Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naïve infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naïve African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naïve children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.

We compared interleukin-12 (IL-12) and other cytokine activities during and after an acute clinical episode in a matched-pair case-control study of young African children who presented with either mild or severe Plasmodium falciparum malaria. The acute-phase, pretreatment plasma IL-12 and alpha interferon (IFN-␣) levels, as well as the acute-phase mitogen-stimulated whole-blood production capacity of IL-12, were significantly lower in children with severe rather than mild malaria. IL-12 levels, in addition, showed strong inverse correlations both with parasitemia and with the numbers of circulating malaria pigment-containing neutrophils. Acute-phase plasma tumor necrosis factor (TNF) and IL-10 levels were significantly higher in those with severe malaria, and the concentrations of both of these cytokines were positively correlated both with parasitemia and with the numbers of pigment-containing phagocytes in the blood. Children with severe anemia had the highest levels of TNF in plasma. In all the children, the levels in plasma and production capacities of all cytokines normalized when they were healthy and parasite free. The results indicate that severe but not mild P. falciparum malaria in young, nonimmune African children is characterized by down-regulated IL-12 activity, contrasting markedly with the up-regulation of both TNF and IL-10 in the same children. A combination of disturbed phagocyte functions resulting from hemozoin consumption, along with reduced IFN-␥ responses, may contribute to these differential effects.

Interleukin (IL)-12 and transforming growth factor (TGF)-beta1 regulate the balance between pro- and anti-inflammatory cytokines in animal models of malaria. Since the cytokine balance may be an important determinant of whether a protective or a pathogenic immune response develops, plasma cytokine ratios were examined in Gabonese children with various degrees of malarial severity. Severe disease was characterized by high-density parasitemia and severe anemia. IL-12 and TGF-beta1 were significantly lower, whereas tumor necrosis factor (TNF)-alpha and IL-10 were significantly higher in children with severe malaria. The ratios of TGF-beta1/IL-12 and IL-10/IL-12 were significantly higher in the severe, compared with the mild, malaria group. In contrast, ratios of TGF-beta1/TNF-alpha and IL-10/TNF-alpha were significantly lower in the severe malaria group. These results suggest that the inflammatory cascade in severe malaria is characterized by suppression of the protective effects of TGF-beta1 and IL-12, and that overproduction of TNF-alpha may promote deleterious effects, such as severe anemia.

Since the etiologies and clinical outcomes of bacteremia in children with Plasmodium falciparum infections, particularly in areas of holoendemic malaria transmission, are largely unexplored, blood cultures and comprehensive clinical, laboratory, hematological, and nutritional parameters for malaria-infected children (aged 1 to 36 months, n ‫؍‬ 585 patients) were investigated at a rural hospital in western Kenya. After the exclusion of contaminant microorganisms, the prevalence of bacteremia was 11.7% in the cohort (n ‫؍‬ 506), with nontyphoidal Salmonella spp. being the most common isolates (42.4%). Bacteremia was found to occur in a significantly higher proportion of females than males and was associated with elevated blood glucose concentrations and lowered malaria parasite and hemoglobin (Hb) levels compared to those in abacteremic participants. In addition, the incidences of respiratory distress and severe malarial anemia (SMA; Hb level of <6.0g/dl) were nonsignificantly greater in children with bacteremia. Mortality was 8.5-fold higher in children with bacteremia. Multivariate logistic regression analyses revealed that bacteremia was significantly associated with reduced incidences of high-density parasitemia (HDP; >10,000/l) and increased incidences of malnutrition (i.e., underweight; weight-for-age Z score of <؊2 using the NCHS system). Since previous studies showed that bacteremia caused by Gram-negative organisms is associated with enhanced anemia and mortality, multivariate logistic regression was also performed separately for randomly age-and gender-matched children with bacteremia caused by Gram-negative organisms (n ‫؍‬ 37) and for children found to be abacteremic (n ‫؍‬ 74). These results revealed that the presence of bacteremia caused by Gram-negative organisms was significantly associated with reduced HDP, enhanced susceptibility to respiratory distress, SMA (Hb level of <6.0 g/dl), and being underweight (Z score, <؊2). Data presented here from a region of holoendemic P. falciparum transmission demonstrate that although bacteremia is associated with reduced malaria parasitemia, a number of unfavorable clinical outcomes, including malnutrition, respiratory distress, anemia, and mortality, are elevated in children with bacteremia, particularly in cases of Gram-negative origin.

Results presented here demonstrate that both HIV-1 exposure and HIV-1 infection are associated with increased prevalence of SMA during acute P. falciparum infection, independent of parasite density.

The optimal outcome of a malaria infection is that parasitized cells are killed and degraded without inducing significant pathology. Since much of the pathology of malaria infection can be immune-mediated, this implies that immune responses have to be carefully regulated. The mechanisms by which anti-malarial immune responses are believed to be regulated were discussed at the recent Malaria Immunology Workshop (Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; February 2005). Potential regulatory mechanisms include regulatory T cells, which have been shown to significantly modify cellular immune responses to various protozoan infections, including leishmania and malaria; neutralising antibodies to pro-inflammatory malarial toxins such as glycosylphosphatidylinositol and haemozoin; and self-regulating networks of effector molecules. Innate and adaptive immune responses are further moderated by the broader immunological environment, which is influenced by both the genetic background of the host and by co-infection with other pathogens. A detailed understanding of the interplay between these different immunoregulatory processes may facilitate the rationale design of vaccines and novel therapeutics.

BackgroundThe quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now.MethodsWe investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing.FindingsBased on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys.InterpretationThis study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.

A point mutation in the promoter of the nitric oxide synthase 2 gene (NOS2), termed NOS2(Lambaréné) (NOS2-G954C), protects heterozygous carriers against severe malaria as effectively as the sickle cell trait. In a prospective longitudinal study, 841 individual infections of initially 200 children (151 wild-type vs. 49 NOS2(Lambaréné) carriers) were monitored for 4 years, to assess the rates of malarial attacks in the 2 groups; carriers of the NOS2(Lambaréné) polymorphism were significantly less likely to experience malarial attacks than were others (P=.002). The distribution of the NOS2(Lambaréné) polymorphism was investigated in malaria-endemic areas. It was found to be present with the highest frequency in Africa and at a lower frequency in Asia. Ex vivo studies showed that cells isolated from people with this polymorphism have a 7-fold higher baseline NOS activity, compared with the levels detected in cells from subjects with the wild-type gene (P=.003).