Associations between frequencies of a susceptible TNF-α promoter allele and protective α-thalassemias and malaria parasite incidence in Vanuatu

長崎大学学位論文 学位記番号:博(医)甲第1,181号 学位授与年月日:平成17年3月2

Microscopic Plasmodium falciparum Gametocytemia and Infectivity to Mosquitoes in Cambodia

Although gametocytes are essential for malaria transmission, in Africa many falciparum-infected persons without smear-detectable gametocytes still infect mosquitoes. To see whether the same is true in Southeast Asia, we determined the infectiousness of 119 falciparum-infected Cambodian adults to Anopheles dirus mosquitoes by membrane feeding. Just 5.9% of subjects infected mosquitoes. The 8.4% of patients with smear-detectable gametocytes were >20 times more likely to infect mosquitoes than those without and were the source of 96% of all mosquito infections. In low-transmission settings, targeting transmission-blocking interventions to those with microscopic gametocytemia may have an outsized effect on malaria control and elimination

Efficient Transmission of Mixed Plasmodium falciparum/vivax Infections From Humans to Mosquitoes

BACKGROUND: In Southeast Asia, people are often coinfected with different species of malaria (Plasmodium falciparum [Pf] and Plasmodium vivax [Pv]) as well as with multiple clones of the same species. Whether particular species or clones within mixed infections are more readily transmitted to mosquitoes remains unknown. METHODS: Laboratory-reared Anopheles dirus were fed on blood from 119 Pf-infected Cambodian adults, with 5950 dissected to evaluate for transmitted infection. Among 12 persons who infected mosquitoes, polymerase chain reaction and amplicon deep sequencing were used to track species and clone-specific transmission to mosquitoes. RESULTS: Seven of 12 persons that infected mosquitoes harbored mixed Pf/Pv infection. Among these 7 persons, all transmitted Pv with 2 transmitting both Pf and Pv, leading to Pf/Pv coinfection in 21% of infected mosquitoes. Up to 4 clones of each species were detected within persons. Shifts in clone frequency were detected during transmission. However, in general, all parasite clones in humans were transmitted to mosquitoes, with individual mosquitoes frequently carrying multiple transmitted clones. CONCLUSIONS: Malaria diversity in human hosts was maintained in the parasite populations recovered from mosquitoes fed on their blood. However, in persons with mixed Pf/Pv malaria, Pv appears to be transmitted more readily, in association with more prevalent patent gametocytemia

A novel in vitro model reveals distinctive modulatory roles of Plasmodium falciparum and Plasmodium vivax on naïve cell-mediated immunity

Abstract Background To date, human peripheral blood mononuclear cells (PBMCs) have been used mainly in immune stimulation assays and the interpretation of data can be influenced by the previous immunological history of donors and cross reactivity with other infectious agents. Resolving these limitations requires an alternative in vitro model to uncover the primary response profiles. Methods A novel in vitro model of mononuclear cells (MNCs) generated from haematopoietic stem cells (HSCs) was developed and these cells were then co-cultured with various antigens from Plasmodium falciparum and Plasmodium vivax to investigate the response of naïve immune cells to malaria antigens by flow cytometry. Results In vitro stimulation of naïve lymphocytes showed that CD4+ and CD8+ T lymphocytes were significantly reduced (P < 0.01) by exposure to lysates of infected erythrocytes or intact erythrocytes infected with P. falciparum. The depletion was associated with the expression of CD95 (Fas receptor) on the surface of T lymphocytes. Maturation of T lymphocytes was affected differently, showing elevated CD3+CD4+CD8+ and CD3+CD4−CD8− T lymphocytes after stimulation with cell lysates of P. falciparum and P. vivax, respectively. In addition, antigen presenting monocytes and dendritic cells derived from haematopoietic stem cells showed impaired HLA-DR expression as a consequence of exposure to different species of malaria parasites. Conclusion These results suggest that naïve mononuclear cells differentiated in vitro from HSCs could provide a valid model for the assessment of immunity. P. falciparum and P. vivax malaria parasites could modulate various populations of immune cells starting from newly differentiated mononuclear cells

