Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality

Abstract

Severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-α in SMA has not been reported. As such, we investigated the relationship between IFN-α promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-α production in children (n=663; <36 mos.) residing in a holoendemic P. falciparum transmission region of Kenya. Children with SMA had lower circulating IFN-α than malaria-infected children without severe anemia (P=0.025). Multivariate logistic regression analyses revealed that heterozygosity at −884 (TA) was associated with an increased risk of SMA [OR, 2.80 (95% CI, 1.22–6.43); P=0.015] and reduced IFN-α relative to wild-type (TT; P=0.038). Additional analyses demonstrated that carriage of the −173T/−884A (TA) haplotype was associated with increased susceptibility to SMA [OR, 3.98 (95% CI, 1.17–13.52); P=0.026] and lower IFN-α (P=0.031). Follow-up of these children for 36 mos. revealed that carriers of TA haplotype had greater all-cause mortality than non-carriers (P<0.001). Generation of reporter constructs showed that the IFNA8 wild-type −884TT exhibited higher levels of luciferase expression than the variant alleles (P<0.001). Analyses of malaria-associated inflammatory mediators demonstrated that carriers of TA haplotype had altered production of IL-1β, MIG, and IL-13 compared to non-carriers (P<0.050). Thus, variation at IFNA2 −173 and IFNA8 −884 conditions reduced IFN-α production, and increased susceptibility to SMA and mortality.

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

“…Variations at IFN-α promoter (17470-G/G and L168V-G/G genotypes) or receptor IFNAR1 were associated with protection against severe malaria (43,46), whereas variation at IFNA2-173 and IFNA8-884 reduced IFN-α production and increased susceptibility to severe malarial anemia and mortality (44). Here we showed that the IFN responses to two strains of P. yoelii infection were dramatically different, with mice infected with N67 producing higher IFN-I response than those infected with N67C, whereas mice infected with N67C had higher IFN-γ transcript levels.…”

“…IFN-I and -II responses and the related pathways have been shown to play an important role in controlling malaria parasite infection (12,42), but the exact effects of the IFN on malaria infection remain to be clearly defined (22,(43)(44)(45). Daily injections of a recombinant human IFN-α prevented death by PbANKA cerebral malaria (45), and the majority of ifnar1…”

Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations

“…The core motif for PR-A and PR-B binding is ttaTgtt and the core recognition motif for c-Myb is ttaAgtt thus suggesting that the polymorphism might alter the binding of these transcription factors and thus influence disease outcome. TA genotype of rs10964981 (T/A) is associated with significantly lower circulating IFNa levels and a higher risk of developing severe malarial anaemia (SMA) in Gabonese children (Kempaiah et al, 2012). However genetic association results in our study show an inverse relationship with association of the TA genotype with protection from disease in the non-endemic region.…”

“…Genetic variations/polymorphisms in IFNG, IFNGR1, IFNA cluster and IFNAR1 were selected according to their reported functional relevance in falciparum malaria as well as other infectious diseases, in other world populations (Kempaiah et al, 2012;Khor et al, 2007;Koch et al, 2006Koch et al, , 2005. A total of 24 polymorphisms were selected for the four genes.…”

“…A considerable number of exonic and 5 0 and 3 0 flanking region polymorphisms exist among the IFNA genes. A promoter polymorphism each of IFNA2 and IFNA8 has recently been shown to be associated with reduced IFNa production and increased susceptibility to severe malarial anaemia and mortality in Kenyan populations (Kempaiah et al, 2012). Association of IFNAR1 variants with protection against severe and cerebral malaria in African and South East Asian populations has also been reported (Aucan et al, 2003;Ball et al, 2013;Khor et al, 2007).…”