RESUMO
Mechanisms for differential regulation of gene expression may underlie much of the phenotypic variation and adaptability of malaria parasites. Here we describe transcriptional variation among culture-adapted field isolates of Plasmodium falciparum, the species responsible for most malarial disease. It was found that genes coding for parasite protein export into the red cell cytosol and onto its surface, and genes coding for sexual stage proteins involved in parasite transmission are up-regulated in field isolates compared with long-term laboratory isolates. Much of this variability was associated with the loss of small or large chromosomal segments, or other forms of gene copy number variation that are prevalent in the P. falciparum genome (copy number variants, CNVs). Expression levels of genes inside these segments were correlated to that of genes outside and adjacent to the segment boundaries, and this association declined with distance from the CNV boundary. This observation could not be explained by copy number variation in these adjacent genes. This suggests a local-acting regulatory role for CNVs in transcription of neighboring genes and helps explain the chromosomal clustering that we observed here. Transcriptional co-regulation of physical clusters of adaptive genes may provide a way for the parasite to readily adapt to its highly heterogeneous and strongly selective environment.
Assuntos
Regulação da Expressão Gênica , Genes de Protozoários , Plasmodium falciparum/genética , Análise de Sequência com Séries de Oligonucleotídeos , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of immune targets, encoded by an extremely diverse gene family called var. Understanding of the genetic organization of var genes is hampered by sequence mosaicism that results from a long history of non-homologous recombination. Here we have used software designed to analyse social networks to visualize the relationships between large collections of short var sequences tags sampled from clinical parasite isolates. In this approach, two sequences are connected if they share one or more highly polymorphic sequence blocks. The results show that the majority of analysed sequences including several var-like sequences from the chimpanzee parasite Plasmodium reichenowi can be either directly or indirectly linked together in a single unbroken network. However, the network is highly structured and contains putative subgroups of recombining sequences. The major subgroup contains the previously described group A var genes, previously proposed to be genetically distinct. Another subgroup contains sequences found to be associated with rosetting, a parasite virulence phenotype. The mosaic structure of the sequences and their division into subgroups may reflect the conflicting problems of maximizing antigenic diversity and minimizing epitope sharing between variants while maintaining their host cell binding functions.
Assuntos
Variação Antigênica , Antígenos de Protozoários/genética , Plasmodium falciparum/genética , Plasmodium falciparum/imunologia , Polimorfismo Genético , Proteínas de Protozoários/genética , Recombinação Genética , Sequência de Aminoácidos , Animais , Antígenos de Protozoários/química , Criança , Sequência Conservada , Humanos , Malária Falciparum/parasitologia , Plasmodium falciparum/química , Plasmodium falciparum/classificação , Proteínas de Protozoários/química , Alinhamento de SequênciaRESUMO
BACKGROUND: Antibodies targeting variant antigens expressed on the surface of Plasmodium falciparum infected erythrocytes have been associated with protection from clinical malaria. The precise target for these antibodies is unknown. The best characterized and most likely target is the erythrocyte surface-expressed variant protein family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). METHODS: Using recombinant proteins corresponding to five domains of the expressed A4 var gene, A4 PfEMP1, the naturally occurring antibody response was assessed, by ELISA, to each domain in serum samples obtained from individuals resident in two communities of differing malaria transmission intensity on the Kenyan coast. Using flow cytometry, the correlation in individual responses to each domain with responses to intact A4-infected erythrocytes expressing A4 PfEMP1 on their surface as well as responses to two alternative parasite clones and one clinical isolate was assessed. RESULTS: Marked variability in the prevalence of responses between each domain and between each transmission area was observed, as wasa strong correlation between age and reactivity with some but not all domains. Individual responses to each domain varied strikingly, with some individuals showing reactivity to all domains and others with no reactivity to any, this was apparent at all age groups. Evidence for possible cross-reactivity in responses to the domain DBL4gamma was found. CONCLUSION: Individuals acquire antibodies to surface expressed domains of a highly variant protein. The finding of potential cross-reactivity in responses to one of these domains is an important initial finding in the consideration of potential vaccine targets.
Assuntos
Anticorpos Antiprotozoários/sangue , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Eritrócitos/imunologia , Eritrócitos/parasitologia , Citometria de Fluxo , Geografia , Humanos , Lactente , Quênia , Pessoa de Meia-Idade , Proteínas Recombinantes/genéticaRESUMO
Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control.
Assuntos
Regulação da Expressão Gênica , Interações Hospedeiro-Parasita , Malária Falciparum/transmissão , Plasmodium falciparum/fisiologia , Adaptação Fisiológica , Perfilação da Expressão Gênica , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.
Assuntos
Anemia/prevenção & controle , Malária Falciparum/epidemiologia , Malária Falciparum/genética , Talassemia alfa/genética , Anemia/etiologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Quênia/epidemiologia , Malária Falciparum/complicações , Malária Falciparum/prevenção & controle , Masculino , Prevalência , Fatores de Risco , Seleção Genética , Índice de Gravidade de DoençaRESUMO
Malaria vaccines based on thrombospondin-related adhesive protein of Plasmodium falciparum (Pf TRAP) are currently undergoing clinical trials in humans. This study was designed to investigate naturally acquired cellular immunity to Pf TRAP in adults from a target population for future trials of TRAP-based vaccines in Kilifi, Kenya. We first tested reactivity to a panel of 53 peptides spanning Pf TRAP and identified 26 novel T-cell epitopes. A panel of naturally occurring polymorphic variant epitope peptides were made to the most commonly recognized epitope regions and tested for ability to elicit IFN-gamma, IL-4, and IL-10 production. These data provide for the first time a complex cytokine matrix mapping naturally induced T-cell responses to TRAP and suggest that T-cell responses boosted by vaccination with Pf TRAP could stimulate the release of competing pro- and anti-inflammatory cytokines. They further define polymorphic variants able to boost specific Th1, Th2, and possibly Tr1 reactivity.
Assuntos
Citocinas/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adulto , Sequência de Aminoácidos , Animais , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Antígenos HLA-DR/imunologia , Humanos , Imunidade Celular/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Quênia , Malária Falciparum/prevenção & controle , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
An intercellular adhesion molecule-1 polymorphism (ICAM-1(Kilifi)) is present at a high frequency across sub-Saharan Africa, and its presence may increase susceptibility to cerebral malaria. Here, we report that, compared with children in whom wild-type intercellular adhesion molecule-1 is present, the incidence of nonmalarial fever is significantly lower among those homozygous for ICAM-1(Kilifi). We propose that ICAM-1(Kilifi) may be associated with reduced rates of tissue damage and of death due to sepsis.
Assuntos
Febre/genética , Infecções/genética , Molécula 1 de Adesão Intercelular/genética , Polimorfismo Genético , Febre/epidemiologia , Humanos , Incidência , Lactente , Infecções/epidemiologia , Quênia/epidemiologia , Malária/epidemiologia , Malária/genéticaRESUMO
BACKGROUND: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. METHODS AND FINDINGS: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. CONCLUSIONS: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes.
Assuntos
Malária/genética , Malária/imunologia , Traço Falciforme , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hemoglobina Falciforme/genética , Humanos , Imunidade Inata , Lactente , Recém-Nascido , Quênia , MasculinoRESUMO
Thrombospondin-related adhesive protein (TRAP) of Plasmodium falciparum is currently being tested in human vaccine studies. However, its natural reactivity in the field remains poorly characterized. More than 40% of 217 Kenyan donors responded in an ex vivo interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay to at least one of 14 20mer peptides spanning 42% of the antigen. Reactivity was comparable from early childhood (>1 year of age) to old age, and the maximal precursor frequency of TRAP-specific cells to all 14 peptides was 1 in 4,000. Prospective follow-up for one year indicated that these low-level ex vivo responses to TRAP did not protect against the subsequent development of malaria. Retesting of selected donors after one year showed a complete change in the reactivity pattern, suggesting that malaria-specific ex vivo IFN-gamma ELISPOT assay responses are short lived in naturally exposed donors, even to conserved epitopes. This study provides important information regarding natural reactivity to a key malaria antigen.
