Does apolipoprotein E polymorphism influence susceptibility to malaria?

Outcome of infection varies greatly among people, and in the case of three very different viruses, it is determined by apolipoprotein E (APOE) genotype. APOE might affect outcome of malaria infection also, since apoE protein and the protozoon (like the viruses) share cell entry mediators (heparan sulphate proteoglycans and/or specific apoE receptors). APOE polymorphisms give rise to protein variants that differ in binding strength to these mediators; thus, the extent of competition between apoE and protozoon for cell entry, and hence magnitude of protozoan damage, might depend on apoE isoform. Genotypes of infants infected with malaria were examined. It was found that APOE epsilon 2 homozygotes became infected at an earlier age than those carrying the other genotypes, the difference being statistically significant. Parasite densities, all of which were low, did not differ significantly. This effect, although based on small numbers, suggests that APOE epsilon 2 may be a risk factor for early infection.     

Innate immunity to malaria—The role of monocytes

Monocytes are innate immune cells essential for host protection against malaria. Upon activation, monocytes function to help reduce parasite burden through phagocytosis, cytokine production, and antigen presentation. However, monocytes have also been implicated in the pathogenesis of severe disease through production of damaging inflammatory cytokines, resulting in systemic inflammation and vascular dysfunction. Understanding the molecular pathways influencing the balance between protection and pathology is critical. In this review, we discuss recent data regarding the role of monocytes in human malaria, including studies of innate sensing of the parasite, immunometabolism, and innate immune training. Knowledge gained from these studies may guide rational development of novel antimalarial therapies and inform vaccine development.     

Sixty years trying to define the malaria burden in Africa: have we made any progress?

Controversy surrounds the precise numbers of malaria deaths and clinical episodes in Africa. This would not have surprised malariologists working in Africa 60 years ago as they began to unravel the enigma that is ‘malaria’. Malaria is a complex disease manifesting as a multitude of symptoms, degrees of severity and indirect morbid consequences. Clinical immunity develops quickly and the presence of infection cannot always be used to distinguish between malaria and other illnesses. During the 1950s and 1960s parasite prevalence was used in preference to statistics on malaria mortality and morbidity. An argument is made for a resurrection of this measure of the quantity of malaria across Africa as a more reliable means to understand the impact of control.     

Production of IFN-γ by CD4(+) T cells in response to malaria antigens is IL-2 dependent

T-cell immune responses are critical for protection of the host and for disease pathogenesis during infection with Plasmodium species. We examined the regulation of CD4(+) T-cell cytokine responses during infection with Plasmodium berghei ANKA (PbA). CD4(+) T cells from PbA-infected mice produced IFN-γ, IL-4 and IL-10 in response to TCR stimulation at levels higher than those from uninfected mice. This altered cytokine response was dependent on parasitemia. To examine the specificity of the response, mice were adoptively transferred with CD4(+) T cells from OT-II TCR transgenic mice and were infected with PbA expressing OVA. Unexpectedly, CD4(+) T cells from the OT-II-transferred wild-type PbA-infected mice showed high levels of IFN-γ production after stimulation with OVA and the cells producing IFN-γ were not OT-II but were host CD4(+) T cells. Further investigation revealed that host CD4(+) T cells produced IFN-γ in response to IL-2 produced by activated OT-II cells. This IFN-γ response was completely inhibited by anti-CD25 mAbs, and this effect was not due to the block of the survival signals provided by IL-2. Furthermore, IFN-γ production by CD4(+) T cells in response to PbA antigens was dependent on IL-2. These findings suggest the importance of IL-2 levels during infection with malaria parasites and indicate that CD4(+) T cells can produce IFN-γ without TCR engagement via a bystander mechanism in response to IL-2 produced by other activated CD4(+) T cells.     

Is vector body size the key to reduced malaria transmission in the irrigated region of Niono, Mali?

Malaria vectors can reach very high densities in villages near irrigated rice fields in Africa, leading to the expectation that malaria should be especially prevalent there. Surprisingly, this is not always the case. In Niono, Mali, villages from nonirrigated areas have higher malaria prevalence than those within the irrigated regions, which suffer from higher mosquito numbers. One hypothesis explaining this observation is that mosquitoes from irrigated fields with high densities are inefficient vectors. This could occur if higher larval densities lead to smaller mosquitoes that suffer elevated mortality. Three predictions of the hypothesis were studied. First, the effect of larval density on larval body size was measured for both Anopheles gambiae Giles and Anopheles funestus Giles. Second, the relationship between larval and adult body size was tested. Third, evidence of an effect of adult size on survivorship in both irrigated and nonirrigated villages during the wet and dry seasons was sought. There was a modest positive relationship between densities of immatures and larval size, and a strong relationship between larval and adult size. Furthermore, adult survivorship was higher in nonirrigated areas. However, there was no effect of size on survivorship between comparable samples from both the irrigated and nonirrigated zones. Although density may have a causal relationship with reduced transmission in the irrigated areas of Niono, it is unlikely to be because higher density leads to smaller body size and lower survivorship.     

