Antibodies to Plasmodium circumsporozoite protein (CSP) inhibit sporozoite's cell traversal activity.
Plasmodium sporozoites are deposited in the skin of the mammalian host by Anopheles mosquitoes. To continue the life cycle, the sporozoites have to invade the host's hepatocytes, where they transform into exoerythrocytic forms (EEFs) inside a parasitophorous vacuole. During their route from the skin to the liver, the parasites traverse the capillary epithelium in the dermis to enter the blood circulation, and cross the endothelium of liver sinusoids to enter the parenchyma. Cell traversal by sporozoites is usually measured by quantifying dyes that enter or are released from cells during incubation with salivary gland sporozoites. These methods do not distinguish cell traversal from cell wounding. Here we validate an assay that quantifies cell traversal of sporozoites through monolayers of MDCK cells that form tight junctions. We compared cell traversal of wt sporozoites and of parasites lacking the Type I membrane protein TLP (TRAP-like protein) previously implicated in cell traversal. We provide direct evidence that TLP ko sporozoites are defective in cell traversal and that they are retained inside the MDCK cytoplasm. We then used the MDCK assay to study the effect of a monoclonal antibody (3D11) to the circumsporozoite protein (CSP) on the parasite's cell traversal. We show that 3D11 inhibits cell traversal at nanomolar concentrations. We conclude that antibodies elicited by CSP-based vaccines are likely to inhibit the migration of sporozoites from the skin to the liver.
Michael Heidelberger Division of Immunology, Department of Pathology, New York University School of Medicine, NY 10016, USA. samishra@jhsph.edu
Satish
S
Mishra
Ruth S
RS
Nussenzweig
Victor
V
Nussenzweig
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000913:Antibodies, Protozoan / Q000276:immunology*; D002460:Cell Line; D004285:Dogs; D017097:Electric Impedance; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D019108:Tight Junctions / Q000276:immunology
D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D047908:Intracellular Signaling Peptides and Proteins; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan