IFNL4 Genotypes Predict Clearance of RNA Viruses in Rwandan Children With Upper Respiratory Tract Infections.

Belson Rugwizangoga,Anna Martner,Johan Aurelius,Kristoffer Hellstrand,Brynja Ármannsdóttir,Malin S. Nilsson,Staffan Nilsson,Maria E. Andersson,Jean-Claude Kabayiza,Magnus Lindh

doi:10.3389/fcimb.2019.00340

Abstract

Polymorphisms in the interferon lambda gene locus (IFNL) such as the IFNL4 genetic variants rs12979860 and rs368234815 are predictive of resolution of hepatitis C virus infection, but information about the impact of these variants in other infections is scarce. This study aimed at determining the potential impact of IFNL4 variation for the clearance of respiratory tract pathogens in Rwandan children (≤5 years old, n = 480) seeking medical care for acute respiratory infections. Nasopharyngeal swabs were retrieved from all children at the first hospital referral and from 161 children at follow-up visits 2 weeks later. The swabs were analyzed for pathogens by real-time PCR and for host cell IFNL4 genotype at rs12979860 and rs368234815. Approximately 1/3 of the children were homozygous for the rs12979860 T allele and the rs368234815 ΔG allele, which are overrepresented in subjects of African descent. These IFNL4 variants were significantly associated with reduced clearance of RNA viruses. Our results suggest that IFNL4 genotypes that are common among subjects of African descent may determine inefficacious clearance of RNA viruses from the respiratory tract.

Highlights

In humans, the type III family of interferons comprises four proteins (IFN-λ1-4) (Hemann et al, 2017)
While details of the biological and pathophysiological role of IFN-λs are only partly understood, IFN-λs exert broad antiviral activity, similar to type I IFNs, and may participate in defense against viruses at epithelial surfaces (Mordstein et al, 2010). This notion is supported by the distribution of IFN-λ receptors, which is largely confined to epithelial surfaces, and by experimental studies implying a role for IFN-λ in protection against epithelial pathogens (Sommereyns et al, 2008; Prokunina-Olsson, 2019)
The formation of IFN-λ4 is regulated by a dinucleotide frameshift variant, IFNL4- G at rs368234815, which is located within exon 1 of IFNL4 (Griffiths et al, 2015; Prokunina-Olsson, 2019)

Summary

Introduction

The type III family of interferons (interferons lambda, IFN-λ) comprises four proteins (IFN-λ1-4) (Hemann et al, 2017). Polymorphisms in IFNL4, including rs12979860 and rs368234815, predict viral clearance in subjects infected with hepatitis C virus (HCV) (ProkuninaOlsson, 2019). The frequency of the unfavorable IFNL4 genotypes is several-fold higher among Africans (35–40% TT at rs12979860) than among Esat-Asians and Caucasians (10–15% TT) (Ge et al, 2009; Indolfi et al, 2014; The 1000 Genomes Project Consortium, 2015) These racial differences largely mirror the likelihood of resolution of HCV infection, which is considerably lower in subjects of African descent than in Caucasians (Indolfi et al, 2014; Roberts et al, 2014; Griffiths et al, 2015)

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