Disease In Malaria Research Articles

Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria.

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human-mosquito-malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient.

Liver-stage Plasmodium infection tunes clinical outcomes

Chora and colleagues show that infection of the liver by Plasmodium modulates severity of disease in the experimental cerebral malaria (ECM) model by generating gamma delta (ɣδ) T cells that produce IL-17. This work calls into question the long-standing assumption that liver infection does not modulate severity of malaria.

Uso de modelos de primatas neotropicais para pesquisa em malária: um histórico dos 25 anos de colaboração entre o Laboratório de Pesquisa em Malária (IOC, Fiocruz) e o Centro Nacional de Primatas (IEC, SVS)

Malaria remains a significant public health problem and, responsible for 409,000 deaths annually, mainly due to infection by Plasmodium falciparum. Thus, the development of an effective vaccine has been a research priority to address the problem. There is no licensed vaccine, and although more than 30 antigens have been identified as candidates, none of them has yet generated a solid prospect that an effective vaccine may be available in the coming years. Therefore, it is essential to search for new, more immunogenic, more effective and safer vaccine candidates. The neotropical, non-human primates (NHP) of the genera Saimiri and Aotus are recommended as experimental models for the study of human malaria because these animals can be infected with the Plasmodium that infect humans. The Laboratory of Malaria Research (LabMal, Fiocruz) studies the mechanisms of defense and disease in malaria and uses the Saimiri and Aotus experimental models for preclinical evaluation of antimalarial vaccine candidates and for conducting studies of immunity acquisition mechanisms and physiopathogenesis of malaria. To carry out the studies, LabMal established a partnership with the Centro Nacional de Primatas (CENP) of the Instituto Evandro Chagas, which resulted in the expansion of Saimiri sciureus colonies, placing CENP among the few institutions in the world that have this resource for malaria research. The present paper is a retrospective of the results obtained during 25 years of partnership between LabMal and CENP in the use of Saimiri and Aotus as study models for research and development of an antimalarial vaccine.

Sex differences in concentrations of HMGB1 and numbers of pigmented monocytes in infants and young children with malaria.

Sex remains a key biological variable affecting human innate and adaptive immune responses to infection and in pathogenesis of diseases. In malaria, females demonstrate higher concentrations of antibodies and rates of severe adverse events and mortality following malaria vaccination. Although monocytes/macrophages play a crucial role in disease and protection in malaria, no studies have investigated sex differences in their functions in production of proinflammatory cytokines and chemokines in malaria-infected subjects. Here, we show significant sex differences in serum concentrations of HMGB1, a non-histone chromatin-associated protein, and numbers of pigmented monocytes, which are both markers of severe malaria, in infants and young children <5years old from a malaria endemic region in Northern Uganda. Female infants and young children with clinical malaria had significantly higher HMGB1 concentrations than males, and female infants and young children with asymptomatic malaria had significantly lower numbers of pigmented monocytes than males with asymptomatic malaria. There was (1) a significant correlation between HMGB1 concentrations and pigmented monocyte numbers in female but not male infants; and (2) a significant correlation between HMGB1 concentrations and parasite densities in female but not male infants. These findings suggest that female infants and young children with clinical malaria might be at a greater risk of morbidity characterized by higher serum HMGB1 levels.

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BackgroundCerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. MethodsQuantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. ResultsWe found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. ConclusionsOur findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Caspase-8 mediates inflammation and disease in rodent malaria

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.

Allelic variation of msp-3α gene in Plasmodium vivax isolates and its correlation with the severity of disease in vivax malaria.

