Cytoadherence and the resulting sequestration of infected red blood cells are a hallmark of P. falciparum malaria. Previous studies have emphasized the major contribution of the knob complex and particularly the major parasite antigen, PfEMP1, in mediating cytoadherence during the last 20 hours of asexual development of P. falciparum parasites. Mature sexual stages of P. falciparum only appear in the peripheral blood after 8-10 days of development, and sequestration of immature sexual stages in anatomical niches must be absolutely crucial for successful transmission of these parasites to the mosquito vector. Where is that anatomical niche, and what is the molecular basis for cytoadherence in sexual stages? The experimental approaches outlined in this application aim to distinguish the three possible mechanisms by which developing sexual stages induce cytoadherence, and to identify the corresponding sequestration profiles in patient tissues: i) Developing sexual stages cytoadhere through the same determinants as asexual stages, i.e., the same PfEMP1 is expressed on the infected red blood cell surface. This would result in largely overlapping sequestration profiles for asexual and sexual stages. ii) They cytoadhere through the same mechanisms asexual stages, but using a different determinant, i.e., a PfEMP1 specific to sexual development. This situation would likely result in gametocyte-specific site of sequestration, similar to placental sequestration of parasites expressing a conserved PfEMP1 variant. iii) They cytoadhere through a different mechanism altogether, i.e., a molecule (or class of molecules) other than PfEMP1. In this case, the sequestration profile would also be different from that of asexual stages. Sexual P. falciparum stages are a major target for both drug- and vaccine-based strategies to block transmission of the parasite in endemic areas. In the context of widespread resistance against the currently used drug formulations that almost exclusively target asexual development within the red blood cell, transmission-blocking strategies have gained renewed interest and are now a major focus of worldwide efforts to reduce the burden of malaria. The proposed experiments are in line with these efforts as they aim to elucidate a mechanism crucial for the survival and development of malaria transmission stages in the human host.

Public Health Relevance

Strategies aiming at blocking the transmission of malaria parasites play a central role in the current efforts to eradicate malaria worldwide. It is therefore crucial to understand the key properties of transmission stages in the human host and the mosquito vector. One of these properties is the sequestration of developing sexual stages in deep tissues, before they eventually emerge in the blood circulation as mosquito-infective mature gametocytes. Here we propose a comprehensive analysis of the mechanisms of cytoadherence and sites of sequestration of developing transmission stages in the human host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077558-03
Application #
8286320
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rao, Malla R
Project Start
2010-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$404,663
Indirect Cost
$157,163
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Mantel, Pierre-Yves; Marti, Matthias (2014) The role of extracellular vesicles in Plasmodium and other protozoan parasites. Cell Microbiol 16:344-54
Joice, Regina; Nilsson, Sandra K; Montgomery, Jacqui et al. (2014) Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci Transl Med 6:244re5
Marti, Matthias; Spielmann, Tobias (2013) Protein export in malaria parasites: many membranes to cross. Curr Opin Microbiol 16:445-51