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

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.

IFN-λ4 is associated with increased risk and earlier occurrence of gastrointestinal, respiratory and malarial infections in Malian children

“…Recently, a genetic association was reported for IFNL4 -rs12979860-T and rs368234815-dG alleles with impaired clearance of respiratory RNA viruses in nasal swabs of children from Rwanda (11). The observed effect was in the same direction as for clearance of HCV reported in many studies, suggesting that the negative impact of IFN-λ4 on clearance of RNA viruses is not limited by HCV but extends to respiratory RNA viruses.…”

“…This could be because respiratory symptoms recorded during clinic visits in our study were very common (were experienced by 97.7% of children during follow-up), and occurred very early in life, with the median timing of the first RI episode being 16 weeks of age. Furthermore, RI episodes were defined very broadly, without stratifying by specific viral etiology, as was done in the study in Rwanda (11). In addition to bacterial and viral etiology, respiratory symptoms might also be caused by helminths (pinworms, roundworms, etc) transiting through the lungs during their life cycle.…”

“…The strong associations between the IFNL3 / IFNL4 genetic variants and HCV clearance have been well established and replicated by multiple studies. Additionally, a recent study reported an association between the IFNL4 genetic polymorphisms (rs12979860 and rs368234815) and the clearance of respiratory RNA viruses in children from Rwanda (11). To further explore the hypothesis that type III IFNs might impact the immune response to diverse pathogens, we analyzed detailed health records of 914 Malian children and genotyped their DNA for the functional polymorphisms IFNL4 -rs368234815 and IFNL3 -rs4803217.…”

PNPLA3 and TLL-1 polymorphisms affect disease severity in patients with COVID-19

“…We have used, for the rst time to our knowledge in the eld of SARS-CoV-2, nucleic acid extracts generated from swabs during the diagnostic processing COVID-19 to evaluate the host's genetic pro le. This approach, originally devised for other respiratory viruses, had suggested that the IFN lambda system could be a determinant of the outcome of such infections [11]. Albeit we could not nd any signi cant relation between the IFN lambda system and the outcome of COVID-19, the perspective of using genetic material obtained from swabs could be of major relevance for wide, population-based studies of the genetic background of people infected by SARS-CoV-2.…”

“…As proof of the key role type III IFNs in the regulation of immunity response, single nucleotide polymorphisms in genes IFNLs were strongly associated with outcomes to viral infection [14]. It has been reported that the homozygosity for IFNL3 (rs12979860) and IFNL4 (rs368234815) variants, overrepresented in African descent, is associated with a reduction of viral clearance in children affected by acute respiratory infections sustained by Rhinovirus and Coronavirus [11]. Since subjects with rs12979860 CC and rs368234815 TThaplotype were reported to be more effective in clearing RNA viruses, possibly due to an up-regulation of in ammatory pathways, we aimed to assess whether the outcome of SARS-CoV-2 infection is conditioned by these polymorphisms.…”