Interferon-gamma enhances the effect of antimalarial chemotherapy in murine Plasmodium vinckei malaria

Most nonimmune patients with Plasmodium falciparum infection are no longer cured by such standard antimalarial drugs as chloroquine. Thus, alternative treatment regimens are necessary. A combination therapy was tested consisting of a subcurative dose of chloroquine and interferon-gamma (IFN-gamma) in BALB/c mice with lethal Plasmodium vinckei malaria. Treatment with either agent alone prolonged median survival by 1-2 days compared with placebo-treated mice. However, a combination of 80 micrograms of chloroquine given at the time of infection plus 1 x 10(4) units of IFN-gamma/day for 11 days (starting 3 days before infection) cured 83% of infected mice. Moreover, these mice showed solid immunity when challenged with the homologous strain of P. vinckei. However, when these mice were infected with the heterologous strain of Plasmodium berghei, the same degree of parasitemia developed as did in P. berghei-infected control mice. Thus, the combination of chemotherapy with the cytokine IFN-gamma leads to substantial improvement of antimalarial treatment and to a rapid development of strain-specific immunity in murine P. vinckei malaria.     

瑞香素杀疟原虫裂殖体的作用

[目的 ]研究中药瑞香素在体外和体内的杀裂殖体作用。 [方法 ]在恶性疟原虫FCCl株常规体外培养中测试瑞香素杀裂殖体活性 ,并按“四天抑制性试验”在感染伯氏疟原虫ANKA株的小鼠中测定不同剂量瑞香素的体内抗疟活性。 [结果 ]体外试验中瑞香素在 1～ 10 μmol L剂量范围内有明显杀灭裂殖体作用 ,而体内试验中按D4减虫率与感染鼠在 30d内的平均生存天数评价 ,5 0或 10 0mg kg .d- 1 × 4d瑞香素灌胃以及 10 ,5 0或 10 0mg kg.d- 1 × 4d瑞香素腹腔注射给药在伯氏鼠疟原虫ANKA株感染鼠中的抗疟作用与 10mg kg .d- 1 × 4d氯喹 (CQ)灌胃的疗效相似。 [结论 ]瑞香素在体外和体内均有一定的杀裂殖体作用。     

Rifampicin antagonizes the effect of choloroquine on chloroquine-resistant Plasmodium berghei in mice

Chloroquine (CQ)-resistant Plasmodium falciparum appears to decrease CQ accumulation in its food vacuole by enhancing its efflux via an active membrane pump, which has been reported to be a P-glycoprotein-like transporter. Rifampicin (RIF) is a P-glycoprotein inhibitor and also has some antimalarial activity. It is hoped that a combination of choloroquine-rifampicin (CQ + RIF) would be advantageous in the treatment of CQ-resistant malaria. Swiss albino mice were inoculated with CQ-resistant P. berghei intraperitoneally, and studied for the effect of CQ versus the combination of CQ + RIF at various doses on the clearance of parasitemia, the survival of the mice, and the recrudescence of malaria. Paradoxically, RIF decreased the survival rate and rate of clearance of parasitemia and increased the rate of recrudescence significantly when combined with various doses of CQ. Our results indicated that RIF worsened the course of the disease, and we concluded that RIF should not be combined with CQ in the treatment of malaria.     

Lactobaciilus casei ssp. rhamnosus enhances non specific protection against Plasmodium chabaudi AS in mice

