The malaria parasite has been studied for decades, but surprisingly little is known about how it behaves in humans to cause disease. Now an international team including scientists at the Broad Institute of MIT and Harvard has for the first time measured which of the parasite's genes are turned on or off during actual infection in humans, unearthing surprising behaviors and opening a window on the most critical aspects of parasite biology.
The work is reported in the Nov. 28 advance online edition of Nature.
The study's conclusions spring from the genomic analysis of parasites in their natural state, derived directly from patients residing in Senegal, and also from the researchers' use of innovative computational approaches to interpret their results. These computational methods helped to identify three distinct biological states of the malaria parasite: an active growth-based state, a starvation response and an environmental stress response, presumably related to the body's inflammatory reaction to the parasite.
This physiological diversity was previously unknown and may help explain the widely varying course of the disease in different patients, from mild, flu-like illness to coma and even death.
"For the first time, we have glimpsed the biology of the malaria parasite in one of its most important environments--humans," said co-senior author Aviv Regev, a member of the Broad Institute and an assistant professor of biology at MIT. "Our unique computational approach holds promise not only for understanding the malaria pathogen, but likely other important microbes as well."
In its natural state, the malaria parasite, Plasmodium falciparum, leads a complicated life. It proceeds through a series of distinct developmental stages in humans and mosquitoes, the main vector for disease transmission. Malaria researchers typically circumvent this complexity by studying the parasite in cultured cells. Yet in this artificial setting, few differences have been found in the genes that are turned on or off in various strains of P. falciparum. That uniformity is surprising, because it fails to explain the drastically different courses experienced by malaria patients.
To explore the basis for these differences, the scientists set out to observe P. falciparum in its natural environment: the human circulatory system. Using small samples of blood collected from more than 40 malaria patients in Senegal, the team worked meticulously to devise a method for isolating genetic material from parasites, allowing them to determine which of the nearly 6,000 P. falciparum genes are switched on or off during infection in humans. Importantly, all of the patients involved in the study harbored similar-looking parasites, yet their symptoms varied widely.
From the parasites in patients' blood, the researchers simultaneously measured the activity level, or "expression," of every P. falciparum gene.
The key to interpreting these results lay in two computational tools first developed to study the genomics of human cancer cells. By adapting these tools for malaria, the researchers were able to identify distinct groups of parasites, each marked by characteristic sets of active and inactive genes.
The biological underpinnings of these groups were made clearer through a second innovative approach: systematically comparing P. falciparum--whose genes and genome are poorly understood--to baker's yeast, an organism that has been extensively characterized at the genetic level. Since the malaria parasite and baker's yeast are both single-celled eukaryotes, it is possible they may share some of the same cellular machinery and could also respond in some similar ways to their surroundings.
In the end, the researchers were able to describe three different classes of parasites, one of which displayed features associated with a well-known form of parasite metabolism. The other groups, however, were very unusual, reflecting modes of parasite behavior that had never before been described.
"For decades, our knowledge of the parasite has been driven solely by studies in cultured cells, not in humans," said co-author Dyann Wirth, a professor at the Harvard School of Public Health and co-director of the Broad Institute's Infectious Disease Initiative. "Our work underscores the importance of studying the malaria parasite in its natural environment and will hopefully spark novel approaches to malaria drug discovery."
Additional authors of this study are from the following organizations: Brigham and Women's Hospital; University of California, Riverside; Novartis Research Foundation; Le Dantec Hospital, Cheikh Anta Diop University, Dakar, Senegal; the Whitehead Institute for Biomedical Research; and the Scripps Research Institute.