Malarial parasites are the masters of hiding in plain sight. Once the parasite enters the body—typically via a mosquito bite—it swiftly enters liver cells and rapidly divides. The parasites then creep into the bloodstream, hiding inside red blood cells. By doing so, they can evade circulating immune cells while waiting to be transmitted to their next host.
The two most important malaria parasites are Plasmodium falciparum and Plasmodium vivax, with the latter present across most of the malaria-endemic countries. Notably, P. vivax relapses and can cause recurrent episodes of malaria that are the main determinant of morbidity and mortality. Once the parasite enters the blood, it sniffs out young red blood cells called reticulocytes as a hiding spot.
However, how exactly P. vivax does that is still unknown.
According to Laurent Rénia, senior fellow and principal investigator at the A*STAR’s Infectious Diseases Laboratories (ID Labs), the clues are in the cell surface receptors that facilitate the parasite’s entry into reticulocytes.
To boost progress in the race for a P. vivax vaccine, Rénia and his colleague, Benoît Malleret, along with local and international collaborators started by establishing the full set of cell surface proteins on reticulocytes. From this list, they eliminated proteins that overlapped with the expression profiles of other red blood cells. Only two leads that were exclusively expressed by reticulocytes remained.
The first, CD71, was a known receptor for P. vivax. By exploiting the sensitivity of cells expressing CD71 to treatment with the protease trypsin, the team revealed a second receptor, CD98, that had not been previously described in the context of malaria infections.
Following up on this lead, the scientists screened a library of P. vivax genes to pinpoint which of them formed the ‘key’ to unlocking reticulocyte entry via CD98. In the process, they discovered the missing link to be a surface antigen called PvRBP2a, delineating a previously undocumented pathway of parasite invasion.
Their discovery of a novel antigen-receptor pair redefines our understanding of P. vivax infection. “The parasite uses either of these two receptors sequentially or alternatively. Perhaps different parasite strains also use different pathways,” said Rénia, noting that these pathways represent prime targets for vaccine development. To aid in vaccine design, the team is also now looking to identify the regions recognized by neutralizing antibodies.