OBJECTIVE: To evaluate the capacity of Lactobacillus casei ssp. rhamnosus to enhance resistance against Plasmodium chabaudi chabaudi AS. MATERIAL AND METHODS: NIH mice were IP injected with viable lactobacillus casei seven days (LC1 group) or 7 and 14 days (LC2 group) before the challenge (day 0) with Plasmodium chabaudi parasitized red blood cells (pRBC). Control mice were inoculated with pRBC only. When parasitaemia was resolved, naive mice were injected with spleen cells from each group. The parasitaemia was measured. Nitric oxide (NO*) in serum was determined. RESULTS: Mice from the LC1 group presented a reduction in parasitaemia, with a prepatent period of five days, parasitaemia lasted 11 days, and the peak was (36.3 % pRBC) on the 12th day post-infection. Mice from the LC2 group showed a prepatent period of five days, parasitaemia lasted eight days, and the peak (30 % pRBC) was of on the 11th day. In the control, the prepatent period was three days, the parasitaemia lasted 15 days, and the peak (51% pRBC) was on day nine. Mice inoculated with spleen cells from the LC2 group showed a prepatent period of 21 days, parasitaemia lasted seven days, and the peak (13.5% pRBC) was on the 26th day. CONCLUSION: L. casei enhanced nonspecific resistance to P. chabaudi, as indicated by longer prepatent periods, reduced parasitaemia, and reduction in the viability of the parasites recovered from the spleen of infected mice, along with high concentrations of NO* in serum.     

伯氏疟原虫氯喹抗性逆转的实验观察

目的 寻找伯氏疟原虫氯喹抗性逆转剂.方法 将健康昆明小鼠72只(雌、雄各半)每只腹腔注射0.2 ml伯氏疟原虫ANKA株氯喹敏感系(chloroquine sensitive,CS)或由其选育的高抗氯喹系(chloroquine resistance,CR),按下述随机分组后灌胃给药治疗,观察各组疗效.(1)小鼠感染CS疟原虫30 min后随机均分为4组,每组6只,给D-6182{(Z,Z)-N,N,N-三甲基-2,3-双[(1-氧代-9-十八碳烯酸)-氧代]-1-丙胺基盐酸盐|、C-2832[胆畄醇-3-N-(二甲胺基乙基)氨甲酸酯]、Ket(酮替酚)、0.1%西黄蓍胶(对照组),连续灌药5 d.于D1至D7每天每鼠取尾血涂片作常规镜检,确定各实验组的原虫血症.(2)小鼠感染CR疟原虫后第3天随机均分为8组,每组6只,给D-6182、C-2832、Ket组、氯喹组、0.1%西黄蓍胶对照组及给予D-6182、C-2832、Ket后2 h再加灌服小剂量12 mg/(kg·d)氯喹(5%ED90),连续5 d.每鼠于D4至D7每天取尾血涂片作常规镜检,确定各实验组的原虫血症,并计算各组的原虫减虫率.结果 (1)感染伯氏疟原虫CS株的小鼠,分别灌服80 mg/(kg·d)D-6182、120 mg/(kg·d)C-2832或10 mg/(kg·d)Ket连续5 d,各给药组与对照组小鼠的原虫感染率自D1至D4逐日上升,至D4达峰值,D5时对照组小鼠原虫感染率继续上升,而各给药组维持在D4的峰值水平.(2)感染伯氏疟原虫CR株的小鼠给适宜剂量的C-2832、D-6182或Ket后2 h加灌服小剂量氯喹12 mg/(kg·d)(5%ED90),此后连续5 d(D3-D7),于D4原虫减虫率可达到97.77%、99.28%或96.73%,而在D7可达到99.81%、98.87%或100.00%.结论 C-2832和D-6182两种化合物对伯氏疟原虫CR株感染小鼠的氯喹抗性具有逆转作用,其逆转能力与Ket相当.     