Assuntos
Interferon gama/biossíntese , Vacinas Antimaláricas/normas , Malária Falciparum/prevenção & controle , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunidade Celular , Lactente , Interferon gama/química , Quênia/epidemiologia , Leucócitos Mononucleares/imunologia , Longevidade , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Projetos Piloto , Proteínas de Protozoários/química , Fatores de Risco , Linfócitos T/imunologiaRESUMO
Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Sequência de Bases , DNA de Protozoário/genética , Genoma de Protozoário/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Quênia , Malária Falciparum/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
BACKGROUND: The reservoir of Plasmodium infection in humans has traditionally been defined by blood slide positivity. This study was designed to characterize the local reservoir of infection in relation to the diverse var genes that encode the major surface antigen of Plasmodium falciparum blood stages and underlie the parasite's ability to establish chronic infection and transmit from human to mosquito. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the molecular epidemiology of the var multigene family at local sites in Gabon, Senegal and Kenya which differ in parasite prevalence and transmission intensity. 1839 distinct var gene types were defined by sequencing DBLα domains in the three sites. Only 76 (4.1%) var types were found in more than one population indicating spatial heterogeneity in var types across the African continent. The majority of var types appeared only once in the population sample. Non-parametric statistical estimators predict in each population at minimum five to seven thousand distinct var types. Similar diversity of var types was seen in sites with different parasite prevalences. CONCLUSIONS/SIGNIFICANCE: Var population genomics provides new insights into the epidemiology of P. falciparum in Africa where malaria has never been conquered. In particular, we have described the extensive reservoir of infection in local African sites and discovered a unique var population structure that can facilitate superinfection through minimal overlap in var repertoires among parasite genomes. Our findings show that var typing as a molecular surveillance system defines the extent of genetic complexity in the reservoir of infection to complement measures of malaria prevalence. The observed small scale spatial diversity of var genes suggests that var genetics could greatly inform current malaria mapping approaches and predict complex malaria population dynamics due to the import of var types to areas where no widespread pre-existing immunity in the population exists.
Assuntos
Variação Genética/genética , Malária Falciparum/epidemiologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , África/epidemiologia , Criança , Pré-Escolar , Frequência do Gene/genética , Genoma de Protozoário/genética , Geografia , Humanos , Lactente , Malária Falciparum/transmissão , Repetições de Microssatélites/genética , Epidemiologia Molecular , Plasmodium falciparum/patogenicidadeRESUMO
BACKGROUND: The gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait [HbAS]) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete. METHODS: We studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya. RESULTS: The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes. CONCLUSIONS: The present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases.
Assuntos
Malária Falciparum/epidemiologia , Traço Falciforme , Pré-Escolar , Estudos de Coortes , Humanos , Quênia/epidemiologia , Razão de Chances , Prevalência , Fatores de RiscoRESUMO
The variant surface antigens expressed on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria and are encoded, at least in part, by a family of var genes, about 60 of which are present within every parasite genome. Here we use semi-conserved regions within short var gene sequence "tags" to make direct comparisons of var gene expression in 12 clinical parasite isolates from Kenyan children. A total of 1,746 var clones were sequenced from genomic and cDNA and assigned to one of six sequence groups using specific sequence features. The results show the following. (1) The relative numbers of genomic clones falling in each of the sequence groups was similar between parasite isolates and corresponded well with the numbers of genes found in the genome of a single, fully sequenced parasite isolate. In contrast, the relative numbers of cDNA clones falling in each group varied considerably between isolates. (2) Expression of sequences belonging to a relatively conserved group was negatively associated with the repertoire of variant surface antigen antibodies carried by the infected child at the time of disease, whereas expression of sequences belonging to another group was associated with the parasite "rosetting" phenotype, a well established virulence determinant. Our results suggest that information on the state of the host-parasite relationship in vivo can be provided by measurements of the differential expression of different var groups, and need only be defined by short stretches of sequence data.