Malaria is a global socio-economic burden of which Plasmodium vivax contributes for about 70-80 million cases on an annual basis worldwide and 60-65% cases in India. Diversity observed in highly polymorphic Merozoite Surface Protein-3α (msp-3α) encoded by MSP-3 gene family, has been used efficiently for genotyping of P. vivax infection. This study aims to correlate the severity of clinical symptoms with parasite load, genotype of P. vivax and multiplicity of infection. Based on clinical symptoms classification, 31 (67.9%) out of 46 cases were found to be severe while 15 (32.6%) were non-severe and correlation of the severity of vivax infection with parasite load was not observed. Analysis of msp3-α allele genotype showed that out of 31 severe cases, 19 (61.2%) were single-clone infection cases whereas 12 (38.7%) were multi-clone infections. Similarly, out of 15 non-severe cases, 9 (60%) were single clone and 6 (40%) were multi-clone infections indicating the absence of a correlation between the multiplicity of infection and disease severity. Allele frequency observed was 65.9%, 23.4%, 23.4%, and 28.2% for allele A, B, C and D, respectively. An important finding was the greater distribution of allele D than alleles B and C, which has been reported as a rare allele otherwise. Further, of 13 cases with allele D, 76.9% (10/13) cases were severe. This study showed the absence of a correlation between the severity of clinical symptoms with parasite load and multiplicity of infection but at the same time drives a possibility of severe vivax malarial symptoms to have an association with the persistence of allele D in the population. This upon exploration can lead to the development of a target in detection of severe cases of malaria.

Serum Angiopoietin-1 and -2 and VEGF are associated with severe disease in vivax malaria.

Malaria continues to be a significant public health problem in tropical countries including India; however, there are limited tools to predict occurrence of severe disease due to malaria. This study was designed to evaluate the role of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular endothelial growth factor (VEGF) and Asymmetric Dimethylarginine (ADMA)as disease biomarkers in uncomplicated malaria (UM) and severe malaria (SM). This is a prospective observational study carried out at All India Institute of Medical Sciences (AIIMS), tertiary referral hospital in New Delhi, India. The study population included patients diagnosed with malaria (Plasmodium falciparum or Plasmodium vivax) either by rapid diagnostic kit test or positive peripheral smear and age more than 12 years. Forty-nine patients (25 with SM, 24 with UM) and 22 controls were recruited. In addition to routine investigations, serum concentrations of Ang-1, Ang-2, VEGF and ADMA were measured using ELISA technique. We observed Ang-1 serum levels to be significantly lower in patients with severe malaria (7775 pg/ml) compared to uncomplicated malaria (17629 pg/ml) and healthy controls (43472 pg/ml) [p <0.001]. Ang-2 levels were significantly higher in severe malaria (11100 pg/ml) compared to uncomplicated malaria (7315 pg/ml) and healthy controls (3679 pg/ml) (p <0.001). The ratio of Ang-2/Ang-1 was significantly higher in patients with severe malaria. VEGF serum levels was significantly lower in severe malaria (130.36 pg/ml) compared to uncomplicated malaria (317.3 pg/ml). The Ang-1, Ang-2 and VEGF levels were able to differentiate severe malaria from uncomplicated malaria caused by P. vivax but not with P. falciparum. We conclude that Ang-1, Ang-2 and VEGF are markers of disease severity in vivax malaria.

Profound Alteration of Host Response in Severe Malarial Anemia By Sickle Cell Disease: Reduction of Parasite Sequestration and Inflammation, Upregulation of Angiopoietin-2

