ABSTRACT
BACKGROUND: In Plasmodium falciparum infections, proinflammatory cytokine response is implicated in control of parasite multiplication as well as in disease pathogenesis. However, the regulation of proinflammatory and anti-inflammatory cytokine balance and its relation to disease severity remains poorly understood. METHODS: We examined cytokines gene expression by quantitative real time-PCR technique in a case control study comprising of P. falciparum infected (n=58) and non infected (n=30) groups. P. falciparum infected were further stratified as complicated and uncomplicated as per WHO criterion and parasitaemia levels. RESULTS: Higher expression of IL-2, IL-12α and TGF-ß with decreased levels of IL-10 was seen in P. falciparum positivity. Complicated malaria was associated with enhanced expression of IFN-γ and TGF-ß but lower IL-2 and IL-12α in comparison to uncomplicated malaria. Modeling of data suggested higher expression of IL-12α to be predictive of uncomplicated malaria [Odds ratio=3.074, 95% CI (1.254-7.536)] and was negatively associated with complicated malaria outcome (p=0.014). Interestingly, the probability of complicated malaria in males with elevated TNF-α expression was three times higher [p=0.05; Odds ratio=3.412, 95% CI (0.98-11.848)]. Age was also seen to be a factor with higher IL-8 in diseased young (p=0.012). CONCLUSION: Our data suggested induction of balanced cytokine response in uncomplicated malaria while cytokine dysregulation with a role for TGF-ß was indicated in complicated malaria. TH cells did not appear to be the source of increased IFN-γ expression associated with malaria severity.
Subject(s)
Interferon-gamma/metabolism , Interleukin-12/metabolism , Interleukin-2/metabolism , Malaria, Falciparum/complications , Transforming Growth Factor beta/metabolism , Adolescent , Adult , Age Factors , Case-Control Studies , Child , Child, Preschool , Female , Gene Expression Regulation , Humans , Infant , Interferon-gamma/genetics , Interleukin-12/genetics , Interleukin-2/genetics , Malaria, Falciparum/genetics , Malaria, Falciparum/metabolism , Male , Transforming Growth Factor beta/genetics , Young AdultABSTRACT
Infectious diseases have been postulated to play an important role in exerting pressure and in selection of TLR polymorphisms. Single nucelotide polymorphisms (SNPs) of TLR4 have been reported to show unique distributions in populations from Africa, Asia and Europe, and malaria is suggested to influence these patterns. In this context, we examined association of TLR polymorphisms with the risk of malaria in two ethnic groups-the Austro-Asiatics and Tibeto-Burmans-from malaria endemic districts of Assam to understand the influence of malaria in selection of TLRs in these genetically-distinct populations. TLR9 (T-1237C) mutation was positively associated with complicated (P = 0.001) and frequent (P = 0.035) malaria in Austro-Asiatics (relative risk = 0.595 95% CI: 0.479-0.836), but not in Tibeto-Burmans. Nonetheless, these alleles were not in Hardy-Weinberg Equilibrium in Tibeto-Burmans (P < 0.001). In contrast, the TLR9 1486T/C genotype was favourable where it was negatively associated with complicated malaria (Fishers exact P = 0.014). Sequencing data revealed that the two populations differed in nucleotide diversity of the TLR9 promoter region. Enhanced expression of TLR4 (P = 0.05), but not of TLR9, was associated with complicated malaria. Austro-Asiatics appeared to have accumulated favourable genotypes of TLR9, perhaps because of their longer exposure to malaria.
Subject(s)
Ethnicity , Malaria/genetics , Racial Groups , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 9/genetics , DNA Mutational Analysis , Disease Progression , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , India , Malaria/epidemiology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Risk , Toll-Like Receptor 4/geneticsABSTRACT
Receptors encoded within the Natural Killer Cell (NKC) complex and Killer Immunoglobulin like (KIRs) genomic regions have been suggested to influence malaria pathogenesis and infection susceptibility. We have examined KIR locus in relation to risk of infection and disease in Tea tribes (TT) of Austro Asiatic affinity and Tibeto-Burman (TB) populations from malaria endemic regions of Assam. Consistent with differences in their genetic background, KIR gene loci frequencies differed in studied groups. Surprisingly, KIR3DS1 frequency in TT was low (17%) and comparable to that reported from African populations. KIR3DL1 frequency was positively associated with malaria severity (Pearson phi, R(2) = 0.297 p = 0.006) and logistic regression modelling predicted KIR3DL1 as a risk factor in complicated malaria [Odds Ratio (95% C.I)] = [6.39 (1.34-30.60)]. An interaction between ethnicity and KIR3DL1 was also seen where higher proportion of KIR3DL1 positive and complicated malaria patients belonged to Tea tribes (p = 0.009). Notably, four activating genes protected from frequent malaria (p = 0.02) while six activating genes enhanced the risk of complicated malaria (p = 0.05). Combination of KIR2DS4, KIR2DS4del, KIR2DS5 negatively influenced disease outcome in Tea tribes (p = 0.048) but not in Tibeto-Burman. In conclusion our data indicates KIR gene loci differentially influenced malaria outcome in Tea tribes and Tibeto-Burman and that four activating genes appeared to provide optimal activation that protected from frequent episodes of malaria. Our data also indicated KIR3DS1 to be an ancestral genotype, maintained at low frequency possibly by malaria in the Austro Asiatic tribes.
Subject(s)
Ethnicity/genetics , Genetic Predisposition to Disease , Malaria/genetics , Receptors, KIR/genetics , Adolescent , Adult , Aged , Animals , Child , Child, Preschool , Cohort Studies , Female , Gene Frequency , Humans , India , Killer Cells, Natural/immunology , Linkage Disequilibrium , Malaria/immunology , Male , Middle Aged , Prospective Studies , Receptors, KIR3DL1/genetics , Young AdultABSTRACT
Polymorphism in MSP1 gene generated by insertion/deletion of repeats causing repeat length polymorphisms is widely used as a marker for parasite genotyping. Elucidating Plasmodium falciparum clonal composition in relation to transmission intensity and other epidemiological factors in endemic areas is crucial to understanding the dynamics of host-parasite relationship and the development of immunity in malaria. We have examined here the allelic diversity of P. falciparum and attempted to understand the polymorphism and distribution of alleles of MSP1 with transition in transmission season and with differences in malaria epidemiology between sites. MSP1 diversity expressed as mean number of distinct alleles per isolate was 0.68 at Dimakusi and was much higher (p=0.007) than seen at Guabari (0.336) and Kondoli (0.45) as was multiplicity of infection at 4.12, indicating the highest diversity at this site. Size polymorphism of the allelic families at Guabari was distinctly different from Kondoli but shared similarity with Dimakusi. Infections in high transmission summer season tended to be more complex with higher number of alleles. The frequency of alleles of RO33 and MAD20 allelic families at Guabari was found to be different between the two transmission periods. A 380 base pair allele of RO33 was over represented in high transmission summer season and seen frequently in isolates with high parasitaemia. At Kondoli allele distribution of only MAD20 was found to be different in each study year. Study site and ethnicity but not age of the study population were identified as risk factors in infection complexity. The present study demonstrates that allelic composition of P. falciparum varied with study site and between periods of high and low transmission as well as in different years of study.
