Cyclooxygenase-2 haplotypes influence the longitudinal risk of malaria and severe malarial anemia in Kenyan children from a holoendemic transmission region

Abstract

Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 −512 C > T, −608 T > C, −765 G > C, and −1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2-70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the −608 CC mutant allele (RR = 0.746, P = 1.811 × 10 −4 ) and −512C/−608T/−765G/−1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both

Differential Gene Expression in Host Ubiquitination Processes in Childhood Malarial Anemia

“…Although the molecular basis of severe malaria has not been fully elucidated, our studies have demonstrated that susceptibility to varying malaria clinical outcomes is conditioned, at least in part, by variation in genes that code for soluble mediators of inflammation (Perkins et al, 2013;Achieng et al, 2019;Anyona et al, 2020). To expand the knowledge base on the etiology of severe malaria, we investigated transcriptional profiles in a panel of 84 genes involved in the ubiquitination process in children with acute malaria.…”

Complement component 3 mutations alter the longitudinal risk of pediatric malaria and severe malarial anemia

“…2 Previous studies from our group have shown that polymorphic variability, particularly in immune response genes, influences the risk of malaria and SMA at enrollment and over the follow-up period. 3–5…”

Integrative analysis of microRNA and mRNA expression profiles of monocyte-derived dendritic cells differentiation during experimental cerebral malaria

“…Our network analysis showed that miR‐16‐5p and miR‐491‐5p have potential targets related to neuroinflammation and DC maturation: MiRNA‐491‐5p has 2 targets, TLR9 and MYD88, crucial molecules for the development of protective immunity to malaria 41 . Among the miR‐16‐5p target genes are CD40, CXCL10, IFNGR2, and PTGS2, all previously described as implicated in the pathogenesis of ECM 42,43 …”

“…41 Among the miR-16-5p target genes are CD40, CXCL10, IFNGR2, and PTGS2, all previously described as implicated in the pathogenesis of ECM. 42,43 One of the limitations of the analysis performed here is that is based CD8+ T cells are the main source of IFN in the SP and lungs. 11,12,46 Since the T lymphocytes are in high frequency in the SP, but not in the BM, we believe that in IFN -treated mice, but not in PbA-infected mice, this cytokine reaches high enough levels to induce BM-MO differentiation into BM-MODC.…”