Introduction. Plasmodium falciparum malaria is a major cause of morbidity in African children with sickle cell anemia (SCA). Factors associated with severe disease and mortality in malaria, including tumor necrosis factor (TNF)-alpha and components of the angiopoietin (Angpt)-Tie-2 system, have also been implicated in the pathogenesis and clinical severity of SCA. However, there is no data on how these factors are altered in children with SCA during severe malaria. Methods. A total of 232 children who presented with severe malarial anemia (hemoglobin &lt; 5 g/dL with Plasmodium parasitemia on peripheral blood smear) were enrolled in a prospective study of severe malaria at Mulago National Referral Hospital in Kampala, Uganda. No child had known SCA at the time of severe malarial anemia diagnosis. Samples from enrolled children were subsequently tested by genotyping for the presence of hemoglobin S (HbS) using a TaqMan assay at rs334. Clinical and laboratory parameters, plasma markers of inflammation and endothelial activation, and the estimated total, sequestered, and circulating parasite biomass were compared in children with HbSS compared to HbAA. Results. The study cohort included 208 children with HbAA (90.4%), 22 children with HbSS (9.6%), and 2 with HbAS. Children with HbSS were older than children with HbAA (Table 1), so all comparisons were adjusted for age. Children with HbSS versus HbAA did not differ significantly in duration of symptoms, clinical signs, disease severity, or degree of peripheral P. falciparum parasitemia. However, children with HbSS had significantly lower concentrations of PfHRP2, a marker of total parasite biomass, and lower levels of estimated sequestered parasite biomass (Table 1). Children with HbSS had pronounced leukocytosis, a feature of chronic inflammation in SCA, but had significantly lower concentrations of the inflammatory biomarkers C-reactive protein and alpha-1-acid glycoprotein and the pro-inflammatory cytokine TNF-alpha than children with HbAA (Table 1). In contrast, concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation that has been associated with mortality in severe malaria, were 3-fold greater in children with HbSS than HbAA (Table 1), and were associated with an increased risk of post-discharge recurrent malaria in the cohort, after adjustment for age, sex, and hemoglobin S genotype (odds ratio per log-10 increase in Angpt-2 [95% confidence interval], 2.11 [1.01, 4.38]). Conclusion. In this population, undiagnosed SCA is common in children with severe malarial anemia. During episodes of severe malarial anemia, children with SCA suppress parasite sequestration and inflammation but upregulate Angpt-2, which may increase risk of recurrence of malaria. Disclosures Conroy: ALC: Patents &amp; Royalties: angiopoietin-1, angiopoietin-2. Ware:Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Bristol Myers Squibb: Other: Research Drug Donation.

B cell profiling in malaria reveals expansion and remodelling of CD11c+ B cell subsets.

Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute P. falciparum malaria for the first time, or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that ~80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only ~40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated- and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared to individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay with a half-life of ~300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary- and secondary B cell responses during infection.

Glycocalyx Breakdown Is Associated With Severe Disease and Fatal Outcome in Plasmodium falciparum Malaria.

BackgroundInteractions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated.MethodsWe prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay.ResultsA total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39; 3.10, 0.46–4.5 and 4.64, 2.02–15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability.ConclusionsIncreased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria.

Effects of Aging on Parasite Biomass, Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Plasmodium knowlesi and Plasmodium falciparum Malaria

In populations pauci-immune to malaria, risk of severe malaria increases with age. This is particularly apparent in Plasmodium knowlesi malaria. However, pathophysiological mechanisms underlying knowlesi malaria, and of the age-related increase in risk of severe malaria in general, are poorly understood. In Malaysian patients aged ≥12 years with severe (n = 47) and nonsevere (n = 99) knowlesi malaria, severe (n = 21) and nonsevere (n = 109) falciparum malaria, and healthy controls (n = 50), we measured parasite biomass, systemic inflammation (interleukin 6 [IL-6]), endothelial activation (angiopoietin-2), and microvascular function, and evaluated the effects of age. Plasmodium knowlesi parasitemia correlated with age (Spearman's correlation coefficient [rs] = 0.36; P < .0001). In knowlesi malaria, IL-6, angiopoietin-2, and microvascular dysfunction were increased in severe compared to nonsevere disease, and all correlated with age, independent of parasitemia. In falciparum malaria, angiopoietin-2 increased with age, independent of parasite biomass (histidine-rich protein 2 [HRP2]). Independent risk factors for severe malaria included parasitemia and angiopoietin-2 in knowlesi malaria, and HRP2, angiopoietin-2, and microvascular dysfunction in falciparum malaria. Parasite biomass, endothelial activation, and microvascular dysfunction are associated with severe disease in knowlesi malaria and likely contribute to pathogenesis. The association of each of these processes with aging may account for the greater severity of malaria observed in older adults in low-endemic regions.

A High Malaria Prevalence Identified by PCR among Patients with Acute Undifferentiated Fever in India.

