Researchers from
Seattle Biomedical Research Institute (Seattle BioMed), the University of
Copenhagen and the University of Edinburgh have uncovered new knowledge related
to host-parasite interaction in severe malaria, concerning how malaria
parasites are able to bind to cells in the brain and cause cerebral malaria –
the most lethal form of the disease.
Three related papers will be published in the May
21 online edition of PNAS (Proceedings of the National Academy of Sciences)
highlighting this research.
"Identifying the molecules that allow
malaria parasites to
'stick' to the brain takes us one step closer to new treatments," said
Joseph Smith, Ph.D., leader of the Seattle team.
Red blood cells infected with
the malaria
parasite Plasmodium falciparum, the type most lethal to humans, bind
to receptors on cells lining blood vessel walls, which helps the parasite avoid
being detected and killed by the spleen.
The binding is mediated by one of several members
of a family of parasite proteins called P. falciparum erythrocyte membrane
protein 1, or PfEMP1. A single PfEMP1 mediates placental malaria – the cause of
malaria during pregnancy, which kills thousands of women and causes premature
births and low-birth weight babies each year – but other PfEMP1 types causing
life-threatening disease in young children are unknown.
To hone in on specific PfEMP1 types associated with
severe malaria, Thomas Lavstsen, Ph.D., and his team from the University of
Denmark used molecular techniques to compare the levels of different PfEMP1
transcripts in blood samples from children hospitalized in the pediatric ward
of the Korogwe District Hospital in Tanzania.
"Our research revealed that genes encoding two
distinct types of PfEMP1 - named domain cassettes 8 and 13 - were tied to cases
of severe malaria, suggesting that those proteins might be suitable targets in
efforts aimed at curbing the disease," explained Lavstsen. Co-author
Louise Turner, Ph.D. adds "Another important aspect of our study is that
we show these PfEMP1 domain cassettes are recognized by natural acquired
immunity in young African children, which gives us hope that we can base a
vaccine on the discovered PfEMP1 types."
In a related paper in this issue, Antoine
Claessens, Ph.D., who works in the lab of Alexandra Rowe, D. Phil., of the
University of Edinburgh, reports that these particular PfEMP1 types – domain
cassettes 8 and 13 – mediate the binding of infected red blood cells to cells
that line blood
vessels in the brain.
"This provides us with new molecules that
could be targeted to develop drugs to treat the most deadly forms of
malaria," said Rowe. "In addition, because animal models for cerebral malaria are
currently unavailable, we believe our findings might lead to a laboratory tool
for testing drugs and vaccines that block the binding of the parasite to blood
vessels in the brain."
Marion Avril, Ph.D., who works in the Smith lab at
Seattle BioMed, reports in this issue that domain cassette 8 encodes binding
activity for brain blood vessel cells. Additionally, the authors uncovered a
potential explanation for the evolutionary persistence of parasite protein
variants that mediate cerebral malaria, an often-fatal disease that tends to
wipe out the parasite's host.
"Because those brain-binding variants can also
bind to blood vessels in the skin, heart, and lung, the parasite might
sequester in those organs," Smith explained. "Together, the findings
could help researchers better address the lingering problem of childhood
malaria."
"It's been a 15-year journey since this gene
family was discovered, but the coming together of these three studies, which
all identify the same key players in severe malaria, is an
important milestone," said Rowe. "We're excited to have this knowledge
and begin to apply it to developing new solutions for malaria."
Provided by Seattle
Biomedical Research Institute
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