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MicroRNA-155 enhances T cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease

View Article: PubMed Central - PubMed

ABSTRACT

Background: MicroRNAs (miRNAs) are noncoding RNAs that modulate cellular gene expression, primarily at the post-transcriptional level. We sought to examine the functional role of miR-155 in a model of viral-induced neuroinflammation.

Methods: Acute encephalomyelitis and immune-mediated demyelination were induced by intracranial injection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into C57BL/6 miR-155+/+ wildtype (WT) mice or miR-155−/− mice. Morbidity and mortality, viral load and immune cell accumulation in the CNS, and spinal cord demyelination were assessed at defined points post-infection. T cells harvested from infected mice were used to examine cytolytic activity, cytokine activity, and expression of certain chemokine receptors. To determine the impact of miR-155 on trafficking, T cells from infected WT or miR-155−/− mice were adoptively transferred into RAG1−/− mice, and T cell accumulation into the CNS was assessed using flow cytometry. Statistical significance was determined using the Mantel-Cox log-rank test or Student’s T tests.

Results: Compared to WT mice, JHMV-infected miR-155−/− mice developed exacerbated disease concomitant with increased morbidity/mortality and an inability to control viral replication within the CNS. In corroboration with increased susceptibility to disease, miR-155−/− mice had diminished CD8+ T cell responses in terms of numbers, cytolytic activity, IFN-γ secretion, and homing to the CNS that corresponded with reduced expression of the chemokine receptor CXCR3. Both IFN-γ secretion and trafficking were impaired in miR-155−/−, virus-specific CD4+ T cells; however, expression of the chemokine homing receptors analyzed on CD4+ cells was not affected. Except for very early during infection, there were not significant differences in macrophage infiltration into the CNS between WT and miR-155−/− JHMV-infected mice, and the severity of demyelination was similar at 14 days p.i. between WT and miR-155−/− JHMV-infected mice.

Conclusions: These findings support a novel role for miR-155 in host defense in a model of viral-induced encephalomyelitis. Specifically, miR-155 enhances antiviral T cell responses including cytokine secretion, cytolytic activity, and homing to the CNS in response to viral infection. Further, miR-155 can play either a host-protective or host-damaging role during neuroinflammation depending on the disease trigger.

No MeSH data available.


Related in: MedlinePlus

Increased morbidity/mortality in JHMV-infected miR-155βˆ’/βˆ’ mice was associated with elevated viral titers within the brain. WT (n = 12) and miR-155βˆ’/βˆ’ mice (n = 12) were infected via i.c. injection with 200 PFU of JHMV. Clinical scores (a) and survival (b) were assessed throughout infection. The increase in both clinical disease and mortality correlated with an impaired ability to control viral replication within the brains at the indicated times p.i. c Statistical significance was determined using Mantel-Cox log-rank test or one-tailed, unpaired, Student’s T tests. Data are representative of at least two independent experiments; *p < 0.05; **p < 0.01; ***p < 0.001
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Fig1: Increased morbidity/mortality in JHMV-infected miR-155βˆ’/βˆ’ mice was associated with elevated viral titers within the brain. WT (n = 12) and miR-155βˆ’/βˆ’ mice (n = 12) were infected via i.c. injection with 200 PFU of JHMV. Clinical scores (a) and survival (b) were assessed throughout infection. The increase in both clinical disease and mortality correlated with an impaired ability to control viral replication within the brains at the indicated times p.i. c Statistical significance was determined using Mantel-Cox log-rank test or one-tailed, unpaired, Student’s T tests. Data are representative of at least two independent experiments; *p < 0.05; **p < 0.01; ***p < 0.001

Mentions: Age-matched WT or miR-155βˆ’/βˆ’ mice were i.c. inoculated with JHMV (200 PFU), and the severity of clinical disease and survival were monitored. JHMV-infected miR-155βˆ’/βˆ’ mice demonstrated delayed onset of disease compared to WT mice, yet clinical disease was sustained in miR-155βˆ’/βˆ’ animals compared to WT mice (Fig.Β 1a). By day 30 p.i., 85Β % of WT and 54Β % of miR-155βˆ’/βˆ’ mice had survived (Fig.Β 1b). Assessment of viral titers within the brains of infected mice revealed similar titers 5Β days p.i.; however, by day 7 p.i., WT mice had dramatically reduced viral titers, and by day 14 p.i., titers were below the level of detection (~100 PFU/g) (Fig.Β 1c). In contrast, JHMV-infected miR-155βˆ’/βˆ’ mice were unable to control viral replication and demonstrated high viral titers out to 21 p.i. (Fig.Β 1c). Collectively, these data indicate that miR-155 expression enhances immune-mediated control of viral replication within the CNS.Fig. 1


MicroRNA-155 enhances T cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease
Increased morbidity/mortality in JHMV-infected miR-155βˆ’/βˆ’ mice was associated with elevated viral titers within the brain. WT (n = 12) and miR-155βˆ’/βˆ’ mice (n = 12) were infected via i.c. injection with 200 PFU of JHMV. Clinical scores (a) and survival (b) were assessed throughout infection. The increase in both clinical disease and mortality correlated with an impaired ability to control viral replication within the brains at the indicated times p.i. c Statistical significance was determined using Mantel-Cox log-rank test or one-tailed, unpaired, Student’s T tests. Data are representative of at least two independent experiments; *p < 0.05; **p < 0.01; ***p < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5015201&req=5

Fig1: Increased morbidity/mortality in JHMV-infected miR-155βˆ’/βˆ’ mice was associated with elevated viral titers within the brain. WT (n = 12) and miR-155βˆ’/βˆ’ mice (n = 12) were infected via i.c. injection with 200 PFU of JHMV. Clinical scores (a) and survival (b) were assessed throughout infection. The increase in both clinical disease and mortality correlated with an impaired ability to control viral replication within the brains at the indicated times p.i. c Statistical significance was determined using Mantel-Cox log-rank test or one-tailed, unpaired, Student’s T tests. Data are representative of at least two independent experiments; *p < 0.05; **p < 0.01; ***p < 0.001
Mentions: Age-matched WT or miR-155βˆ’/βˆ’ mice were i.c. inoculated with JHMV (200 PFU), and the severity of clinical disease and survival were monitored. JHMV-infected miR-155βˆ’/βˆ’ mice demonstrated delayed onset of disease compared to WT mice, yet clinical disease was sustained in miR-155βˆ’/βˆ’ animals compared to WT mice (Fig.Β 1a). By day 30 p.i., 85Β % of WT and 54Β % of miR-155βˆ’/βˆ’ mice had survived (Fig.Β 1b). Assessment of viral titers within the brains of infected mice revealed similar titers 5Β days p.i.; however, by day 7 p.i., WT mice had dramatically reduced viral titers, and by day 14 p.i., titers were below the level of detection (~100 PFU/g) (Fig.Β 1c). In contrast, JHMV-infected miR-155βˆ’/βˆ’ mice were unable to control viral replication and demonstrated high viral titers out to 21 p.i. (Fig.Β 1c). Collectively, these data indicate that miR-155 expression enhances immune-mediated control of viral replication within the CNS.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: MicroRNAs (miRNAs) are noncoding RNAs that modulate cellular gene expression, primarily at the post-transcriptional level. We sought to examine the functional role of miR-155 in a model of viral-induced neuroinflammation.

Methods: Acute encephalomyelitis and immune-mediated demyelination were induced by intracranial injection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into C57BL/6 miR-155+/+ wildtype (WT) mice or miR-155&minus;/&minus; mice. Morbidity and mortality, viral load and immune cell accumulation in the CNS, and spinal cord demyelination were assessed at defined points post-infection. T cells harvested from infected mice were used to examine cytolytic activity, cytokine activity, and expression of certain chemokine receptors. To determine the impact of miR-155 on trafficking, T cells from infected WT or miR-155&minus;/&minus; mice were adoptively transferred into RAG1&minus;/&minus; mice, and T cell accumulation into the CNS was assessed using flow cytometry. Statistical significance was determined using the Mantel-Cox log-rank test or Student&rsquo;s T tests.

Results: Compared to WT mice, JHMV-infected miR-155&minus;/&minus; mice developed exacerbated disease concomitant with increased morbidity/mortality and an inability to control viral replication within the CNS. In corroboration with increased susceptibility to disease, miR-155&minus;/&minus; mice had diminished CD8+ T cell responses in terms of numbers, cytolytic activity, IFN-&gamma; secretion, and homing to the CNS that corresponded with reduced expression of the chemokine receptor CXCR3. Both IFN-&gamma; secretion and trafficking were impaired in miR-155&minus;/&minus;, virus-specific CD4+ T cells; however, expression of the chemokine homing receptors analyzed on CD4+ cells was not affected. Except for very early during infection, there were not significant differences in macrophage infiltration into the CNS between WT and miR-155&minus;/&minus; JHMV-infected mice, and the severity of demyelination was similar at 14&nbsp;days p.i. between WT and miR-155&minus;/&minus; JHMV-infected mice.

Conclusions: These findings support a novel role for miR-155 in host defense in a model of viral-induced encephalomyelitis. Specifically, miR-155 enhances antiviral T cell responses including cytokine secretion, cytolytic activity, and homing to the CNS in response to viral infection. Further, miR-155 can play either a host-protective or host-damaging role during neuroinflammation depending on the disease trigger.

No MeSH data available.


Related in: MedlinePlus