducible gene MX2 in small intestinal tissue of untreated GF mice, GF mice injected for 10 days with Poly(I:C), MNV.CR6 mono-associated GF mice (GF+MNV), and conv mice indicate that the poly(I:C) injection procedure induces an IFN-I response. Values represent fold induction of MX2 compared to untreated GF mice after normalizing to Gapdh. (b-d) Quantification of the villi width (b), granules (c) and CD3+ cells in the small intestine of same mice of H&E stained small intestinal sections. (e-h) Percentages of CD4+TCRβ+ (e), CD8+TCRβ+ cells (g), and IFN-γ producing CD4+ (f) and CD8+ (h) T cells from the SI LP. N = 6 mice/group. ns = not significant, ***p<0.001, and ****p<0.0001. All graphs display means ± SEM from at least two independent experiments.

Mentions: To gain better resolution into the response evoked by MNV and commensal bacteria, we performed RNA deep sequencing analyses (RNA-seq) on whole intestinal tissue harvested from untreated GF mice, GF mice 10 days after inoculation with MNV.CR6, and GF mice reconstituted with the bacterial flora from conventional mice (Fig. 3a, Extended data table 1). Pathway analysis of the transcripts induced by commensal bacteria indicated alterations in the metabolic state, immunity, and blood vessel morphogenesis. MNV.CR6 induced a more limited gene expression pattern associated with lymphoid cell development and immune responses, many of which are related to the antiviral type I interferon (IFN-I) response (Extended data table 1a). Consistent with the shared ability of MNV and bacteria to reverse abnormalities in GF mice, the overlapping gene set contained genes associated with development and function of hematopoietic lineage cells (Fig. 3a, Extended data table 1c). The IFN-I signature induced by MNV.CR6 prompted us to examine whether the effect of viral infection was dependent on IFN-I signaling. The intestine of untreated IFNα receptor knockout mice (IFNAR−/−) displayed a normal appearance, while ABX-treatment of these mice led to similar abnormalities in intestinal morphology and T cell numbers as described above (Fig. 3b-h). However, MNV.CR6 infection did not have a detectable effect on ABX-treated IFNAR−/− mice despite productive replication (Fig. 3i, Extended data fig. 1b), indicating that virus-mediated reversal of these abnormalities is dependent on IFN-I signaling. Inducing IFN-I gene expression through poly(I:C) injection was sufficient to increase villus width in GF but did not have a noticeable effect on intestinal T cells (Extended data figure 8). Thus, IFN-I signaling likely functions in conjunction with other pathways to confer the full effect of MNV infection. Indeed, transcriptional analyses supports a large overlap between the genes induced by MNV.CR6 and bacterial colonization of GF mice that are not associated with IFN-I (Extended data table 1c).


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

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

Type I interferon induction by Poly(I:C) changes small intestinal architecture without affecting the T cell compartment(a) qRT-PCR quantification of the type I interferon (IFN-I) inducible gene MX2 in small intestinal tissue of untreated GF mice, GF mice injected for 10 days with Poly(I:C), MNV.CR6 mono-associated GF mice (GF+MNV), and conv mice indicate that the poly(I:C) injection procedure induces an IFN-I response. Values represent fold induction of MX2 compared to untreated GF mice after normalizing to Gapdh. (b-d) Quantification of the villi width (b), granules (c) and CD3+ cells in the small intestine of same mice of H&E stained small intestinal sections. (e-h) Percentages of CD4+TCRβ+ (e), CD8+TCRβ+ cells (g), and IFN-γ producing CD4+ (f) and CD8+ (h) T cells from the SI LP. N = 6 mice/group. ns = not significant, ***p<0.001, and ****p<0.0001. All graphs display means ± SEM from at least two independent experiments.
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Figure 13: Type I interferon induction by Poly(I:C) changes small intestinal architecture without affecting the T cell compartment(a) qRT-PCR quantification of the type I interferon (IFN-I) inducible gene MX2 in small intestinal tissue of untreated GF mice, GF mice injected for 10 days with Poly(I:C), MNV.CR6 mono-associated GF mice (GF+MNV), and conv mice indicate that the poly(I:C) injection procedure induces an IFN-I response. Values represent fold induction of MX2 compared to untreated GF mice after normalizing to Gapdh. (b-d) Quantification of the villi width (b), granules (c) and CD3+ cells in the small intestine of same mice of H&E stained small intestinal sections. (e-h) Percentages of CD4+TCRβ+ (e), CD8+TCRβ+ cells (g), and IFN-γ producing CD4+ (f) and CD8+ (h) T cells from the SI LP. N = 6 mice/group. ns = not significant, ***p<0.001, and ****p<0.0001. All graphs display means ± SEM from at least two independent experiments.
Mentions: To gain better resolution into the response evoked by MNV and commensal bacteria, we performed RNA deep sequencing analyses (RNA-seq) on whole intestinal tissue harvested from untreated GF mice, GF mice 10 days after inoculation with MNV.CR6, and GF mice reconstituted with the bacterial flora from conventional mice (Fig. 3a, Extended data table 1). Pathway analysis of the transcripts induced by commensal bacteria indicated alterations in the metabolic state, immunity, and blood vessel morphogenesis. MNV.CR6 induced a more limited gene expression pattern associated with lymphoid cell development and immune responses, many of which are related to the antiviral type I interferon (IFN-I) response (Extended data table 1a). Consistent with the shared ability of MNV and bacteria to reverse abnormalities in GF mice, the overlapping gene set contained genes associated with development and function of hematopoietic lineage cells (Fig. 3a, Extended data table 1c). The IFN-I signature induced by MNV.CR6 prompted us to examine whether the effect of viral infection was dependent on IFN-I signaling. The intestine of untreated IFNα receptor knockout mice (IFNAR−/−) displayed a normal appearance, while ABX-treatment of these mice led to similar abnormalities in intestinal morphology and T cell numbers as described above (Fig. 3b-h). However, MNV.CR6 infection did not have a detectable effect on ABX-treated IFNAR−/− mice despite productive replication (Fig. 3i, Extended data fig. 1b), indicating that virus-mediated reversal of these abnormalities is dependent on IFN-I signaling. Inducing IFN-I gene expression through poly(I:C) injection was sufficient to increase villus width in GF but did not have a noticeable effect on intestinal T cells (Extended data figure 8). Thus, IFN-I signaling likely functions in conjunction with other pathways to confer the full effect of MNV infection. Indeed, transcriptional analyses supports a large overlap between the genes induced by MNV.CR6 and bacterial colonization of GF mice that are not associated with IFN-I (Extended data table 1c).

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