Development Of Severe Malaria Research Articles

Impact of the COVID-19 pandemic on malaria in pregnancy indicators in Northern Uganda: a joinpoint regression analysis

ABSTRACT Background Pregnancy is both a risk factor for P. falciparum infection and development of severe malaria. In low- and middle-income countries, the COVID-19 pandemic severely impacted health systems, including utilization of maternal services. This study aimed to assess trends in delivering malaria in pregnancy-related health-care services before and during COVID-19 in Northern Uganda. Methods An interrupted time-series study comparing pre-COVID-19 (January 2018 to April 2020) and COVID-19 (May to December 2021) periods, based on the date the first COVID case was detected. The study involved 30 health facilities in Northern Uganda with 22,650 estimated pregnancies per year, 14% of which took place in hospital. Monthly data were sourced from District routinely collected indicators. Trends were analyzed by joinpoint regression models. Results From the onset of the COVID pandemic in Uganda (May 2020), we found a significant reduction in the number of women accessing a fourth antenatal care visit (from APC + 183.5 to + 4.98; p < 0.001) and taking at least three doses of intermittent preventive treatment in pregnancy (IPTp, from APC + 84.28 to -63.12; p < 0.001). However, we found no significant change in the trend of the total number of pregnant women managed as outpatients or hospitalized for malaria, as well as in the number of women attending their first antenatal visit and in the number of institutional deliveries. Conclusions In our study, the COVID-19 pandemic significantly reduced access to ANC visits and IPTp uptake. However, the healthcare system maintained its capacity for managing malaria cases, first antenatal visits, and institutional deliveries. Trial registration: This study has been registered on the ClinicalTrials.gov public website on 26 April 2022. ClinicalTrials.gov Identifier: NCT05348746.

The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis

ObjectivesSevere malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal. MethodsA single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a genetic variant that is known to alter IL-6 signaling. We tested this, then took this forward as an instrument to perform Mendelian randomization (MR) in MalariaGEN, a large cohort study of patients with severe malaria at 11 worldwide sites. ResultsIn MR analyses using rs2228145, we did not identify an effect of decreased IL-6 signaling on severe malaria (odds ratio 1.14, 95% confidence interval 0.56-2.34, P = 0.713). The estimates of the association with any severe malaria subphenotype were similarly null, although with some imprecision. Further analyses using other MR approaches had similar results. ConclusionThese analyses do not support a causal role for IL-6 signaling in the development of severe malaria. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria.

Impact of antimalarial resistance and COVID-19 pandemic on malaria care among pregnant women in Northern Uganda (ERASE): protocol of a prospective observational study

BackgroundUganda accounts for 5% of all malaria cases and deaths reported globally and, in endemic countries, pregnancy is a risk factor for both acquisition of P. falciparum infection and development of severe malaria. In recent years, malaria control has been threatened by COVID-19 pandemic and by the emergence, in Northern Uganda, of both resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine.MethodsIn this facility-based, prospective, observational study, pregnant women will be recruited at antenatal-care visits and followed-up until delivery. Collected data will explore the incidence of asymptomatic parasitemia and malaria-related outcomes, as well as the attitudes towards malaria prevention, administration of intermittent preventive treatment, healthcare seeking behavior and use of insecticide-treated nets. A subpopulation of women diagnosed with malaria will be recruited and their blood samples will be analyzed for detection of genetic markers of resistance to artemisinin derivatives and sulfadoxine-pyrimethamine. Also, to investigate the impact of COVID-19 on malaria care among pregnant women, a retrospective, interrupted-time series will be conducted on at the study sites for the period January 2018 to December 2021.DiscussionThe present study will explore the impact of COVID-19 pandemic on incidence of malaria and malaria-related adverse outcomes, along with the prevalence of resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. To our knowledge, this is the first study aiming to explore the combined effect of these factors on a cohort of pregnant women.Trial registration: This study has been registered on the ClinicalTrials.gov public website on 26th April, 2022. ClinicalTrials.gov Identifier: NCT05348746.

Expression of Single-Domain Soluble and Disulfide-Folded PfEMP1 Antigens in the Escherichia coli SHuffle Expression System.

