Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection

Abstract

Abnormal prion protein (PrP Sc ) generated from the cellular isoform of PrP (PrP C ) is assumed to be the main or sole component of the pathogen, called prion, of transmissible spongiform encephalopathies (TSE). Because PrP is a host-encoded protein, acquired immune responses are not induced in TSE. Meanwhile, activation of the innate immune system has been suggested to partially block the progression of TSE; however, the mechanism is not well understood. To further elucidate the role of the innate immune system in prion infection, we investigated the function of interferon regulatory factor 3 (IRF3), a key transcription factor of the MyD88-independent type I interferon (IFN) production pathway. We found that IRF3-deficient mice exhibited significantly earlier onset with three murine TSE strains, namely, 22L, FK-1, and murine bovine spongiform encephalopathy (mBSE), following intraperitoneal transmission, than with wild-type controls. Moreover, overexpression of IRF3 attenuated prion infection in the cell culture system, while PrP Sc was increased in prion-infected cells treated with small interfering RNAs (siRNAs) against IRF3, suggesting that IRF3 negatively regulates PrP Sc formation. Our findings provide new insight into the role of the host innate immune system in the pathogenesis of prion diseases.

Microglia in prion diseases

“…The chemokine CXCL13 is also upregulated in prion disease (42,71); however, knockout of its receptor, CXCR5, did not alter prion pathogenesis after intracerebral inoculation of RML prions (73). (55). These results indicate that IRF3 negatively regulates PrP Sc formation and prion pathogenesis, providing new insight into the role of the innate immune system in the response to prion infection.…”

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

“…The hydrolytic autoclaving and formic acid method for PRNP Sc staining has been described previously. 49 Statistical analysis. The unpaired t-test or Welch's correction was used for comparison between the two groups.…”

Protective role of MyD88-independent innate immune responses against prion infection

“…Although the pathological changes, such as the degree of degeneration and also the accumulation of PK resistant PrP in the brains of terminally ill mice were not obviously different between WT and IRF3−/−, innate immune responses mediated via IRF3 seemed to inhibit, in part at least, the disease progress. Using prion infected cell cultures, we were able to demonstrate that stimulation of IRF3 inhibits the production of PrP Sc , and expression levels of IRF3 bore an inverse relation to resistance to prion infection 30 . These results, therefore, indicate that IRF3 in the MyD88-independent pathway signaling cascades is a key molecule in the host defense mechanism against prion pathogenesis.…”

“…In our study, IRF3 knockout (IRF3−/−) mice died significantly earlier than wild-type (WT) mice following intra-peritoneal inoculation with 22L, Fukuoka-1 (FK-1), or a mouse-adapted BSE (mBSE) strain. The accumulation of PrP Sc in the spleens was detected earlier in the IRF3−/− mice compared with WT mice 30 . Although the pathological changes, such as the degree of degeneration and also the accumulation of PK resistant PrP in the brains of terminally ill mice were not obviously different between WT and IRF3−/−, innate immune responses mediated via IRF3 seemed to inhibit, in part at least, the disease progress.…”