Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality

Anyona, Samuel B.; Kempaiah, Prakasha; Raballah, Evans; Ouma, Collins; Were, Tom; Davenport, Gregory C.; Konah, Stephen; Vulule, John; Hittner, James B.; Gichuki, Cecilia; Ong’echa, John Michael; Perkins, Douglas J

doi:10.1128/iai.05601-11

Cited by 15 publications

(19 citation statements)

References 47 publications

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“…Construction of haplotypes and additional modeling, controlling for identical co-variates, demonstrated that carriage of the −173T/−884A (TA) haplotype increased susceptibility to SMA to an even greater extent than that observed for the IFNA8 −884 TA genotype. These findings support our previous investigations showing that polymorphic variation in the promoter regions of innate immune response genes are important for conditioning susceptibility to SMA (Anyona et al 2011; Keller CC 2009; Ouma et al 2008; Ouma et al 2010; Ouma et al 2006). …”

Section: Discussionsupporting

confidence: 92%

“…This hypothesis is consistent with the fact that IFN-α plays an important central role in protection against a number of infectious diseases (Beilharz et al 1997; Bogdan 2000; Garcia et al 2007; Izaguirre et al 2003; Luty et al 2000; Ong'echa et al 2011; Vigario et al 2001; Vilcek 2006). Although SMA is a leading cause of mortality in the study region (Anyona et al 2011; Brabin et al 2001; Were et al 2011), none of the haplotypes examined were significantly associated with SMA throughout the follow-up period. This may be largely related to the fact that the children died at home and, as such, SMA was not diagnosed, but could have been captured indirectly in the analyses examining all-cause mortality.…”

Section: Discussionmentioning

confidence: 81%

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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

et al. 2012

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 81%

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

et al. 2012

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“…For example, injection of hemozoin into Balb/c mice led to the upregulation of transcripts encoding IL-6 and chemokines CCL2, CCL3, and CCL4 (Jaramillo et al, 2004). In addition, levels of IL-23 were higher in the peripheral blood of Kenyan children with malaria anemia (Ong'echa et al, 2008), whilst IL-18 promoter haplotypes that result in elevated IL-18 expression during acute infection have been associated with increased risk of SMA (Anyona et al, 2011). Gabonese children with severe malaria were found to have elevated levels of CCL3 and CCL4 in their circulation (Ochiel et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Acute Plasmodium berghei Mouse Infection Elicits Perturbed Erythropoiesis With Features That Overlap With Anemia of Chronic Disease

et al. 2020

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Severe malaria anemia is one of the most common causes of morbidity and mortality arising from infection with Plasmodium falciparum. The pathogenesis of malarial anemia is complex, involving both parasite and host factors. As mouse models of malaria also develop anemia, they can provide a useful resource to study the impact of Plasmodium infections and the resulting host innate immune response on erythropoiesis. In this study, we have characterized the bone marrow and splenic responses of the erythroid as well as other hematopoietic lineages after an acute infection of Balb/c mice with Plasmodium berghei. Such characterization of the hematopoietic changes is critical to underpin future studies, using knockout mice and transgenic parasites, to tease out the interplay between host genes and parasite modulators implicated in susceptibility to malaria anemia. P. berghei infection led to a clear perturbation of steady-state erythropoiesis, with the most profound defects in polychromatic and orthochromatic erythroblasts as well as erythroid colony-and burst-forming units (CFU-E and BFU-E), resulting in an inability to compensate for anemia. The perturbation in erythropoiesis was not attributable to parasites infecting erythroblasts and affecting differentiation, nor to insufficient erythropoietin (EPO) production or impaired activation of the Signal transducer and activator of transcription 5 (STAT5) downstream of the EPO receptor, indicating EPO-signaling remained functional in anemia. Instead, the results point to acute anemia in P. berghei-infected mice arising from increased myeloid cell production in order to clear the infection, and the concomitant release of pro-inflammatory cytokines and chemokines from myeloid cells that inhibit erythroid development, in a manner that resembles the pathophysiology of anemia of chronic disease.

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“…IL-18, a pro-inflammatory cytokine with diverse pleiotropic effects, induces interferon gamma production by natural killer cells, T cells, and activated macrophages. IL-18 also regulates both T helper 1 (Th1) and Th2 responses, thus playing an important role in the inflammatory process [24]. …”

Section: Discussionmentioning

confidence: 99%

Correlation between Inflammatory Biomarkers and Red Blood Cell Life Span in Chronic Hemodialysis Patients

Zhang

et al. 2017

Blood Purif

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Background and Objectives: The pathogenesis of anemia in hemodialysis (HD) patients is dependent on multiple factors, with decreased red blood cell life span (RBCLS) being a significant contributor. Although the impact of reduced RBCLS on anemia is recognized, it is still a subject that is not well researched. The objective of this study was to investigate the relationship between RBCLS and inflammatory biomarkers in chronic HD patients. Design, Setting, Participants, and Measurements: RBCLS was calculated from alveolar carbon monoxide concentrations measured by gas chromatography. Interleukins (IL) IL-6, IL-18, IL-10, and high sensitivity C-reactive protein were measured using bead-based multiplex assay. Measurements were carried out at baseline and during follow-up. The associations between RBCLS and inflammatory biomarkers were evaluated using linear mixed effects models. Results: RBCLS measurements were available for 54 HD patients. Their average age was 58.5 ± 14.4 years, 68.5% were males, 48.1% were diabetics, and the HD vintage was 51 ± 48 months. In 4 patients, RBCLS was measured once, while in 50 patients, up to 5 repeated RBCLS measurements were available. RBCLS was 73.2 ± 17.8 days (range 37.7-115.8 days). No association was found between RBCLS and any of the inflammatory biomarkers. Of note, RBCLS was positively correlated with levels of uric acid (p = 0.02) and blood urea nitrogen (BUN; p = 0.01), respectively. Conclusion: Our study suggests that inflammation pathways reported by these biomarkers only have a limited role in causing premature RBC death. The positive correlation with uric acid and BUN warrants further studies.

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Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality

Cited by 15 publications

References 47 publications

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

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

Acute Plasmodium berghei Mouse Infection Elicits Perturbed Erythropoiesis With Features That Overlap With Anemia of Chronic Disease

Correlation between Inflammatory Biomarkers and Red Blood Cell Life Span in Chronic Hemodialysis Patients

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