The genome of Plasmodium falciparum has an A/T content of around 81%. This, together with a high cysteine content and the high molecular weight of several proteins, make the expression of recombinant parasite proteins in heterologous systems challenging. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins composed of several Duffy-binding like (DBL) and cysteine-rich inter-domain region (CIDR) domains involved in cytoadhesion to human host receptors and development of severe malaria. Expression of correctly folded single- and multiple-domain PfEMP1 fragment regions containing cysteines forming disulfide bonds, remains particularly difficult. Nevertheless, expression of single DBL and CIDR domains has been successful and this protocol describes the expression and purification of single-domain soluble PfEMP1 fragments using the Escherichia coli SHuffle expression system.

Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case\u2013control study in Congolese children

BackgroundBlackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children.MethodsThis is a case–control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping.ResultsA total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87–829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06–0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF.ConclusionThis pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

The Effect of Frequent Exposure to P. falciparum, HIV-Infection and Other Co-Morbidities on Development of Severe Malaria in Malawian Adults.

AimPlasmodium falciparum malaria predominantly affects children residing in endemic areas. However, recently a significant number of Malawian adults, who otherwise should have attained some malaria-specific immunity, have been observed to succumb to either uncomplicated malaria (UM) or severe malaria (SM). In addition, it is still unknown whether HIV is a contributing factor to SM in Malawian non-pregnant adults. We conducted this study to determine clinical and demographic features that characterize Malawian adults presenting with UM or SM.MethodsStudy participants were recruited when they presented at Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi with UM or SM and had their demographic details recorded after consenting to participate in the study. Malaria infection was confirmed by Malaria Rapid Diagnostic Test (MRDT) and malaria slide microscopy. A venous blood sample was collected before treatment for various analyses.ResultsBoth HIV-infected and HIV-uninfected participants were at risk of presenting with either UM or SM although there were more (37%) SM cases among those who were HIV-infected compared to those who were HIV-uninfected (28%) but the difference was not significant but similar numbers of UM cases (61% for HIV-uninfected and 60% for HIV-infected). Previous visit to areas of high malaria transmission was not associated with presenting with either UM or SM. HIV/malaria co-infected participants were more likely to be found with a positive blood culture result (Diphtheriods, Stenotophomonas maltophilia, Salmonella typhimurium and Staphylococcus aureus) and were at a higher risk of dying compared to HIV-uninfected malaria patients.ConclusionAlthough HIV-infection was associated with high mortality in those co-infected with HIV and malaria, recurrent malaria episodes and having other diseases co-existing with malaria infection were the main factors associated with the development of SM in this study cohort. Further studies need to be done to determine how the host immunity is affected in those co-infected with HIV and malaria.

Cerebral Plasmodium falciparum malaria: The role of PfEMP1 in its pathogenesis and immunity, and PfEMP1-based vaccines to prevent it.

Malaria, a mosquito‐borne infectious disease caused by parasites of the genus Plasmodium continues to be a major health problem worldwide. The unicellular Plasmodium‐parasites have the unique capacity to infect and replicate within host erythrocytes. By expressing variant surface antigens Plasmodium falciparum has evolved to avoid protective immune responses; as a result in endemic areas anti‐malaria immunity develops gradually over many years of multiple and repeated infections. We are studying the role of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed by asexual stages of P. falciparum responsible for the pathogenicity of severe malaria. The immunopathology of falciparum malaria has been linked to cyto‐adhesion of infected erythrocytes to specific host receptors. A greater appreciation of the PfEMP1 molecules important for the development of protective immunity and immunopathology is a prerequisite for the rational discovery and development of a safe and protective anti‐disease malaria vaccine. Here we review the role of ICAM‐1 and EPCR receptor adhering falciparum‐parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of developing a vaccine targeted specifically to prevent this disease.

Sticking for a Cause: The Falciparum Malaria Parasites Cytoadherence Paradigm.