伯氏疟原虫ANKA株抗哌喹系小鼠模型免疫学分析

目的观察伯氏疟原虫(Plasmodium berghei,Pb)ANKA抗哌喹(PQR)系小鼠模型的免疫学特征方法64只昆明小鼠随机分为3组,A组和C组各16只,B组32只(其中16只用于观察存活天数)。A组B组小鼠分别经腹腔感染伯氏疟原虫ANKA株哌喹敏感系(PbPQS)和抗性系(PbPQR)红内期原虫1×10~7个(200μl血),C组(健康对照组)注射等量生理盐水。每组于感染后4、8、12和16d各取4只小鼠,取尾血制薄血膜镜检,计算红细胞原虫感染率(简称原虫率)。脱颈处死小鼠,无菌取脾制备脾淋巴细胞悬液,用CCK-8法测定各组小鼠脾淋巴细胞经刀豆球蛋白A(ConA)刺激后的增殖反应,用Griess法和ELISA分别测定脾淋巴细胞培养上清中N0含量和γ干扰素(IFN-γ)水平。另取10只昆明小鼠,每鼠腹腔接种PbPQR系原虫约1×10~7个,待原虫率上升后下降,典型的原虫转变为蓝染细胞时,腹腔感染PbPQS系原虫(1×10~6个)进行攻击感染,观察小鼠原虫率和小鼠存活情况。结果 A组小鼠平均存活(9.0±3.0)d,感染后6～12d原虫率均>50%,出现严重贫血。感染后16d,B组小鼠全部存活,原虫率为(26.66±2.54)%。A、B两组小鼠的脾淋巴细胞经Con A刺激后增殖显著,感染后12d,分别为0.65±0.08和0.86±0.20(P<0.01)。脾淋巴细胞培养上清中,N0含量随感染时间延长而上升,感染后12d,A、B和C组分别为(48.80+3.49)、(54.80±2.17)和(7.80±0.71)μmol/L,三者比较差异有统计学意义(P<0.01)、A组脾淋巴细胞培养上清中IFN-γ水平随感染时间延长而上升,感染后12d达到最高,为(752.20+39.49)pg/ml,B组于感染后8d升至峰值[(855.80±33.65)pg/ml],感染后12d降至(620.20±27.11)pg/ml;感染后8d和12d,A组和B组IFN-γ水平的差异有统计学意义(P<0.01)。用PbPQS系攻击感染PbPQR系小鼠模型后10d,原虫率为(2.44±2.07)%,随之逐渐消失,感染后40d未检出虫体,无小鼠死亡。结论伯氏疟原虫ANKA株哌喹抗性系感染小鼠的脾淋巴细胞增殖水平、NO水平和IFN-γ含量均显著高于PbANKA株PQS系感染小鼠,可诱导小鼠产生一定保护性免疫反应。     

Insect-borne and culture-derived metacyclic Trypanosoma cruzi: differences in infectivity and virulence

We report in this paper significant differences in the virulence of insect-derived and cultured metacyclic forms of Trypanosoma cruzi which are morphologically indistinguishable. Mice infected intraperitoneally with 10(3) metacyclic T. cruzi isolated from Rhodnius prolixus showed average parasitemia levels greater than 2 X 10(5) organisms/ml around day 10 post-infection (when first measured) and peak levels recorded on day 16 post-infection exceeded 4 X 10(7) organisms/ml. None of these animals survived after 30 days post-infection. In contrast, in mice infected with 10(3) or 10(4) metacyclic forms from axenic cultures the highest average parasitemia was approximately 10(4) organisms/ml and occurred around day 19 post-infection. In these animals, parasitemias declined with time to become undetectable and no mortality was recorded over the 100-day observation period. There was also a marked difference in the 50% lethal dose of insect- and culture-derived metacyclics. The value for the former was 670 parasites whereas none of the mice infected intraperitoneally with up to 10(6) cultured metacyclics died. These results point to a marked difference in the biological properties of insect-borne and cultured T. cruzi metacyclics under our experimental conditions and caution against extending results obtained with the latter to vector-transmissible metacyclics, at least in infectivity and virulence studies.     

