Sticking for a Cause: The Falciparum Malaria Parasites Cytoadherence Paradigm

Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.

Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta, and that dissect the relation between timing of infection and outcome, could allow improved targeting of preventive treatments and development of a vaccine for use in pregnant women.

Polymeric microspheres are extensively researched for applications in drug and vaccine delivery. However, upon administration into the body, microspheres are primarily cleared via phagocytosis by macrophages. Although numerous studies have reported on the biochemical pathways of phagocytosis, relatively little is known about the dependence of phagocytosis on particle size. Here, we investigate the previously unexplained dependence of phagocytosis on particle size. Rat alveolar macrophages and IgG-opsonized and non-opsonized polystyrene microspheres were used as model macrophages and drug delivery particles. Phagocytosis, attachment and internalization were measured by flow cytometry and time-lapse video microscopy. Particles possessing diameters of 2-3 microm exhibited maximal phagocytosis and attachment. Rate of internalization, however, was not affected significantly by particle size. Maximal attachment of 2-3 microm microspheres is hypothesized to originate from the characteristic features of membrane ruffles in macrophages. Elimination of ruffles via osmotic swelling nearly eliminated the peculiar size-dependence of phagocytosis. A simple mathematical model is presented to describe the dependence of phagocytosis on particle size. The dependence of phagocytosis on particle size originated primarily from the attachment step. These results reveal the importance of controlling drug delivery particle size distribution and selecting the size appropriate for avoiding or encouraging phagocytosis.