After a successful invasion, malaria parasite Plasmodium falciparum extensively remodels the infected erythrocyte cellular architecture, conferring cytoadhesive properties to the infected erythrocytes. Cytoadherence plays a central role in the parasite's immune-escape mechanism, at the same time contributing to the pathogenesis of severe falciparum malaria. In this review, we discuss the cytoadhesive interactions between P. falciparum infected erythrocytes and various host cell types, and how these events are linked to malaria pathogenesis. We also highlight the limitations faced by studies attempting to correlate diversity in parasite ligands and host receptors with the development of severe malaria.

Correlation of malaria parasitaemia with peripheral blood monocyte to lymphocyte ratio as indicator of susceptibility to severe malaria in Ghanaian children

BackgroundEven though malaria is generally on the decline due extensive control and elimination efforts, it still remains a public health problem for over 40% of the world’s population. During the course of malaria infection, parasites and red blood cells come under oxidative stress and there is host immune response in an attempt to protect the red blood cells. The frequency of monocytes and lymphocytes in peripheral blood might, therefore, be expected to reflect the state of an individual’s immune response to the infection. Circulating monocytes and lymphocytes could therefore serve as an index in relation to malaria parasitaemia. The purpose of this study was to determine whether the relative count of monocytes to lymphocytes in peripheral blood (M:L ratio) can predict parasitaemia and, therefore, the severity of malaria infection.MethodsTwo millilitre of venous blood sample were taken from participants by venisection into anticoagulant tubes. Thick and thin blood films were made and stained with Giemsa and examined for malaria parasites. Whole blood specimen were analysed for full blood count using ABX Pentra 60 C+ automated haematological analyzer. Data was entered into Microsoft Word and analysed using Statistical Package for Social Sciences (SPSS, Version 20.0) and Graphpad prism. Spearman’s correlation was used to determine correlation between occurrences of clinical malaria and the monocytes and lymphocytes ratio. Statistical significance was taken as p ≤ 0.05 with 95% confidence interval.ResultsThe study comprised of 1629 (m = 896; f = 733) children up to 5 years presenting with clinical malaria as cases and 445 (m = 257; f = 188) apparently healthy children as controls. The results indicated that there was a significant positive correlation between the monocytes to lymphocytes ratio and the presence of parasites (p = 0.04) and the level of parasitaemia within the age group of 0–3 years (p = 0.02) and 4–5 years (p = 0.03).ConclusionsThe monocyte to lymphocyte ratio obtained correlated positively with the presence of malaria as well as the level of parasitaemia. The outcome of this work implies that monocyte to lymphocyte ratio can be used to predict the level of parasitaemia and together with other factors, the development of severe malaria.

Risk factors for severe malaria among hospitalized patients in the United States, 2000-2014.

Factors associated with the development of severe malaria have not been well described for cases occurring in the United States (US). Severe malaria hospitalizations data from the 2000-2014 Nationwide Inpatient Sample were analyzed. Frequencies were reported by demographic, clinical, species, financial, geographic, and institutional characteristics, and trends and disparities were identified. Logistic regression models were used to identify potential predictors for severe disease among those with malaria. From 2000 to 2014, there were an estimated 4823 severe malaria cases, representing 21.9% of all malaria-related hospitalizations, including 182 severe malaria deaths. Severe malaria was most common among inpatients who were male, Black, aged 45-64 years, and hospitalized in the South Atlantic division of the US. Older age was associated with higher odds of severe malaria, cerebral malaria, ARDS, severe anemia, and renal failure. Males had higher odds of developing renal failure and jaundice, while females had higher odds of developing severe anemia. HIV infection was associated with increased odds of severe malaria, severe anemia, and renal failure. Primary and secondary prevention measures, such as pre-travel consultations, chemoprophylaxis, and early diagnosis and treatment, should be emphasized and improved among high-risk prospective travelers to malaria endemic countries.