IgG isotype to C-terminal 19 kDa of Plasmodium vivax merozoite surface protein 1 among subjects with different levels of exposure to malaria in Brazil

Subclasses of antibodies to the C-terminal 19 kDa fragment of the Plasmodium vivax merozoite surface protein 1 (PvMSP-1₁₉) were assessed among subjects with distinct degrees of malaria exposure in the Brazilian endemic area. The PvMSP-1₁₉ specific IgG1and IgG3 levels were low among subjects with long-term exposure (~19 years) when compared to subjects less and sporadically exposed (<1 year). No statistically difference was observed in IgG subclass distribution of antibodies from symptomatic Plasmodium-infected patients, asymptomatic parasite carriers and non-infected subjects living in a same mesoendemic area. Subjects briefly exposed to a P. vivax outbreak living in a rural community outside the endemic area were also evaluated to measure the persistence of specific antibodies. IgG anti-PvMSP-1₁₉ antibodies persisted in 40% of the subjects who had had malarial symptoms 8 months before and decreased after 7 years (28%). Specific IgG1 were the predominant isotype. Our study emphasizes the highly immunogenicity of the PvMSP-1₁₉ and points toward its possible use as a potential malaria vaccine.     

Blood coagulation in falciparum malaria—a review

Falciparum malaria infection influences blood coagulation by various interacting pathobiological mechanisms, the most important being the overwhelming response of the host to sepsis resulting in a cytokine storm. In addition, the parasite infects the red cells leading to changes in the red cell phospholipid composition which supports blood coagulation. Red cells infected with Plasmodium falciparum also adhere to deeper tissue capillary endothelium leading to profound damage to endothelial cells leading to further activation. This results in widespread consumption of platelets and activation of blood coagulation which at times culminates in a clinically and pathologically detectable disseminated intravascular coagulation (DIC). Monocyte–macrophage system also gets activated in this infection compounding the hypercoagulable state. Heavy parasitaemia leading to occlusion of hepatic microcirculation leads to abnormalities in synthesis and secretion of coagulation factors and their inhibitors. Drugs used in the treatment for falciparum malaria can cause thrombocytopaenia, bone marrow suppression and haemolytic anaemia, all of which can interfere indirectly with blood coagulation. Microparticle formation from platelets, red cells and macrophages also causes widespread activation of blood coagulation, and this recently observed mechanism is the focus of intense research in many other inflammatory and neoplastic conditions where there is activation of blood coagulation system. Thus, in severe falciparum malaria, there is activation of blood coagulation system along with thrombocytopaenia, even before widespread DIC and coagulation failure occur.     

FcγRIIa polymorphism and anti-malaria-specific IgG and IgG subclass responses in populations differing in susceptibility to malaria in Burkina Faso

FcγRIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in FcγRIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of FcγRIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20 years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of FcγRIIa R131H polymorphism was found. Individuals with the R allele of FcγRIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. FcγRIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the FcγRIIa R allele compared to the H allele.     

α-Tocopheryl succinate-suppressed development of cerebral malaria in mice

Parasitology Research - α-Tocopheryl succinate (α-TOS), a derivative of vitamin E, is synthesized by esterification of α-tocopherol. It has been reported that α-TOS inhibits the...     

Genetic diversity and deletion of Plasmodium falciparum histidine-rich protein 2 and 3: a threat to diagnosis of P. falciparum malaria

BackgroundPfHRP2-based rapid diagnostic tests (RDTs), based on the recognition of the Plasmodium falciparum histidine-rich protein 2, are currently the most used tests in malaria detection. Most of the antibodies used in RDTs also detect PfHRP3. However, false-negative results were reported. Significant variation in the pfhrp2 gene could lead to the expression of a modified protein that would no longer be recognized by the antibodies used in PfHRP2-based RDTs. Additionally, parasites lacking the PfHRP2 do not express the protein and are, therefore, not identifiable.AimsThis review aims to assess the pfhrp2 and pfhrp3 genetic variation or the prevalence of gene deletion in areas where malaria is endemic and describe its implications on RDT use.SourcesPublications of interest were identified using PubMed, Google Scholar and Google.ContentMore than 18 types of amino acid repeats were identified from the PfHRP2 sequences. Sequencing analysis revealed high-level genetic variation in the pfhrp2 and pfhrp3 genes (>90% of variation in Madagascar, Nigeria or Senegal) both within and between countries. However, genetic variation of PfHRP2 and PfHRP3 does not seem to be a major cause of false-negative results. The countries that showed the highest proportions of pfhrp2-negative parasites were Peru (20%–100%) and Guyana (41%) in South America, Ghana (36%) and Rwanda (23%) in Africa. High prevalence of pfhrp2 deletion causes a high rate of false-negatives results.ImplicationsPresence of parasites lacking the pfhrp2 gene may pose a major threat to malaria control programmes because P. falciparum-infected individuals are not diagnosed and properly treated.     

Elevated basal hepcidin levels in the liver may inhibit the development of malaria infection: Another piece towards solving the malaria puzzle?

