Distinct roles of protein kinase R and toll‐like receptor 3 in the activation of astrocytes by viral stimuli

Abstract

Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis.

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

“…45,46 Thus, dsRNA could induce PKR activation. Recently, 2AP was suggested to have suppressive effect on other kinases; 47 therefore, further studies to explore the roles of PKR and other kinases in VZV infection are needed.…”

The role of chemokines during herpes simplex virus-1 infection

“…This study did not address chemokine production specifically, and it is likely that any contribution to HSE susceptibility from reduced NF-kBdriven chemokine production in these patients is minor in comparison to the contribution from reduced IFN production, as IRAK-4 is required for optimal NF-kB activation even following TLR3 stimulation (51). However, this result does suggest that dsRNA detection is a critical step in innate recognition of HSV-1 infection implicating TLR3 which is expressed in human neurons, microglia, and astrocytes (53)(54)(55). Pattern recognition receptors responsible for dsRNA detection, such as TLR3, PKR, and MDA5 may play key roles in cytokine and chemokine production responsible for immunological control of HSV-1 reactivation from latency.…”

Melanoma Differentiation-Associated Gene 5 Is Critical for Protection against Theiler's Virus-Induced Demyelinating Disease

“…TMEV-induced cytokine gene expression, as well as viral replication, is dependent on the NF-B pathway (19,25,35). NF-B activation following viral infection requires TLR3 and TLR2 (42,43) and is partially dependent on PKR (3,35). However, the induction of type I IFNs and IRF3/IRF7 activation, critical for type I IFN production, are not fully dependent on the presence of TLRs (43).…”