Malaria Parasite Survival Depends on Conserved Binding Peptides' Critical Biological Functions

Biochemical, structural and single amino acid level analysis of 49 Plasmodium falciparum protein regions (13 sporozoite and 36 merozoite proteins) has highlighted the functional role of each conserved high activity binding peptide (cHABP) in cell host-microbe interaction, involving biological functions such as gliding motility, traversal activity, binding invasion, reproduction, nutrient ion transport and the development of severe malaria. Each protein's key function in the malaria parasite's asexual lifecycle (pre-erythrocyte and erythro-cyte) is described in terms of cHABPs; their sequences were located in elegant work published by other groups regarding critical binding regions implicated in malarial parasite invasion. Such cHABPs represent the starting point for developing a logical and rational methodology for selecting an appropriate mixture of modified cHABPs to be used in a completely effective, synthetic antimalarial vaccine. Such methodology could be used for developing vaccines against diseases scourging humanity.

RIFINs are adhesins implicated in severe Plasmodium falciparum malaria.

Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs--preferentially of blood group A--to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.

Binding of subdomains 1/2 of PfEMP1-DBL1α to heparan sulfate or heparin mediates Plasmodium falciparum rosetting.

The capacity of Plasmodium falciparum parasitized erythrocytes (pRBC) to adhere to the endothelial lining in the microvasculature and to red blood cells (RBC) is associated with the virulence of the parasite, the pathogenesis and development of severe malaria. Rosetting, the binding of uninfected RBC to pRBC, is frequently observed in individuals with severe malaria and is mediated by the N-terminal NTS-DBL1α domain of the adhesin Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed at the surface of the pRBC. Heparan sulfate has been suggested to be an important receptor for the NTS-DBL1α variant IT4var60 expressed by the parasite FCR3S1.2. Here, we have determined the binding site of NTS-DBL1α (IT4var60) to the RBC and heparin using a set of recombinant, mutated proteins expressed in and purified from E. coli. All the variants were studied for their ability to bind to RBC, their capacities to disrupt FCR3S1.2 rosettes, their affinities for heparin and their binding to rosette-disruptive mAbs. Our results suggest that NTS-DBL1α mediates binding to RBC through a limited number of basic amino acid residues localized on the surface of subdomains 1 (SD1) and 2 (SD2). The SD2-binding site is localized in close proximity to one of two previously identified binding sites in the rosetting PfEMP1 of the parasite PaloAlto-varO. The binding site in SD2 of NTS-DBL1α could represent a template for the development of anti-rosetting drugs.

Vitamin D insufficiency is common in Ugandan children and is associated with severe malaria.

Vitamin D plays an increasingly recognized role in the innate and adaptive immune response to infection. Based on demonstrated roles in up-regulating innate immunity, decreasing inflammation, and reducing the severity of disease in illnesses such as tuberculosis and influenza, we hypothesized that poor vitamin D status would be associated with severe malaria. We measured 25-hydroxyvitamin D [25(OH)D] by immunoassay in a sample of Ugandan children aged 18 months –12 years with severe malaria (cerebral malaria or severe malarial anemia, n = 40) and in healthy community children (n = 20). Ninety-five percent of children with severe malaria (n = 38) and 80% of control children (n = 16) were vitamin D-insufficient [plasma 25(OH)D <30 ng/mL]. Mean plasma 25(OH)D levels were significantly lower in children with severe malaria than in community children (21.2 vs. 25.3 ng/mL, p = 0.03). Logistic regression revealed that for every 1 ng/mL increase in plasma 25(OH)D, the odds of having severe malaria declined by 9% [OR = 0.91 (95% CI: 0.84, 1.0)]. These preliminary results suggest that vitamin D insufficiency may play a role in the development of severe malaria. Further prospective studies in larger cohorts are indicated to confirm the relationship of vitamin D levels to severity of malaria infection and to investigate causality.

Imported Plasmodium falciparum malaria in Istanbul, Turkey: risk factors for severe course and mortality

We describe the epidemiological, clinical features and risk factors for the morbidity and mortality of imported Plasmodium falciparum malaria cases during the last 10 years in Istanbul, Turkey. The epidemiological, clinical and laboratory data of cases in six tertiary care hospitals in Istanbul between 2002 and 2012 were analysed. Seventy patients (65 males, five females; median age 37; range: 14-84) were included. Sixty-five (93%) patients had travelled to African countries and the remaining five to other malarious countries. Seventeen (24%) had a history of previous malarial episodes; eight (13%) developed recrudescence during the first month; 22 (31%), 17 (24%), 20 (29%) and three (4%) cases had cerebral malaria, cholestatic icterus, malarial hepatitis and respiratory distress syndrome on admission, respectively. Six of 12 patients with severe falciparum malaria died. Clinically, the presence of alteration in mental status, icterus, hypoglycaemia, disseminated intravascular coagulation and malarial hepatitis were statistically significant for the development of severe malaria and mortality. Recrudescence should not be forgotten, especially in uncomplicated cases.

