Primed Innate Immune Responses in Monocytes from Kenyan Children with Uncomplicated Falciparum Malaria. (4th October 2017)

• Record Type: Journal Article
• Authors: Dobbs, Katherine; Embury, Paula; Vulule, John; Odada, Peter; Rosa, Bruce; Mitreva, Makedonka; Kazura, James; Dent, Arlene
• Is Part Of: Open forum infectious diseases. Volume 4(2017)Supplement 1
• Page Start: S223
• Page End: S223
• Publication Date: 2017-10-04
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofx163.461
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Monocytes are innate immune cells that play a key role in host protection and pathogenesis during malaria. We sought to determine whether uncomplicated falciparum malaria in children modulates Toll-like receptor (TLR) responsiveness in monocytes. Methods: Freshly isolated monocytes were obtained from 8 children in western Kenya at presentation with acute uncomplicated malaria and 6 weeks following treatment and from 4 malaria-naïve North Americans (NAM). Monocytes were cultured for 18 hours with media alone, a TLR4 agonist (LPS), or a TLR2/TLR1 agonist (Pam3CSK4). Supernatant cytokine concentrations were measured using a magnetic bead-based immunoassay. Genomic DNA was isolated from monocytes from the same 8 acute-recovery pairs for DNA methylation analysis using the MethylationEPIC array. Monocyte gene expression profiles were analyzed in another 6 acute-recovery pairs and 5 NAM using a targeted digital RNA sequencing panel. Results: Both acute and recovery monocytes showed robust and equivalent responses to LPS and Pam3CSK4, with markedly increased production over media alone of IL-1ß, IL-6, IL-8, IL-10, IL-12p40, and TNF (Friedman test P < 0.05). Compared with NAM, acute and recovery monocytes showed greater magnitude of responses to LPS and Pam3CSK4, especially for IL-6, IL-12p40, and TNF (Kruskal–Wallis test P < 0.05). Monocyte gene expression for the cytokines IL-1-alpha, IL-1ß, IL-6, IL-8, and TNF was not different between acute and recovery, though these genes were significantly overexpressed in acute and recovery monocytes compared with NAM (FDR adjusted P < 0.0001). DNA methylation analysis showed significant differential methylation in acute vs. recovery monocytes in the promoter regions for IL1A, IL1R1, IL10, CXCR5, and CCR5 (FDR adjusted P < 0.05). Conclusion: These data suggest that uncomplicated malaria in children has a priming effect on innate immune responses that is maintained several weeks after clinical recovery, which may be mediated in part by epigenetic changes such as altered DNA methylation patterns. Disclosures: All authors: No reported disclosures.