R01AI158536

Uncovering the Parasite and Host Determinants of Plasmodium vivax Hypnozoite Formation and Development Using Single Cell Sequencing and Human Liver-Chimeric Mice

The human malaria-causing parasite Plasmodium vivax is geographically the most widespread of all the Plasmodium species. P. vivax is a major cause of morbidity in endemic regions of Asia, Oceania, Central and South America, as well as the Horn of Africa. In these regions, P. vivax infections in pregnant women significantly contribute to early pregnancy loss, reduced birth weight, and infant mortality.

Notably, P. vivax is a major concern in the arena of malaria eradication due to its unique biology. Specifically, P. vivax sporozoite infectivity of hepatocytes does not always lead to the onset of schizogony and transition to blood stage disease, as is the case for P. falciparum. Rather, a sporozoite can enter a host hepatocyte, dedifferentiate, and then lie dormant within the host hepatocyte for weeks, months, or even years before reactivating. This dormant or latent liver stage form is known as the hypnozoite, and in continued efforts towards malaria elimination and eradication, the hypnozoite is a formidable foe.

Indeed, the endemicity of P. vivax throughout tropical as well as temperate climate zones is attributed to the parasite's ability to form hypnozoites, which, after reactivating, cause relapses of blood stage infection and concomitant transmission. Antimalarial drugs almost exclusively target the symptomatic blood stage of the life cycle and do not target the hypnozoite. Thus, treatment of P. vivax blood stage infections with standard drug regimens allows for further relapses and will not aid in disease eradication.

Historically, the only approved drug active against P. vivax hypnozoites was primaquine, although an improved 8-aminoquinoline drug, tafenoquine, has recently received approval for the treatment of relapsing malaria. Unfortunately, primaquine's short half-life, long dosage regimen, and incompatibility with glucose-6-phosphate dehydrogenase deficiency prevent its use for mass elimination campaigns. Thus, there is a need for novel interventions that will negatively affect hypnozoite formation, survival, and relapse.

Therefore, the research in this proposal aims to shed biological insight on the hypnozoite. This application aims to address three critical biological questions pertaining to P. vivax hypnozoite biology, and answering these questions should aid in the discovery of novel interventions to prevent hypnozoite relapse and the continued spread of P. vivax disease. Specifically, are there intrinsic factors that are pre-programmed in the P. vivax sporozoite that determine its fate once it reaches the liver to become either a replicating schizont or a dormant hypnozoite? How does the dormant hypnozoite manipulate its host cell in order to maintain its long-term residency? Can we develop a model of hypnozoite relapse in order to gain insight into the triggers that promote hypnozoite reactivation?

Using a human-liver chimeric mouse model alongside innovative methods of single cell isolation and transcriptional profiling, we hope to begin to address these challenges.

Seattle Children's Hospital

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Seattle, Washington 981095235 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 259% from $946,707 to $3,399,010.