IFN-\u03bb4 genetic variants influence clinical malaria episodes in a cohort of Kenyan children

Gabriela Samayoa-Reyes,Katherine Sabourin,Rosemary Rochford,Ludmilla Prokunina-Olsson,Sidney Ogolla,Conner Jackson,Arlene E Dent,Adeola Obajemu

doi:10.1186/s12936-021-03689-z

Abstract

BackgroundInterferon (IFN)- λ4, a type III IFN, production is controlled by a dinucleotide frameshift variant (rs368234815-dG/TT) within the first exon of the IFNL4 gene. Carriers of the IFNL4-dG allele but not the IFNL4-TT allele are able to produce the IFN-λ4 protein. Patients with hepatitis C virus that do not produce the IFN-λ4 protein have higher rates of viral clearance suggesting a potential inhibitory role of IFN-λ4 in liver-tropic infections.MethodsIn this study, it was investigated whether children infected with Plasmodium falciparum, which has a well-characterized liver stage infection, would be more susceptible to clinical malaria relative to their IFNL4-rs368234815 allele. A cohort of 122 children from a malaria holoendemic region of Kenya was analysed. Episodes of clinical malaria and upper respiratory tract infections (URTIs) were determined using information collected from birth to 2 years of age. The dinucleotide frameshift variant IFNL4-rs368234815-dG/TT was genotyped using a TaqMan assay.ResultsIn this cohort, 33% of the study participants had the dG/dG genotype, 45% had the dG/TT genotype, and 22% had TT/TT genotype. The number and time to first episode of clinical malaria and URTIs with respect to the IFNL4-rs368234815 allele was evaluated. It was found that children that carried the IFNL4-rs368234815-dG allele had an increased number of clinical malaria episodes. In addition, there was a significant association between earlier age of first malaria infection with carriers of the IFNL4-dG allele (p-value: 0.021).ConclusionThe results suggest that the ability to produce IFN-λ4 negatively affects host immune protection against P. falciparum malaria in Kenyan children.

Highlights

Interferon (IFN)- λ4, a type III IFN, production is controlled by a dinucleotide frameshift variant within the first exon of the IFNL4 gene
To evaluate time to first upper respiratory tract infections (URTIs), Kaplan Meier estimators were calculated, and a log rank test was used to Characteristics of study population To evaluate whether genetic variants in IFN-λ4 play a role in P. falciparum and upper respiratory tract infection frequency, clinical data collected from 122 children that were part of a previously described birth cohort based in Western Kenya where malaria transmission is holoendemic [12, 13] was analysed
In order to further evaluate the observed significant difference in birth weight between IFNL4- rs368234815 dG allele ( IFNL4- dG allele) and the IFNL4-rs368234815 TT/TT genotype, the relationship between maternal malaria during pregnancy and IFNL4 was analysed and no significant difference was found between the two groups (Chi-square test; p-value: 0.297)

Summary

Introduction

Interferon (IFN)- λ4, a type III IFN, production is controlled by a dinucleotide frameshift variant (rs368234815-dG/TT) within the first exon of the IFNL4 gene. Patients with hepatitis C virus that do not produce the IFN-λ4 protein have higher rates of viral clearance suggesting a potential inhibitory role of IFN-λ4 in liver-tropic infections. Type III interferons (IFNs) are antiviral cytokines with a broad antiviral activity that induce hundreds of interferon-stimulated genes (ISGs) [2, 3]. They provide a localized immune response at epithelial surfaces and if this response is successful, type I and type II IFN responses are suppressed [2]. A dinucleotide frameshift variant (rs368234815dG/TT) within the first exon of the IFNL4 gene controls

Methods

Results

Discussion

Conclusion