What We Study

Defining clinical and sterile immunity to P. falciparum infection using systems biology approaches

Funding organization: National Institute of Allergy and Infectious Diseases (K08)

Each year malaria afflicts ~200 million people and causes over 430,000 deaths, primarily among African infants. Although a first-generation malaria vaccine is now available, it is only modestly effective in the target population of African infants; thus, a better understanding of natural immunity to Plasmodium falciparum, the deadliest of malaria parasites, in young African children can inform efforts to develop the next generation of malaria vaccines. Using samples collected from young Malian children before and during natural P. falciparum infections, this study aims to identify predictors and mechanisms of malaria immunity that aid the development of future malaria vaccines.

Evaluating the role of P53 pathways in malaria

Funding organization: National Institute of Allergy and Infectious Diseases

Understanding the mechanisms contributing to pathological inflammation during malaria and the processes that govern the control of malaria parasites within the host can provide insight for the development of adjunctive therapies against this deadly infection. Using human samples and relevant model systems, we will investigate the interactions between multiple stages of the Plasmodium parasite and p53 pathways within relevant host tissues and how such interactions impact malaria pathogenesis and infection biology. Results from this study will provide mechanistic insight into the role of p53 in modulating malaria-induced pathogenesis and liver-stage infection, which may identify druggable targets for interventions aimed at mitigating malaria disease severity and/or liver-stage prophylaxis.

Investigating gene regulatory networks in immune cells of children who differ in susceptibility to malaria infection using single-cell approaches

Funding organization: National Institute of Allergy and Infectious Diseases

The complexity of the interactions between the human immune system and Plasmodium falciparum, the parasite responsible for the overwhelming majority of the ~400,000 annual malaria deaths, has impeded the development of a highly effective malaria vaccine. We propose using single-cell sequencing approaches to identify cell types and gene regulatory networks that may be important in controlling the parasite using samples collected from Malian children who remained free of parasitemia despite evidence of natural malaria exposure. Results from this study may lead to the identification of immune correlates of malaria protection and a better understanding of why sustained protection from parasitemia through natural malaria exposure is rarely observed.

Validation and characterization of antibody responses to Plasmodium falciparum antigens identified by protein array screening

Funding organization: National Institute of Allergy and Infectious Diseases

A highly effective and durable malaria vaccine is widely viewed as a much-needed tool for sustainable reduction of malaria. We propose to evaluate two Plasmodium falciparum antigens as malaria vaccine candidates by determining whether naturally acquired IgG antibodies against conserved regions of these proteins can predict malaria protection in a longitudinal cohort study of Malian children and adults and exhibit anti-parasitic activity in vitro. Successful completion of this project will provide insight on the genetic diversity of these two antigens and provide evidence as to whether conserved regions within these antigens are the targets of naturally acquired protective immunity against malaria.

Systems analysis to understand protective immunity induced by an attenuated sporozoite malaria vaccine in African infants

Funding organization: Doris Duke Charitable Foundation

In this collaborative study, now published in *JCI Insight*, we performed a molecular and cellular “systems” analysis of blood samples obtained from Kenyan infants who were enrolled in a randomized, placebo controlled clinical trial of a radiation-attenuated, live sporozoite malaria vaccine called PfSPZ vaccine (the KSPZV1 trial). We found that inflammatory gene signatures and a combination of monocytes and anti-sporozoite antibodies at the pre-vaccination baseline were associated with lack of protection in infants who received the highest and most effective dose of the PfSPZ Vaccine and protection in infants who received placebo. The results also suggest that baseline inflammation may reduce the effectiveness of the PfSPZ Vaccine by limiting sporozoite-specific CD8+ T cell responses rather than affecting antibody responses.

Assessing the Impact of Treatment of Asymptomatic Malaria Infections on Inflammation and Cognition in Schoolchildren

Funding organization: National Institute of Allergy and Infectious Diseases

Asymptomatic malaria infections caused by the Plasmodium falciparum parasite, while not clinically apparent, have significant individual and public health consequences, including chronic anemia, susceptibility to bacterial infections, and maintenance of onward transmission by serving as parasite reservoirs. Such infections can also adversely impact cognitive performance in school-aged children, but the potential mechanisms by which this occurs has not been well-studied. This project will measure blood inflammatory biomarkers and cognitive performance in asymptomatic children naturally infected with P. falciparum before and after anti-malarial treatment to determine whether clearance of parasitemia leads to improvements in cognitive performance by reducing systemic inflammation.

Human antibodies offer broad inhibition against variable proteins of the malaria parasite.

Mature beyond their years: young children who escape detection of parasitemia despite living in settings of intense malaria transmission.

Subclinical Inflammation in Asymptomatic Schoolchildren With Plasmodium falciparum Parasitemia Correlates With Impaired Cognition.

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine.

Isotype switching in human memory B cells sets intrinsic antigen-affinity thresholds that dictate antigen-driven fates.

Plasmodium knowlesi in pig-tailed macaques: a potential new model for malaria vaccine research.

A psychometric evaluation of the NIH Toolbox fluid cognition tests adapted for Swahili and Dholuo languages in Kenyan children and adolescents.

Accumulation of neutrophil-phagocytic antibody features tracks with naturally acquired immunity against malaria in children.

Neither the African-centric S47 nor P72 variant of TP53 is associated with reduced risk of febrile malaria in a Malian cohort study.

Haemophilus ducreyi Infection Induces Oxidative Stress, Central Metabolic Changes, and a Mixed Pro- and Anti-inflammatory Environment in the Human Host.

Longitudinal IgG antibody responses to Plasmodium vivax blood-stage antigens during and after acute vivax malaria in individuals living in the Brazilian Amazon.

Evaluation of an ultrasensitive HRP2–based rapid diagnostic test for detection of asymptomatic Plasmodium falciparum parasitaemia among children in western Kenya.

Plasma amino acid concentrations in children with severe malaria are associated with mortality and worse long-term kidney and cognitive outcomes.

The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya.

Translation and Cultural Adaptation of NIH Toolbox Cognitive Tests into Swahili and Dholuo Languages for Use in Children in Western Kenya.

Experience counts in the malaria response.

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season.

Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection.

Decoding the complexities of human malaria through systems immunology.

A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation.

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host.

Whole-blood transcriptomic signatures induced during immunization by chloroquine prophylaxis and Plasmodium falciparum sporozoites.

Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria.

Whole-Blood Transcriptional Signatures Composed of Erythropoietic and NRF2-Regulated Genes Differ Between Cerebral Malaria and Severe Malarial Anemia.

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages.

Extent and Dynamics of Polymorphism in the Malaria Vaccine Candidate Plasmodium falciparum Reticulocyte-Binding Protein Homologue-5 in Kalifabougou, Mali.

Protein-Specific Features Associated with Variability in Human Antibody Responses to Plasmodium falciparum Malaria Antigens.

Synergistic malaria vaccine combinations identified by systematic antigen screening.

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities.

Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection.

Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria.