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



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.



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.



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.
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Laura L
LL
Dickey
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Colleen L
CL
Worne
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Jessica L
JL
Glover
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA. tom.lane@utah.path.edu.
Thomas E
TE
Lane
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA. ryan.oconnell@path.utah.edu.
Ryan M
RM
O'Connell
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D018352:Coronavirus Infections / Q000150:complications* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009422:Nervous System Diseases / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000502:physiology*; D013997:Time Factors
D016207:Cytokines; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse
Demyelination; Neuroinflammation; T cells; Virus; miR-155