自然调节性T细胞对脑型疟疾易感鼠和抵抗鼠感染结局的影响

目的探讨自然调节性T细胞(nTregs)在伯氏疟原虫感染过程中的活化特点及其与疾病进展的相关性。方法用伯氏疟原虫ANKA分别感染C57BL/6、BALB/c和DBA/2小鼠,计数红细胞感染率;感染前和感染后3、5、8d制备脾细胞悬液,流式细胞术检测脾细胞悬液中nTregs百分含量;ELISA和Griess方法检测脾细胞培养上清IFN-γ、IL-10和NO水平。结果C57BL/6小鼠感染后8～11d死于脑疟,BALB/c和DBA/2小鼠感染后3～4w死于贫血和过度虫体血症。3种小鼠于感染后3d,nTregs百分数达到峰值后逐渐下降,于感染后8d,C57BL/6小鼠nTregs百分数下降最为显著并明显低于正常水平,整个感染过程中,C57BL/6小鼠的nTregs百分含量显著低于BALB/c和DBA/2小鼠。3种小鼠脾细胞培养上清IFN-γ、NO和IL-10水平于感染后开始升高,感染后5d达到峰值,感染后8d与感染后5d相比,C57BL/6小鼠IFN-γ、NO水平轻微下降,IL-10水平显著下降;BALB/c和DBA/2小鼠IFN-γ、NO水平显著下降,IL-10水平轻微下降。并且C57BL/6小鼠IFN-γ、NO水平高于BALB/c和DBA/2小鼠,而IL-10水平低于BALB/c和DBA/2小鼠。3种小鼠感染后脾脏nTregs数量与IFN-γ和NO水平呈负相关,IL-10水平与感染率呈正相关。结论伯氏疟原虫感染过程中,nTregs数量的动态变化与宿主感染结局密切相关。     

The pharmacodynamic study of a potent new antimalarial (MC1)

2,3-bis(Trifluoromethyl)-4-(3-hydroxyquinuclidinylquinoline) or MC(1) is a new synthetic compound with potent antimalarial activity in vitro and in vivo studies. The IC(50) values of MC(1) and chloroquine in in vitro culture of Plasmodium falciparum are 7.0x10(-8) and 6.06x10(-7)M, respectively. In an in vivo study using Plasmodium berghei infected mice as the test model, the survival time of the infected mice without drug treatment was 6.00+0.58 days. Chloroquine and MC(1) at an equal dose of 7.5mg/kg, orally administered once daily for 4 days, prolonged the survival time of the infected mice from 6 to 14 days, and more than 28 days, respectively. At the doses that exhibit potent antimalarial activity in vivo, there are no observable toxic effects. Preliminary studies of the pharmacodynamic activity of this newly synthesized compound revealed that at the doses which exhibit potent antimalarial activity, there is no alteration in motor activity such as distance traveled, rotational behavior, and stereotypic activity. The blood glucose was not significantly altered. In the spontaneous beating, isolated right atria of mice, MC(1) exhibits direct negative chronotropism at high concentrations (10(-4)M). This effect is augmented in hyper-K(+) bathing solution. A direct negative chronotropic effect was also observed when mefloquine at 5x10(-5)M was used. Preliminary pharmacodynamic study suggested that MC(1) is a potential new antimalarial drug that should be studied further.     

Trends of tissue hypoxia following chemotherapy of acute malaria in mice]

The effects of antimalarial treatment on the blood oxygen-transporting properties and on the tissue hypoxia were investigated in severe murine malaria, using mice infected with Plasmodium berghei (NK65). Five week old male ddY mice were inoculated intraperitoneally with 1 X 10(7) of P. berghei-infected red blood cells and treated with Fansidar (20 mg/kg body weight sulfadoxine and 1 mg/kg body weight pyrimethamine orally) on day 5 after inoculation. Parasitemia in these mice decreased rapidly on day 1 after treatment. Blood hemoglobin concentration, however, decreased on days 1 and 2 of treatment, then began to increase. The actual oxygen equilibrium curve (OEC) in vivo (actual pH; actual Pco2; 36.5 degrees C) was calculated from the measured OEC and the results of blood gas analysis. Looking from arterial and venous Po2 of each group, blood oxygen-transporting properties decreased markedly on day 2 of treatment. This decrease resulted mainly from the decrease of hemoglobin concentration and also partly from the raised hemoglobin affinity for oxygen. Adenosine triphosphate concentration in liver tissues, however, began to increase on day 1 of treatment. Adenylate energy charge of liver tissues also recovered on day 1. Blood glucose concentration began to increase and blood lactate concentration began to decrease simultaneously on day 1 of treatment. Glucose concentration in liver tissues, in contrast, decreased on days 1 and 2 of inoculation. Lactate concentration in liver tissue decreased earlier on day 1. These data indicate that tissue hypoxia was removed on day 1 following antimalarial treatment although blood oxygen-transporting properties decreased on days 1 and 2 after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

