Induction of innate immune response by SIV in vivo and in vitro: Differential expression and function of RIG-I and MDA5

College

College of Science

Department/Unit

Biology

Document Type

Dissertation

Publication Date

3-2011

Abstract

IFN-P induction occurs during acute SIV infection in the CNS. The pathways that induce IFN-P in SIV-infected macrophages, the major infected cell in the brain, have not been identified. We have examined expression and function of cytosolic RNA sensors, retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) in vivo in SIV-infected brain and in vitro in SIV-infected macaque macrophages. RIG-I and MDA5 mRNA and protein brain expression was quantitated from acute infection to late-stage disease in our consistent, accelerated SIV macaque model. RIG-I and MDA5 mRNA and protein expression peaked during acute infection, but rapidly declined by I 0 days post-inoculation (p.i.). Compared with RIG-I, higher levels of MDA5 mRNA and protein were expressed in the brain during acute infection and late-stage disease. Both proteins are induced in perivascular macrophages and astrocytes upon infection, while being constitutively expressed in uninfected neurons. The level of MDA5 protein expression correlates with the severity of CNS disease at 42 days p.i., and continues until 56 and 84 days p.i. In order to determine whether IFNP is induced through RIG-I or MDA5, SIV-infected monocyte-derived macrophages were treated with either RIG-I or MDA5 siRNAs. The mRNA expression of IFN-inducible gene MxA was shown to be dependent on MDA5, but not RIG-I. We demonstrate that SIV-infection leads to the production of dsRNA in vivo, which may act as the MDA5 ligand. Finally, treatment with endocytosis inhibitor chloroquine also lowered the level of expression of MxA mRNA, suggesting that macrophages induce IFN􀁊 through both MDA5 and TLR pathways. We have demonstrated for the first time the functional role of MDA5 in the innate immune response to SIV infection.

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Disciplines

Viruses

Keywords

Simian immunodeficiency virus; Natural immunity

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