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What Have We Learned from Studies of IFN-? Variants and Hepatitis C Virus Infection?

ABSTRACT: Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-?) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4-?G/TT (rs368234815) variant controls generation of the IFN-?4 protein. Paradoxically, the IFNL4-TT allele, which abrogates IFN-?4, associates with higher rates of spontaneous HCV clearance and better response to treatments for HCV infection. The finding that a "knock-out" allele for IFN-?4 enhances HCV clearance challenges the paradigm of IFNs as antiviral cytokines. Genetic variants in the IFN-? region have also been associated with hepatic inflammation and fibrosis from various etiologies, however, alleles that are linked with improved HCV clearance associates with worse inflammation and fibrosis. These studies demonstrate that GWAS of infectious diseases may yield important and unexpected biological insights.

SUBMITTER: O'Brien TR

PROVIDER: S-EPMC6767860 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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What Have We Learned from Studies of IFN-λ Variants and Hepatitis C Virus Infection?

O'Brien Thomas R TR Jackson Sarah S SS

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20190604 10

Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-λ) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4-ΔG/TT (rs368234815) variant controls generation of the IFN-λ4 protein. Paradoxically, the IFNL4-TT allele, whic ...[more]

PMID: 31161939

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Project description:Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, the exact mechanisms of anti-flu activity of PLSCR1 in relation to its expression compartment and enzymatic activity, and the molecular and cellular mechanisms involved have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. We hypothesize that PLSCR1 protects hosts against IAV infection by regulating type 3 interferon (IFN-λ) signaling pathways. Our results showed that Plscr1 expression was highly induced by IAV infection in vivo and in epithelial cells treated with IFN-λ. We found that Plscr1 knockout (KO) mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for type 3 interferon receptor (Ifn-λr1) expression, and impaired expression of Ifn-λr1 and downstream ISGs may be responsible for delayed viral clearance in Plscr1 KO mice. In addition, Plscr1 interacted with Ifn-λr1 within the epithelial compartment following IAV infection, suggesting Plscr1 may modulate IFN-λ signaling via protein-protein interactions. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1 floxStop Foxj1-Cre + mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility, less inflammation and enhanced Ifn-λr1 expression in IAV infection. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

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What Have We Learned from Studies of IFN-? Variants and Hepatitis C Virus Infection?

Publications

What Have We Learned from Studies of IFN-λ Variants and Hepatitis C Virus Infection?

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