抗疟治疗对宿主保护性免疫影响的实验研究

目的探讨药物治疗对宿主保护性免疫建立的影响。方法用不同剂量氯喹或青蒿琥酯治疗约氏疟原虫(非致死型)感染的BALB/c小鼠。待自愈组清除疟原虫后30d,用约氏疟原虫(非致死型和致死型)以及伯氏疟原虫再次感染。以吉姆萨薄血膜染色法观察小鼠虫体血症水平,采用ELISA法检测脾细胞培养上清中IFN-γ水平和血清中特异性抗体水平。结果自愈组和各治疗组小鼠于初次感染早期均产生高水平IFN-γ,随之抗约氏疟原虫(非致死型)特异性IgG抗体水平显著升高,且无明显差异。对约氏疟原虫(非致死型和致死型)再次攻击小鼠均呈完全抵抗,少数出现低水平一过性虫体血症。而异种疟原虫攻击时小鼠全部感染并死亡。结论氯喹或青蒿琥酯不同剂量治疗不影响小鼠保护性免疫的建立和免疫记忆的维持,特异性IgG抗体是宿主抵御再感染主要的免疫效应分子。     

Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization—World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.     

枸橼酸钠抗凝剂对疟原虫生长活性的影响

目的　了解枸橼酸钠抗凝剂对疟原虫生长活性的影响。　方法　将疟原虫经抗凝剂(ACD,CD和SC)处理后以感染率为指标检测抗凝剂对虫体的影响。未同步化的恶性疟原虫分别使用3种不同浓度抗凝剂于37℃作用3h。处理后的红细胞与正常虫体混合,同时处理后的虫体与正常红细胞混合,随后观察两种培养混合物的感染率以确定抗凝剂作用的靶细胞。同上处理期同步化的疟原虫(环状体,滋养体和裂殖体)以观察抗凝剂作用的期特异性。将伯氏疟原虫用抗凝剂处理后接种小鼠,通过感染率的变化观察抗凝剂对鼠疟的影响。　结果　 3种抗凝剂均可抑制疟原虫的生长,其中ACD影响最甚。以抗凝剂分别处理红细胞和疟原虫,结果表明抗凝剂作用于虫体而非红细胞。处理同步化的虫体表明抗凝剂对裂殖体的抑制最为显著。同样处理伯氏疟原虫后接种小鼠进一步验证了抗凝剂对恶性疟原虫作用的抑制性效应。　结论　ACD对疟原虫的抑制性效应最为明显,SC是疟原虫试验中枸橼酸钠抗凝剂的首选。     

瑞香素抗红外期疟原虫作用的研究

目的　研究瑞香素 (DPNT)抗红外期疟原虫的作用。方法　于ICR小鼠腹腔注射约氏疟原虫子孢子后 0 5h灌胃给药 ,连续 4d。不同剂量的DPNT及DPNT伍用伯氨喹 (PQ)的抗疟作用 ,分别以d7ICR小鼠阴性率及d1 1 或d1 2 ICR小鼠每千个红细胞被原虫感染数作评价 ,并观察DPNT对ICR小鼠血红蛋白浓度的影响。结果　DPNT的剂量范围为每天 10～ 10 0mg/kg ,连服 4d ,d7原虫阴性小鼠数及d1 1 红细胞被感染程度与对照组相比其差异均无显著性 ;DPNT每天 5 0mg/kg和每天PQ5mg/kg配伍组的d7小鼠阴性率与PQ每天 10mg/kg组相当。ICR小鼠DPNT每天 5 0mg/kg组与对照组血红蛋白浓度在d8天有差异。结论　DPNT单独用药 ,无明显抗红外期疟原虫作用 ,但DPNT每天 5 0mg/kg与PQ每天 5mg/kg伍用的抗疟效果与PQ每天 10mg/kg相当。DPNT在短期内可致小鼠贫血。     