Microsatellite Polymorphism in the Heme Oxygenase-1 Gene Promoter Is Associated with Susceptibility to Cerebral Malaria in Myanmar

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum malaria, and its pathogenesis leading to coma remains unknown. Heme oxygenase-1 (HO-1) catalyzes heme breakdown, eventually generating bilirubin, iron and carbon monoxide. The HO-1 gene promoter contains a polymorphic (GT)n repeat which may influence the expression level of HO-1. To explore the correlation between this (GT)n polymorphism and susceptibility to CM, we analyzed the frequencies of the (GT)n alleles in 120 Myanmarese patients with uncomplicated malaria (UM) and 30 patients with CM. The frequency of homozygotes for the short (GT)n alleles (<28 repeats) in CM patients was significantly higher than those in UM patinets (P < 0.008, OR = 3.14). Thus, short (GT)n alleles represent a genetic risk factor for CM

ヴァヌアツのマラリア流行島嶼におけるIL4多型とIgE濃度

血中IgE上昇に帰結するIL4プロモーターの遺伝的変異が,マラリアに対する感受性と相関することが最近の研究によって示唆されてきている.本研究においては集団遺伝学的方法を用いヴァヌアツにおけるマラリア流行度が異なる3島嶼において,IL4-590および+33塩基における変異対立遺伝子頻度,血中総IgEおよび熱帯熱マラリア原虫特異的IgE濃度を調べた.3島嶼は中等度の流行が続くMalakula,中等度の流行だが対策が功を奏しているAneityumおよびマラリア流行がないFutunaである.これらの島嶼住民より採取した血液サンプルよりIL4-590および+33についてそれぞれ計878および750サンプルの解析を行った.変異対立遺伝子頻度はこれら3島嶼間においてC-590Tが0.27～0.39,C+33Tが0.39～0.48の範囲で変動した.両対立遺伝子間には顕著な連鎖不均衡が認められた(p<0.001).これら両変異対立遺伝子ともAneityumにおいてはFutunaより高い頻度で認められた(p<0.05).AneityumにおいてはIL4+33位における変異対立遺伝子の存在する群での血中熱帯熱マラリア原虫特異的IgE濃度は有意に上昇していた(p<0.05).しかしながら,これらの関係はMalakulaにおいては認められなかった.本研究はメラネシア住民集団において当該変異遺伝子頻度に関する最初の報告である.見出された変異対立遺伝子頻度はこれまで報告されている,より高いアジア住民集団とより低いヨーロッパ住民集団の中間の値であった.さらにIL4多型が特異的IgEとマラリア病形の関係に関る遺伝的因子の一つであることが示唆された.Recent findings suggest that susceptibility to malaria is associated with genetic variants in the IL4 promoter region, resulting in the up-regulation of serum IgE. In this study, using a population-based approach, we investigated the mutant allele frequencies at positions -590 and +33 of the IL4 gene and total and Plasmodium (P.) falciparum-specific IgE levels on 3 islands with variable malaria endemicities in Vanuatu: Malakula (meso-endemic), Aneityum (meso-endemic with intervention), and Futuna (non-endemic). A total of 878 and 750 samples were typed for -590 and +33 positions, respectively. Variant allele frequencies varied from 0.27 to 0.39 for C-590T and from 0.39 to 0.48 for C+33T among 3 islands. There was a strong linkage disequilibrium between the 2 alleles (p<0.001). For both mutant alleles higher frequencies were detected in Aneityum than in Futuna (p<0.05). In Aneityum there was a significant association between the carriage of C+33T allele and increased levels of P. falciparum-specific IgE (p<0.05). However these relations were not observed in Malakula. This is the first report on IL4 polymorphisms in Melanesian populations. The observed mutant allele frequencies lay between higher values in Asian populations and rather lower values in Caucasians. The data suggest that IL4 promoter polymorphisms may be one of the genetic factors that explain relations between malaria disease and IgE