Analysis of antibody induction upon immunization with distinct NTS-DBL1α-domains of PfEMP1 from rosetting Plasmodium falciparum parasites

BackgroundRosette-formation of Plasmodium falciparum parasitized erythrocytes is of importance in the development of severe malaria. The parasite-derived molecule PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), central to rosetting, is suggested to be included in a multimeric vaccine targeting severe disease.MethodsThree recombinant NTS-DBL1α-domains of PfEMP1 were generated in Escherichia coli, purified and used for immunization of rats and goats. Antibody titres were determined in ELISA assays and responses were compared in-between different individual animals and species. Reactivity with the parasites was tested in live pRBC using FACS. B-cell epitopes prediction was carried out in silico and compared to the results obtained by peptide microarray. Screening for serological cross-reactivity with heterologous NTS-DBL1α variants was carried out by ELISA, peptide array and FACS on pRBC of different laboratory strains and patient isolates.ResultsAll three NTS-DBL1α-domains induced high titres of antibodies that were biologically active with no apparent difference between constructs covering slightly different parts of the DBL1α-sequence. The different animal species showed comparable titres of antibodies, while variations within individuals of the species could be observed.Mapping of the recognized epitopes revealed that most parts of the molecule were able to induce an antibody response with a tendency for the N and C terminal parts of the molecule for slightly higher recognition. Important differences to the epitopes predicted were found as some of the most conserved parts of the DBL1α-domain contained the main epitopes for antibody reactivity. ELISA assays and peptide microarray demonstrated substantial cross-reactivity to heterologous variants, while binding to native PfEMP1 was observed only in few combinations on the pRBC surface, underlining that mainly internal, conserved and not surface exposed parts of the DBL1α-domain are responsible for this observation.ConclusionBiologically active antibodies can be induced consistently, with high titres, in different animal species and the antibodies elicited by different constructs react with similar epitopes. Induced antibodies recognize epitopes localized in all subdomains of the DBL1α-sequence. Cross-reactivity between NTS-DBL1α-variants is common in ELISA, but rare with live pRBC emphasizing that also internal, conserved areas of PfEMP1 carry important highly immunogenic epitopes of the molecule.

Combined promoter haplotypes of the IL10R genes are associated with protection against severe malaria in Gabonese children

The critical barrier in control of infections remains the failure of the immune system to clear parasites despite antigen recognition. We examined and validated possible association of regulatory immune gene polymorphisms in a cohort of children with mild and severe malaria. We focussed on two precursors of the Interleukin 10 Receptor (IL10R) gene namely the IL10R alpha and IL10R beta that play a fundamental role in initiation of signal transduction. Initial screening across 40 Gabonese adult individuals revealed two promoter variants for the IL10R alpha and three for the IL10R beta precursor, respectively. Validation of these variants for their allelic gene expression by transient transfection assays exhibited an altered expression in rs56356146 and rs7925112 of the IL10R alpha (P < 0.5); rs8178435 and rs999788 in the IL10R beta constructs (P < 0.0001), respectively. We further investigated the functional role of those SNP variants exhibiting altered expression in a cohort of children with mild and severe malaria. We genotyped 145 children with mild and 185 children with severe malaria for IL10R alpha; for IL10R beta, 102 children with mild and 101 children with severe malaria. We found that none of the SNP variants had any significant association neither in children with mild or severe malaria. The haplotype -185/-116 of IL10R alpha (TT) in combination with the haplotype -754/-750 of IL10R beta (AC) contributed towards mild malaria in comparison to severe malaria [TT + AC odds ratio of 0.73 (95% CI 0.56-0.94) P = 0.01]. This study may provide a better understanding on the role of IL10R promoter allelic variants contribution to a protective effect on the development of severe malaria.