Increased parasitaemia and delayed parasite clearance in Schistosoma mansoni and Plasmodium berghei co-infected mice

Identifying factors that contribute to malaria susceptibility, severity and treatment failure remains one of the major research areas in malaria control strategies. In the present study, we superinfected Schistosoma mansoni infected mice with a lethal strain Plasmodium berghei ANKA to assess whether or not infection with S. mansoni affects parasite development, parasitaemia and parasite reduction or clearance following antimalarial treatment. Mice infected with P. berghei alone were used as control. The mice were followed for parasite development and parasitaemia between days 4 and 9 post-infection. On day 9, after taking blood samples, the mice were orally treated with 100mg/kg of chloroquine and then with 10mg/kg for three consecutive days. Parasite reduction/clearance and mortality were followed between days 10 and 13 post-treatment. The results showed, that superinfection with S. mansoni enhanced P. berghei parasite development, increased parasitaemia and mortality, and delayed reduction/clearance in parasitaemia. Hence, the results postulate that co-infections with schistosome and malaria parasites would aggravate malarial severity and prolong parasite reduction or clearance after chemotherapy in humans. This would necessitate the need for considering schistosome infection in clinical as well as therapeutic management of malaria patients in areas where the two diseases are co-endemic.     

Randomized comparison of chloroquine and amodiaquine in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children.

The increasing resistance of Plasmodium falciparum to chloroquine (CQ) has created an urgent need for the evaluation of alternative, effective, safe, cheap, readily available and affordable antimalarial treatments. In the present study, the efficacy of amodiaquine (AQ) in the treatment of acute, symptomatic, uncomplicated, P. falciparum malaria was compared with that of CQ, each drug being given at 10 mg/kg per day for 3 days (days 0, 1 and 2). The 210 subjects (104 given AQ and 106 CQ) were Nigerian children aged 5 months-12 years. Fever-clearance times (FCT), parasite densities on days 1-4 and parasite-clearance times (PCT) were all significantly lower with AQ than with CQ. Mean (S.D.) PCT, for example, were 2.6 (0.8) days with AQ and 3.0 (1.0) days with CQ (P = 0.001). The cure rates obtained on days 14, 21 and 28 - 98.1% v. 79.3% (P =0.000), 97.1% v. 64.2% (P = 0.00001) and 95.2% v. 58.5% (P = 0.0000000) with AQ and CQ, respectively - were all also significantly higher with AQ. All but two of the 20 subjects who were considered CQ-treatment failures by day 14 (i.e. two RIII, two RII and 16 RI) responded to subsequent treatment with AQ, with PCT (but not FCT) significantly shorter than during their initial treatment with CQ. In siblings in whom there was clustering of infections, the cure rates were 100% with AQ (N =12) and 63.6% with CQ (N = 11; P = 0.03). Adverse reactions to CQ and AQ were similar and tolerable: pruritus in 10 and 11 children in the AQ and CQ groups, respectively, and gastro-intestinal disturbances which occurred in three children from each group. Haematological parameters were not adversely affected by either drug. At least in the setting of the present study, AQ appears more effective than CQ, effective against CQ-resistant infections, and well tolerated by children with acute, uncomplicated, P. falciparum malaria. It may therefore be useful as an alternative to CQ in areas of CQ resistance.     

