Expression Of STING Research Articles

E2 Proteins of High Risk Human Papillomaviruses Down-Modulate STING and IFN-κ Transcription in Keratinocytes

In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

Ontogeny and water temperature influences the antiviral response of the Pacific oyster, Crassostrea gigas

Disease is caused by a complex interaction between the pathogen, environment, and the physiological status of the host. Determining how host ontogeny interacts with water temperature to influence the antiviral response of the Pacific oysters, Crassostrea gigas, is a major goal in understanding why juvenile Pacific oysters are dying during summer as a result of the global emergence of a new genotype of the Ostreid herpesvirus, termed OsHV-1 μvar. We measured the effect of temperature (12 vs 22 °C) on the antiviral response of adult and juvenile C. gigas injected with poly I:C. Poly I:C up-regulated the expression of numerous immune genes, including TLR, MyD88, IκB-1, Rel, IRF, MDA5, STING, SOC, PKR, Viperin and Mpeg1. At 22 °C, these immune genes showed significant up-regulation in juvenile and adult oysters, but the majority of these genes were up-regulated 12 h post-injection for juveniles compared to 26 h for adults. At 12 °C, the response of these genes was completely inhibited in juveniles and delayed in adults. Temperature and age had no effect on hemolymph antiviral activity against herpes simplex virus (HSV-1). These results suggest that oysters rely on a cellular response to minimise viral replication, involving recognition of virus-associated molecular patterns to induce host cells into an antiviral state, as opposed to producing broad-spectrum antiviral compounds. This cellular response, measured by antiviral gene expression of circulating hemocytes, was influenced by temperature and oyster age. We speculate whether the vigorous antiviral response of juveniles at 22 °C results in an immune-mediated disorder causing mortality.

Forward genetic analysis of type I interferon responses to cytosolic deoxynucleotides reveals polymorphisms in Tmem173 gene of wild derived MOLF/EiJ mice. (P4201)

Abstract We identified a novel phenotype in wild derived inbred mouse strain, MOLF/EiJ (MOLF). In response to cytosolic DNA or cyclic-diadenylate (c-di-AMP), MOLF macrophages exhibit high levels of IL-6 but very low levels of type I interferon, IFNβ, compared to classical inbred mouse strain C5BL/6J (B6). Furthermore, the IFNβ production is reduced in responses of MOLF macrophages to herpes simplex virus (HSV) and Listeria monocytogenes infection that release double stranded DNA and c-di-AMP into the cytosol, respectively. To identify loci that confer the trait, we used quantitative trait locus (QTL) mapping. We measured the IFNβ production of macrophages from a panel of 2nd filial generation (F2), B6/MOLF intercrossed mice, and genotyped the individual mice for inheritance of loci genome wide. The lack of IFNβ production mapped to a locus that contains Tmem173, a gene that encodes STING. STING is an innate immune cytosolic surveyor that mediates interferon response to cytosolic DNA and c-di-AMP. Sequencing the MOLF transcript of Tmem173 revealed multiple single nucleotide polymorphisms and an 18 base pair deletion in the MOLF allele of Tmem173. Almost all of these polymorphisms encode amino acid changes in the putative transmembrane domains of STING, while the cytosolic fraction is highly conserved. In vitro, expression of MOLF STING in Tmem173-/- murine embryonic fibroblasts (MEFs) shows greatly reduced activation of the IFNβ promoter, compared to C57BL/6.