BACKGROUND: Inflammatory cytokines play a crucial role in the human immune response to infection by malaria. During the initial sporozoite infection of the liver the presence of Interleukin-6 (IL-6) can be determinant. IL-6 controls systemic iron homeostasis through hepcidin, which is produced mainly by hepatocytes. An elevated basal hepcidin level in the liver can be induced by chronic inflammatory disease. Hepcidin is also a peptide with antimicrobial properties. PRESENTATION OF THE HYPOTHESIS: We hypothesize that elevated basal hepcidin levels in the liver inhibit the development of malaria infection. When hepcidin is abundant, hepatocytes sequester iron, and this inhibits sporozoite development in liver-stage malaria infection. TESTING THE HYPOTHESIS: The validity of our hypothesis can be proven by observing sporozoite growth in hepcidin-treated hepatocytes, or in hepatocytes, stimulated with IL-6 to increase hepcidin levels before incubation with malaria sporozoites and observing the effect the hepcidin knockout function has on the infection. IMPLICATIONS OF THE HYPOTHESIS: Confirmation of our hypothesis could help to understand the complexity of the malaria infection.     

HIV immunosupression and malaria: is there a correlation?

The human immunodeficiency virus (HIV) epidemic has resulted in an increase in the prevalence of many opportunistic infections and has caused re-emergence of certain diseases in the developing world. In tropical countries, immunosupression due to HIV infection has resulted in changes in the clinical presentation of endemic infections. Although the immune deficiency caused by HIV infection should presumably lead to an increased frequency of clinical malaria in areas with endemic malarial infection, like India, evidence of the association between HIV and malaria in India is scanty, with only a few studies showing a positive correlation. We hereby report a case of concurrent infection with Plasmodium falciparum malaria and human immunodeficiency virus type 1 (HIV-1) in a young male patient.     

Is ultrasound a useful adjunct for assessing malaria patients?

The value of ultrasonography as an adjunct for diagnosis and monitoring malaria was investigated. In all, 118 patients (male/female 65/53; age 2–78 years, median 29 years) with malaria underwent a standardised abdominal ultrasound examination at baseline. In 62 out of 118 patients, ultrasonography was repeated 21 days later. In the results at baseline, huge splenomegaly with firm organ consistency, consistent with hyperreactive malarious splenomegaly syndrome, was observed in two Cameroonese children. In the other 116 patients, the most common finding was non-specific splenomegaly (96/116, 82.76%), occurring more frequently in non-immune patients (71/78, 91.03%) than in patients who had grown up in malaria-endemic areas (25/38, 65.79%; P<0.002). No correlation was found between liver or spleen size and any clinical parameter. The results on day 21 show that, although splenomegaly after therapy persisted more frequently in patients with malaria recrudescence or relapse (8/8, 100%) than in patients cured (32/54, 59.26%; P<0.0421), the practical value of this finding is questionable. Ultrasonography cannot be regarded as a first-line diagnostic method in patients with malaria.     

Genomic, molecular biology and malaria: new medical perspectives?

The knowledge of genomic structure of man, of Plasmodium falciparum and of its main vector Anopheles gambiae has led to great progress in the understanding of malaria pathophysiology. It may also offer new perspectives for malaria therapy vaccines or control of mosquito-borne transmission. In pathophysiology, genes encoding adhesion plasmodial proteins of their receptors were identified, as well as other genes controlling the patient immune response or the antigenic parasite variability. From a therapeutic point of view, new targets for future antimalarial drugs were identified, mainly in apicoplast (a vestige of vegetal structure incorporated by the parasite during its phylogenic evolution) and several enzymes, particularly proteases. It will be now necessary among these "promising new molecules" to select a few ones (probably no more than 5 or 6) for a pre clinical and clinical pharmaceutical development. Indeed, the industrial possibilities for developing new antimalarial drugs are evidently limited and several other antimalarial drugs are already under development. For future malaria vaccines, several new targets and antigenic proteins were also identified. As for new drugs, a complete evaluation of these antigens is absolutely necessary to select few of them for clinical development. Particularly for malaria, ADN vaccines may offer very promising perspectives with the possibility to obtain both humoral and cellular immunity and to use at the same time a panel of plasmodial antigens. It could be thus possible to obtain a simultaneous immunization against different stages of Plasmodium falciparum (sporozoites, merozoites, gametocytes) and to use, as an adjuvant, a gene encoding a viral protein or a cytokine (GMCSF). In Anopheles gambiae genome, several genes encoding for key-proteins, particularly odorant receptors necessary for blood meals, were identified. Non biting-non transmitting mosquitoes were obtained by genetic manipulation and, from an academic viewpoint, offer a very attractive new perspective for the interruption of malaria transmission. Unfortunately several practical problems remain unsolved and genetically modified mosquitoes do not survive long enough among "wild" strains. On the whole genomic and proteomic gave very exciting scientific results in malaria and, very probably the post-genomic phase will even give more new data. From a practical, medical viewpoint, it is still too early and speculative to imagine their possible applications for malaria control.