Comparison of sulfadoxine-pyrimethamine with and without chloroquine for uncomplicated malaria in Nigeria

While resistance to older antimalarials is increasingly common, newer antimalarials are still not widely available or affordable in much of Africa. Older antimalarials used in combination might be adequately effective in treating uncomplicated malaria. The objective of this study was to determine whether the combination of sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is superior to SP alone in the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian patients. We recruited subjects with malaria, defined as the presence of fever and parasitemia > 2,000/microL, from the outpatient department of a Nigerian teaching hospital. We alternately assigned 280 subjects to receive SP with or without CQ. We assessed clinical and parasitologic responses on days 1, 2, 3, 7, and 14. A total of 114 in the SP + CQ group and 116 in the SP group completed the study. By day 3, 97 (75%) in the SP + CQ group and 52 (42%) in the SP group had cleared their parasitemia (P < 0.001); by day 14, 112 (98%) and 67 (58%), respectively, had cleared their parasitemia (P < 0.001). By day 3, 82 (63%) in the SP + CQ group and 20 (16%) in the SP group were symptom free (P < 0.001). When a modified World Health Organization clinical classification system was used, adequate clinical response occurred in 99 (87%) and 61 (53%) of those in the SP + CQ and SP groups, respectively. RI, RII, and RIII resistance to SP + CQ was 7.9%, 3.5%, and 1.8%, respectively, whereas resistance to SP was 23%, 17%, and 5%, respectively. Combined SP + CQ is superior to SP alone for treatment of uncomplicated malaria in Nigerian patients and may prolong the usefulness of these readily available and affordable drugs.     

Virus vaccine and passive immunization for the prevention of viral myocarditis in mice

The effect of an inactivated virus vaccine and passive immunization was studied in an animal model of viral myocarditis. Encephalomyocarditis (EMC) virus was inactivated by 1:4000 formalin. Four-week-old CD-1 mice were injected subcutaneously and after 7 days intravenously with 0.1 ml vaccine. Seven days after the second vaccine, live EMC virus was inoculated intraperitoneally. None of ten mice with vaccine treatment died or showed myocardial lesions after challenge with EMC virus, whereas all ten mice without vaccine died 5-7 days after EMC virus inoculation and showed severe myocardial lesions. Hyperimmune rabbit serum, made by inactivated EMC virus, had a neutralizing antibody titer of 1:3000. Four-week-old BALB/c mice were injected intramuscularly with 1:10 dilution of hyperimmune rabbit serum in 6 groups (each, n = 10) on day -2, -1, 0, 1, 2, or 3, respectively, after inoculation with 10 plaque-forming units of EMC virus, and observed for 14 days. Eight mice infected with the virus without immune serum died and all ten mice showed severe myocardial lesions. No death or myocardial lesion was seen in mice with hyperimmune rabbit serum given on days -2 to 2. In this model, the virus vaccine prevented development of myocarditis, and passive immunization had a protective effect if given early after infection.     

Flt3 ligand treatment modulates parasitemia during infection with rodent malaria parasites via MyD88‐ and IFN‐γ‐dependent mechanisms

We previously showed that treatment of mice with the Flt3 ligand (Flt3L) prevents development of lethal experimental cerebral malaria and inhibits parasitemia during Plasmodium berghei ANKA (PbA) infection. In this study, we investigated the mechanisms underlying the reduction of parasitemia in Flt3L‐treated mice. Studies using gene knockout mice and antibody treatment indicated that the anti‐parasitemia effect of Flt3L was mediated by innate immune system and was dependent on MyD88, IFN‐γ, IL‐12 and natural killer (NK) cells. The number of NK cells and their ability to produce IFN‐γ was enhanced in Flt3L‐treated mice. Phagocytic activity of splenocytes was increased in Flt3L‐treated mice after PbA infection when compared with that in untreated mice, and this activity was mainly mediated by the accumulation of F4/80^midCD11b⁺ cells in the spleen. In both MyD88^?/? and IFN‐γ^?/? mice, the proportion of F4/80^midCD11b⁺ cells was not increased in the spleen of Flt3L‐treated mice after infection. These correlations suggest that NK cells produce IFN‐γ in Flt3L‐treated mice, and accumulation of F4/80^midCD11b⁺ cells in the spleen is promoted by an IFN‐γ ‐dependent manner, culminating in the inhibition of parasitemia. These findings imply that Flt3L promotes effective innate immunity against malaria infection mediated by interplay among varieties of innate immune cells.