BackgroundApproximately one million malaria cases were reported in India in 2015, based on microscopy. This study aims to assess the malaria prevalence among hospitalised fever patients in India identified by PCR, and to evaluate the performance of routine diagnostic methods.MethodsDuring June 2011-December 2012, patients admitted with acute undifferentiated fever to seven secondary level community hospitals in Assam (Tezpur), Bihar (Raxaul), Chhattisgarh (Mungeli), Maharashtra (Ratnagiri), Andhra Pradesh (Anantapur) and Tamil Nadu (Oddanchatram and Ambur) were included. The malaria prevalence was assessed by polymerase chain reaction (PCR), routine microscopy, and a rapid diagnostic test (RDT) with PCR as a reference method.ResultsThe malaria prevalence by PCR was 19% (268/1412) ranging from 6% (Oddanchatram, South India) to 35% (Ratnagiri, West India). Among malaria positive patients P. falciparum single infection was detected in 46%, while 38% had P. vivax, 11% mixed infections with P. falciparum and P. vivax, and 5% P. malariae. Compared to PCR, microscopy had sensitivity of 29% and specificity of 98%, while the RDT had sensitivity of 24% and specificity of 99%.ConclusionsHigh malaria prevalence was identified by PCR in this cohort. Routine diagnostic methods had low sensitivity compared to PCR. The results suggest that malaria is underdiagnosed in rural India. However, low parasitaemia controlled by immunity may constitute a proportion of PCR positive cases, which calls for awareness of the fact that other pathogens could be responsible for the febrile disease in submicroscopic malaria.

Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

Individuals naturally exposed to Plasmodium falciparum lose clinical immunity after a prolonged lack of exposure. P. falciparum antigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity of P. falciparum antigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinical P. falciparum malaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document that P. falciparum antigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence of P. falciparum exposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack of P. falciparum exposure.

Climate change and children's health

To present the latest data that demonstrate how climate change affects children's health and to identify the principal ways in which climate change puts children's health at risk. Data continue to emerge that further implicate climate change as contributing to health burdens in children. Climate models have become even more sophisticated and consistently forecast that greenhouse gas emissions will lead to higher mean temperatures that promote more intense storms and droughts, both of which have profound implications for child health. Recent climate models shed light upon the spread of vector-borne disease, including Lyme disease in North America and malaria in Africa. Modeling studies have found that conditions conducive to forest fires, which generate harmful air pollutants and damage agriculture, are likely to become more prevalent in this century due to the effects of greenhouse gases added to earth's atmosphere. Through many pathways, and in particular via placing additional stress upon the availability of food, clean air, and clean water and by potentially expanding the burden of disease from certain vector-borne diseases, climate change represents a major threat to child health. Pediatricians have already seen and will increasingly see the adverse health effects of climate change in their practices. Because of this, and many other reasons, pediatricians have a unique capacity to help resolve the climate change problem.

Specific receptor usage in Plasmodium falciparum cytoadherence is associated with disease outcome.

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases.

Combined measurement of soluble and cellular ICAM-1 among children with Plasmodium falciparum malaria in Uganda

BackgroundIntercellular adhesion molecule-1 (ICAM-1) is a cytoadhesion molecule implicated in the pathogenesis of Plasmodium falciparum malaria. Elevated levels of soluble ICAM-1 (sICAM-1) have previously been reported with increased malaria disease severity. However, studies have not yet examined both sICAM-1 concentrations and monocyte ICAM-1 expression in the same cohort of patients. To better understand the relationship of soluble and cellular ICAM-1 measurements in malaria, both monocyte ICAM-1 expression and sICAM-1 concentration were measured in children with P. falciparum infection exhibiting a spectrum of clinical severity.MethodsSamples were analysed from 160 children, aged 0.5 to 10.8 years, with documented P. falciparum malaria in Kampala, Uganda. The patients belonged to one of three pre-study defined groups: uncomplicated malaria (UM), severe non-fatal malaria (SM-s), and fatal malaria (SM-f). Subset analysis was done on those with cerebral malaria (CM) or severe malaria anaemia (SMA). Monocyte ICAM-1 was measured by flow cytometry. sICAM-1 was measured by enzyme immunoassay.ResultsBoth sICAM-1 and monocyte cell-surface ICAM-1 followed a log-normal distribution. Median sICAM-1 concentrations increased with greater severity-of-illness: 279 ng/mL (UM), 462 ng/mL (SM-s), and 586 ng/mL (SM-f), p < 0.0001. sICAM-1 levels were not statistically different among children with CM compared to SMA. Monocyte ICAM-1 expression was significantly higher in cases of UM compared with SM-s or SM-f (p < 0.001) and was higher among the subset of patients with CM compared with SMA, p < 0.0014. The combination of sICAM-1 and cellular ICAM-1 identified distinct categories of patients (UM with low sICAM-1 and higher monocyte ICAM-1, CM with both sICAM-1 and monocyte ICAM-1 high, and SMA with sICAM-1 high but monocyte ICAM-1 low).ConclusionIn this cohort of children with P. falciparum malaria, sICAM-1 levels were associated with severity-of-illness. Patients with UM had higher monocyte ICAM-1 expression consistent with a role for monocyte ICAM-1 in immune clearance during non-severe malaria. Among the subsets of patients with either SMA or CM, monocyte ICAM-1 levels were higher in CM, consistent with the role of ICAM-1 as a marker of cytoadhesion. Categories of disease in pediatric malaria may exhibit specific combinations of soluble and cellular ICAM-1 expression.

