RESUMEN
Cerebral malaria, a reversible encephalopathy affecting young children, is a medical emergency requiring urgent clinical assessment and treatment. We performed a whole-transcriptomic analysis of blood samples from Malian children with cerebral or uncomplicated malaria. We focused on transcripts from pathways for which dysfunction has been associated with neurodegenerative disorders. We found that SNCA, SIAH2, UBB, HSPA1A, TUBB2A, and PINK1 were upregulated (fold-increases, ≥2.6), whereas UBD and PSMC5 were downregulated (fold-decreases, ≤4.39) in children with cerebral malaria, compared with those with uncomplicated malaria. These findings provide the first evidence for pathogenic mechanisms common to human cerebral malaria and neurodegenerative disorders.
Asunto(s)
Malaria Cerebral/genética , Malaria Falciparum/genética , Enfermedades Neurodegenerativas/genética , ATPasas Asociadas con Actividades Celulares Diversas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Niño , Preescolar , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Leucocitos Mononucleares/parasitología , Malaria Cerebral/diagnóstico , Malaria Falciparum/diagnóstico , Masculino , Enfermedades Neurodegenerativas/diagnóstico , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Plasmodium falciparum , Estudios Prospectivos , Complejo de la Endopetidasa Proteasomal , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Reproducibilidad de los Resultados , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo , Regulación hacia Arriba , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.
Asunto(s)
Interleucina-17/genética , Malaria Cerebral/etnología , Malaria Cerebral/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-17/genética , Adolescente , África/epidemiología , Niño , Preescolar , Simulación por Computador , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genética de Población , Genotipo , Humanos , Lactante , Interleucina-17/inmunología , Desequilibrio de Ligamiento , Malaria Cerebral/epidemiología , Malaria Cerebral/inmunología , Masculino , Receptores de Interleucina-17/inmunologíaRESUMEN
BACKGROUND: Severe malaria (SM) due to Plasmodium falciparum causes millions of child deaths in sub-Saharan Africa. It comprises a variety of clinical disorders, including cerebral malaria (CM) and severe anemia (SA). In previous work, we have shown that interferon gamma and interleukin 12 protect against CM. Here, we investigated whether interleukin 4 (IL-4) aggravates the risk of severe disease. METHODS: We prospectively recruited children with CM (n = 240), SA (n = 101), and uncomplicated malaria (UM) (n = 42) in Bamako, Mali, and measured IL-4 production in plasma by enzyme-linked immunosorbent assay. We then assessed the influence of 11 polymorphisms on predisposition to SM by the family-based association test (FBAT). RESULTS: IL-4 concentrations were higher in children with CM than in children with UM during malaria (P = .003). FBAT analyses showed that the most significant association was between the IL4 variable-number tandem repeat (VNTR) 1/2 genotype and SM (P < .001); an association was also observed for IL4 -33 C/T, rs2243267 G/C, rs2243268 C/A, and rs2243282 C/A (P < .05). Interestingly, we found that the plasma concentration of IL-4 was higher in subjects with the IL4 VNTR 1/2 or 1/1 genotype than with the IL4 VNTR 2/2 genotype (P = .003). CONCLUSIONS: These results support the view that IL-4 may be a risk factor for SM. IL-4 may aggravate the disease by interfering with type 1 T helper cell differentiation or by promoting local inflammation at sites of parasite sequestration.
Asunto(s)
Interleucina-4/genética , Malaria Cerebral/genética , Malaria Falciparum/genética , Repeticiones de Minisatélite/genética , Polimorfismo de Nucleótido Simple/genética , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Interleucina-4/sangre , Malaria Cerebral/inmunología , Malaria Falciparum/inmunología , MasculinoRESUMEN
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection. This encephalopathy is characterized by coma and is thought to result from mechanical microvessel obstruction and an excessive activation of immune cells leading to pathological inflammation and blood-brain barrier alterations. IL-22 contributes to both chronic inflammatory and infectious diseases, and may have protective or pathogenic effects, depending on the tissue and disease state. We evaluated whether polymorphisms (n = 46) of IL22 and IL22RA2 were associated with CM in children from Nigeria and Mali. Two SNPs of IL22, rs1012356 (P = 0.016, OR = 2.12) and rs2227476 (P = 0.007, OR = 2.08) were independently associated with CM in a sample of 115 Nigerian children with CM and 160 controls. The association with rs2227476 (P = 0.01) was replicated in 240 nuclear families with one affected child from Mali. SNP rs2227473, in linkage disequilibrium with rs2227476, was also associated with CM in the combined cohort for these two populations, (P = 0.004, OR = 1.55). SNP rs2227473 is located within a putative binding site for the aryl hydrocarbon receptor, a master regulator of IL-22 production. Individuals carrying the aggravating T allele of rs2227473 produced significantly more IL-22 than those without this allele. Overall, these findings suggest that IL-22 is involved in the pathogenesis of CM.