Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, MouseISG12

Abstract

Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.

Interferon-stimulated gene ISG12b2 is localized to the inner mitochondrial membrane and mediates virus-induced cell death

“…Of note, a previous study showed that ISG12b1 protects neonatal mice from lethal encephalitis induced by Sindbis virus infection, but no mechanism was demonstrated. 10 This study demonstrated that mouse ISG12b2 is dramatically induced by DENV infection both in vivo and in vitro. Given the high similarity of amino acid sequences between mouse ISG12b2 and mouse ISG12b1, mouse ISG12b1 may trigger apoptosis in defence against Sindbis virus infection in a manner analogous to that observed for mouse ISG12b2 following DENV infection.…”

“…The expression of mouse ISG12b1 has been shown to significantly delay Sindbis virus-induced death in neonatal mice, providing evidence that ISG12b1 has a role in host antiviral defence. 10 Additionally, mouse ISG12b1 is predominantly expressed in adipose tissue, specifically in the adipocytes, 11,12 wherein it hinders mitochondrial biogenesis and inhibits adipocyte differentiation. 11 Human ISG12a is a mitochondrial protein that enhances sensitivity to DNA damage-induced apoptosis via perturbation of normal mitochondrial function.…”

“…Although 4300 ISGs have been identified, only a few ISGs involved in antiviral effects have been defined, 2,3 including dsRNA-activated protein kinase, 2 0 -5 0 oligoadenylate synthetases, ribonuclease L, Mx-GTPase, and ISG15. [4][5][6] The ISG12 family is a group of small proteins (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) that contain a hydrophobic region (80-120 amino acids) referred to as the ISG12 motif. [7][8][9] In silico analysis has identified four ISG12 genes (6-16, ISG12a, ISG12b, and ISG12c) in humans and three (ISG12a, ISG12b1, and ISG12b2) in mice.…”

Genomic analysis of the host response to hepatitis B virus infection

“…In addition, the IFN-␥-induced GTPases, GBP1 and -2, as well as IFI27 and IFI16, peaked at this time. Interestingly, the murine homologues of GBP1 and IFI27 inhibit vesicular stomatitis virus (12) and Sindbis virus infection in mice (38), respectively, and they are induced in IFN-treated murine hepatocyte cell lines when HBV replication is suppressed (Table 1). Thus, further investigation of the role these genes play in viral clearance during HBV infection appears to be warranted.…”

Avian influenza virus infection induces differential expression of genes in chicken kidney

“…The ISG12 gene belongs to a family of small, interferon alpha (IFNa) inducible genes with unknown function (Gjermandsen et al, 2000). A recent study showed that neuronal ISG12 gene expression is associated with resistance to Sindbis virus-induced encephalitis and its expression significantly delays Sindbis virus-induced death in neonatal mice (Labrada et al, 2002). Apparently, ISG12 may be a proinflammatory factor and function in virus-induced host defense.…”