Genetic Diversity of CD14 Promoter Gene Polymorphism (rs2569190) is Associated With Regulation of Malaria Parasitemia and Susceptibility to Plasmodium falciparum Infection

Abstract

CD14 is a multifunctional receptor expressed on many cell types and has been shown to mediate immune response resulting in the activation of an inflammatory cascade, with polymorphism of its promoter (rs2569190) found to be associated with susceptibility to several diseases. In malaria infection, the CD14 gene demonstrated a pathogenic profile in regulating experimental cerebral malaria, with reports of elevated levels of soluble CD14 in serum of patients but no definitive conclusion. We present a detailed analysis of genetic diversity of CD14 promoter gene (snp −159 C/T; rs2519190) polymorphism between a malaria-infected group and uninfected controls and its association with clinical parameters of disease. Genomic DNA samples obtained from 106 Plasmodium falciparum malaria–infected patients and 277 uninfected controls were elucidated with a polymerase chain reaction-restriction fragment length polymorphism (RFLP) assay. Our results show a significant diversity (P = 3.32E−06) in the genotypic frequency (3.8% versus 22.4%) of the rs2569190 mutant variant between the malaria-infected group and controls, respectively. The mutant allele had the lowest frequency among the malaria-infected group demonstrating its necessity for infection. Mean parasitemia (parasites/μL of blood) was significantly regulated based on CD14 polymorphic profile (19 855 versus 37 041 versus 49 396 for homozygote mutants, heterozygotes, and homozygote wild type, respectively). Interestingly, we found no association between CD14 genetic variants with fever, age of patients, or anemia. How this affects disease severity between subregional and continental groups deserves further clarification, including extending these studies in a larger group and among severe and asymptomatic patients with malaria.

Extensive diversity in the allelic frequency of Plasmodium falciparum merozoite surface proteins and glutamate-rich protein in rural and urban settings of southwestern Nigeria

“…On the other hand, the extensive genetic diversity and complexity of P. falciparum is also considered a major obstacle in the acquisition of natural immunity and vaccine development efforts. The findings in this study are consistent with previous reports that showed that these genes are highly polymorphic among the parasite population in southwestern Nigeria [ 12 , 31 , 32 ]. The genetic diversity analysis in the present study showed that P. falciparum populations in Idi Ayunre (rural) and Eleta (urban) exhibited an overall similar level of high genetic diversity, with MOI of 2.8 and 2.6, respectively.…”

SNP Diversity in CD14 Gene Promoter Suggests Adaptation Footprints in Trypanosome Tolerant N’Dama (Bos taurus) but not in Susceptible White Fulani (Bos indicus) Cattle

“…CD14 gene is a major part of the innate immune system, and one of essential receptors needed to initiate an adequate response to infection [13][14][15]. Encounter with antigens trigger innate immune responses mediated by host genetic variations alongside additional benefits arising from prior exposure to such stimuli that may direct tolerance or susceptibility [18,35]. In this study, we dissected the genetic variation within the core promoter region of bovine CD14 gene to elucidate a deeper understanding of trypanosomosis tolerance in cattle.…”

“…Studies have localized bovine health-related quantitative trait loci (QTL) to the genomic region of the CD14 loci [13,15]. In addition, results from malaria studies have shown CD14 promoter polymorphism to mediate an adaptive protective mechanism against severe disease [16,17], including regulation of parasitemia [18].…”

“…The expression regulation of CD14 gene is therefore critical for the recognition of bacterial lipopolysaccharide during innate immunity [13,15], particularly since CD14 mutant variant (-159T/T) expresses significantly higher soluble CD14 levels in serum than the homozygous or heterozygous genotypes [21]. We have utilized qualitative data on CD14 gene promoter to decipher immune response and susceptibility to malaria infection [18], showing a defective response by mutant variants, driving a cascade that worsens disease and multiple deleterious outcomes [22][23][24]. In addition, we have also shown that there are evolutionarily conserved microRNAs involved in the CD14-mediated immune response during bovine trypanosomosis [25], demonstrating their significance in regulating gene expression [26].…”

In silico analyses of CD14 molecule reveals significant evolutionary diversity potentially associated with speciation and variable immune response in mammals

“…Studies in human, mouse, cattle and sheep have shown that CD14 is significantly involved in innate immunity, playing major roles in susceptibility to tuberculosis, trypanosomosis, malaria and other bacterial infections (Sugawara et al, 2003;Ibeagha-Awemu et al, 2008;Xue et al, 2012;Ojurongbe et al, 2017). Other published reports have shown that there is a higher susceptibility to Mycobacterium tuberculosis infection in CD14 transgenic mice compared to the wild type (Reiling et al, 2002;Weiland et al, 2008).…”