Assuntos
Antígenos de Superfície/genética , Eritrócitos/parasitologia , Regulação da Expressão Gênica , Genes de Protozoários , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Sequência de Aminoácidos , Animais , Variação Antigênica , Antígenos de Superfície/imunologia , Criança , Eritrócitos/imunologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Humanos , Malária Falciparum/imunologia , Dados de Sequência Molecular , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/imunologiaRESUMO
To gain insight into why antibody responses to malarial antigens tend to be short lived, we studied antigen-specific memory B cells from donors in an area where malaria is endemic. We compared antibody and memory B cell responses to tetanus toxoid with those to 3 Plasmodium falciparum candidate vaccine antigens: the C-terminal portion of merozoite surface protein 1 (MSP1(19)), apical membrane antigen 1 (AMA1), and the cysteine-rich interdomain region 1 alpha (CIDR1 alpha ) of a protein from the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. These data are the first to be generated on memory B cells in children who are in the process of acquiring antimalarial immunity, and they reveal defects in B cell memory to P. falciparum antigens. Compared with the results for tetanus toxoid, more donors who were positive for antibody to AMA1 and CIDR1 alpha were negative for memory B cells. These data imply that some exposures to malaria do not result in the establishment of stable populations of circulating antigen-specific memory B cells, suggesting possible mechanisms for the short-lived nature of many anti-malarial antibody responses.
Assuntos
Antígenos de Protozoários/imunologia , Linfócitos B/imunologia , Memória Imunológica , Malária Falciparum/imunologia , Plasmodium falciparum/fisiologia , Adulto , Fatores Etários , Animais , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Humanos , Lactente , Proteínas de Membrana/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Subunidades Proteicas/imunologia , Proteínas de Protozoários/imunologiaRESUMO
Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.
Assuntos
Expressão Gênica , Malária/sangue , Criança , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Humanos , Lactente , Quênia , Contagem de Leucócitos , Malária/imunologia , Masculino , Neutrófilos/metabolismo , Parasitemia , FenótipoRESUMO
Antibodies to the highly diverse variant surface antigens (VSAs) expressed on Plasmodium falciparum-infected erythrocytes are thought to play a role in the development of naturally acquired immunity to malaria. It has been suggested that children gradually acquire immunity through the piecemeal acquisition of antibodies to a large number of VSAs over several years of exposure. However, in a cross-sectional survey of Kenyan children before the malaria-transmission season, the proportion of children with antibodies recognizing randomly sampled VSAs was found to be strikingly higher among children with microscopically detectable P. falciparum infection, compared with those without detectable infection. We suggest that parasitization status may be an important consideration in longitudinal assessments of the protective role of some anti-parasite immune responses and support this suggestion with data from a prospective study of VSA antibodies in a group of children who subsequently had severe malaria.
Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Antígenos de Superfície/imunologia , Eritrócitos/parasitologia , Plasmodium falciparum/imunologia , Testes de Aglutinação , Animais , Estudos de Casos e Controles , Pré-Escolar , Estudos Transversais , Humanos , Lactente , Recém-Nascido , Quênia/epidemiologia , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Parasitemia/epidemiologia , Parasitemia/imunologia , Parasitemia/parasitologiaRESUMO
Both iron deficiency and malaria are common in much of sub-Saharan Africa, and the interaction between these conditions is complex. To investigate the association between nutritional iron status, immunoglobulins, and clinical Plasmodium falciparum malaria, we determined the incidence of malaria in a cohort of children between the ages of 8 months and 8 years who were living on the Kenyan coast. Biochemical iron status and malaria-specific immune responses were determined during 2 cross-sectional surveys. We found that the incidence of clinical malaria was significantly lower among iron-deficient children (incidence-rate ratio [IRR], 0.70; 95% confidence interval [CI], 0.51-0.99; P<.05), that the incidence of malaria was significantly associated with plasma ferritin concentration (IRR for log ferritin concentration, 1.48; 95% CI, 1.01-2.17; P<.05), and that iron status was strongly associated with a range of malaria-specific immunoglobulins. We conclude that iron deficiency was associated with protection from mild clinical malaria in our cohort of children in coastal Kenya and discuss possible mechanisms for this protection.