Heroes or villains? T regulatory cells in malaria infection

Infection with Plasmodium parasites can cause severe disease due to a lack of protective immune responses to clear parasitemia, or to the host's inability to control excessive inflammation resulting in immunopathology. T regulatory cells (Tregs), key mediators of immune homeostasis, are increased in number and modulate disease in human and murine malaria. Several recent studies provide new insights into the mechanisms and functional consequences of Treg induction by P. falciparum. This review integrates and discusses the findings published on Tregs in human and murine malaria to date, with emphasis on Treg induction (host components, kinetics and parasite-dependence) and their diverse roles (protective or pathological) during infection.

New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance

Unlike Plasmodium falciparum, Plasmodium vivax rarely causes severe disease in healthy travellers or in temperate endemic regions and has been regarded as readily treatable with chloroquine. However, in tropical areas, recent reports have highlighted severe and fatal disease associated with P. vivax infection. We review the evidence for severe disease and the spread of drug-resistant P. vivax and speculate how these maybe related. Studies from Indonesia, Papua New Guinea, Thailand and India have shown that 21-27% of patients with severe malaria have P. vivax monoinfection. The clinical spectrum of these cases is broad with an overall mortality of 0.8-1.6%. Major manifestations include severe anaemia and respiratory distress, with infants being particularly vulnerable. Most reports of severe and fatal vivax malaria come from endemic regions where populations have limited access to healthcare, a high prevalence of comorbidity and where drug-resistant P. vivax strains and partially effective primaquine regimens significantly undermine the radical cure and control of this relapsing infection. The mechanisms underlying severe disease in vivax malaria remain poorly defined. Severe, fatal and multidrug-resistant vivax malaria challenge our perception of P. vivax as a benign disease. Strategies to understand and address these phenomena are needed urgently if the global elimination of malaria is to succeed.

Genetic diversity of the msp-1 locus and symptomatic malaria in south-west Nigeria

Genetic characteristics of Plasmodium falciparum may play a role in the clinical severity of malaria infection. We have studied the association between diversity at the merozoite surface protein-1 ( msp-1) locus and the severity of disease in childhood malaria in Ibadan, south-west Nigeria. Two hundred and twenty-three children (median age of 34.5 months) presenting with malaria were enrolled into the study. They comprised 53 children with asymptomatic malaria (ASM), 101 with acute uncomplicated malaria (UM) and 69 with severe malaria (SM). Genotyping of the msp-1 locus was by polymerase chain reaction. The distribution of msp-1 alleles was significantly different between the three groups. Asymptomatic malaria samples had a higher median number of alleles than the other two groups. The type of msp-1 allele detected was significantly associated with the clinical category of malaria. The absence of K1 alleles was associated with a three-fold increase risk of UM and a four-fold increased risk of SM when compared with asymptomatic malaria. The absence of MAD20 alleles was associated with a five-fold increase risk of UM and an eight-fold increase of SM. We have found an association between the msp-1 locus of P. falciparum and clinical severity of malaria in a sample of Nigerian children. Our findings show that the presence of the K1 and MAD20 alleles was significantly associated with ASM and consequently a reduced risk of developing the symptomatic disease.