Severe malaria in Gambian children is not due to lack of previous exposure to malaria.

The reasons why only a small proportion of African children infected with Plasmodium falciparum develop severe or fatal malaria are not known. One possible reason is that children who develop severe disease have had less previous exposure to malaria infection, and hence have less acquired immunity, than children who develop a mild clinical attack. To investigate this possibility we have measured titres of a wide range of anti-P. falciparum antibodies in plasma samples obtained from children with severe malaria, children with mild malaria and from children with other illnesses. Mean antibody levels in patients with malaria were higher than those in patients with other conditions but, with only one exception, there were no significant differences in antibody titres between cases of severe or mild malaria. A parasitized-erythrocyte agglutination assay was used to estimate the diversity of parasite isolates to which children had been exposed; plasma samples obtained from children with cerebral malaria recognized as many isolates as did samples obtained from children with mild disease. Our findings do not provide any support for the view that the development of severe malaria in a small proportion of African children infected with P. falciparum is due to lack of previous exposure to the infection.

Fc gamma Receptor IIa (CD32) Polymorphism and Antibody responses to Asexual Blood‐stage Antigens of Plasmodium falciparum Malaria in Sudanese Patients

In a prospective clinical study in New Halfa Teaching Hospital, the possible association between FcgammaRIIa-R/H131 polymorphism and anti-malarial antibody responses with clinical outcome of Plasmodium falciparum malaria among Sudanese patients was investigated. A total of 256 individuals were consecutively enrolled, comprising 115 patients with severe malaria, 85 with mild malaria and 56 malaria-free controls. Genotyping of FcgammaRIIa-R/H131 dimorphism was performed using gene-specific polymerase chain reaction (PCR) amplification with allele-specific restriction enzyme digestion of the PCR product. The antibody responses to asexual blood-stage antigens were assessed by an enzyme-linked immunosorbent assay. The frequency of the FcgammaRIIa-R/R131 genotype was significantly higher in those with severe malaria when compared with patients with mild malaria, while the FcgammaRIIa-H/H131 genotype showed a significant association with mild malaria. A reduced risk of severe malaria with IgG3 antibodies in combination with the H/H131 genotype was observed. Furthermore, low levels of IgG2 antibodies reactive with the Pf332-C231 antigen were also associated with lower risk of severe malaria in individuals carrying the H131 allele. The levels of IgG1 and IgG3 antibodies were statistically significantly higher in the mild malaria patients when compared with the severe malaria patients. Taken together, our study revealed that the FcgammaRIIa-R/R131 genotype is associated with the development of severe malaria, while the H/H131 genotype is more likely to be associated with mild malaria. Our results also revealed that the natural acquisition of immunity against clinical malaria appeared to be more associated with IgG1 and IgG3 antibodies, signifying their roles in parasite-neutralizing immune mechanisms.

HIGHER PRODUCTION OF PERIPHERAL BLOOD MACROPHAGE MIGRATION INHIBITORY FACTOR IN HEALTHY CHILDREN WITH A HISTORY OF MILD MALARIA RELATIVE TO CHILDREN WITH A HISTORY OF SEVERE MALARIA

Plasmodium falciparum malaria is one of the leading causes of childhood morbidity and mortality in sub-Saharan Africa. The host immune response to P. falciparum is a critical determinant of malarial pathogenesis and disease outcomes. Macrophage migration inhibitory factor (MIF) is a central regulator of innate immune responses to bacterial and parasitic infections. Our recent investigations demonstrated that peripheral blood MIF production was suppressed in children with severe malaria. Because examination of MIF production in children with active disease does not account for the inherent ability of the host to generate MIF, basal circulating MIF and peripheral blood mononuclear cell (PBMC) MIF transcript levels were determined in healthy children with a history of either mild or severe malaria. Children with prior mild malaria had higher plasma MIF levels and PBMC MIF transcripts than children with an identical number of previous episodes of severe malaria. These results suggest that increased basal MIF production may be important in generating immune responses that protect against the development of severe malaria.