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Malaria Research News

By Jim Schnabel

Anopheles’ Shifting Dinner Times

For some female Anopheles mosquitoes, not just any blood meal will do. The nourishing red stuff has to come from humans.

This odd pickiness could pose an obstacle for malaria eradication efforts. Christen Fornadel, PhD, who works in the lab of associate professor Douglas Norris, PhD, MS, at the Johns Hopkins Malaria Research Institute, recently ventured to Macha, Zambia, for a closer look at the problem.

The main carrier of malaria in Macha, the mosquito Anopheles arabiensis, has been found to have different feeding behaviors in different African regions—suggesting that it has the capacity to shift its diet from humans to other animals if nudged. From 2004 to 2007, the government of Zambia issued insecticide-treated bed nets (ITNs) to most households in the area, and as Fornadel says, “if people were protected, since this mosquito is known to feed mostly on cows in other places, we thought maybe we’d see a shift and it would start to prefer feeding on cattle.”

Before the bed nets were introduced, studies by Fornadel, Norris and others had found that local A. arabiensis obtained about 90 percent of their blood meals from humans. During the 2007-2008 and 2008-2009 rainy seasons in Macha, Fornadel spent several weeks pulling all-nighters with a local team, setting up and monitoring mosquito catches, to see whether the malaria-carrying pests had acquired more of a taste for local cattle.

The bad news:  “The mosquitoes we caught were still getting over 90 percent of their blood meals from people, in part by biting before bedtime,” says Fornadel.

The findings represent just a snapshot of mosquito feeding behavior, a complex phenomenon that needs more study. But the results agree with other research in Africa that has found a continued preference for human blood by Anopheles in some areas despite ITN introduction. Fornadel concludes, “On their own, the nets clearly aren’t going to eliminate the disease in the Macha region.”

Another Side of Malaria Mortality

Malaria is best known for its deadly cerebral complications, but a less well-studied complication hits another vital organ, the lungs. “About one in five severe malaria infections causes respiratory disease such as acute respiratory distress syndrome,” says MD/PhD student Ifeanyi Anidi.

Anidi, who works in the lab of Molecular Microbiology and Immunology Professor Alan Scott, PhD, is among a growing band of researchers now looking for ways to understand and defeat these pulmonary complications.

Just as in cerebral malaria, he says, the trouble starts when malarial parasites—typically Plasmodium falciparum—try to evade the spleen by getting out of the bloodstream’s circulation. The sticky proteins they produce cause infected red blood cells to cling to blood vessel walls and clog the smaller lung vessels. Either directly or by provoking a damaging immune reaction, this grab-and-hold process starts to kill the endothelial cells that make up the vessel walls. Fluid then seeps from the bloodstream into the gas-exchange chambers of the lungs, making it harder and harder for victims to breathe. “The process can keep doing damage for days after the infection has been cleared,” says Anidi. “It’s a significant cause of death in severe malaria.”

One big factor in the process is CD36, the endothelial cell-surface receptor to which malarial sticky-proteins are designed to stick. “We’ve found that mice genetically engineered to lack CD36 have much less leakage in the small vessels of their lungs,” Anidi says.

Precisely how CD36 brings about this leakage isn’t yet clear; the receptor is also expressed by invader-gobbling immune cells called macrophages, so it might be a key to the immune reaction seen in affected vessels. But, using mouse models of malaria infection, Anidi and his fellow researchers aim to discover enough about the process to start thinking about ways to damp it somehow in a clinical setting. “It’s a fairly new field and we’re learning a lot very quickly,” he says.

Solving Cerebral Malaria’s Major Mystery

How does cerebral malaria kill? It accounts for nearly 800,000 deaths per year, yet unlike most coma-inducing pathogens, P. falciparum, the cerebral malaria parasite, does not even enter the brain. “It stays inside red blood cells, within the cerebral blood vessels,” notes Monique Stins, PhD, an assistant professor of Neurology in the School of Medicine who frequently collaborates with scientists at the Johns Hopkins Malaria Research Institute.

P. falciparum makes its host cells stick to the linings of blood vessels because they are then less likely to circulate and be eliminated by the filtering spleen. Within the small vessels of the brain, this stickiness causes infected red blood cells to gather and restrict blood flow to some extent. But that doesn’t explain why the brain becomes inflamed and swollen—often raising intracranial pressure enough to cause seizures and death.

Stins and other researchers have been looking at endothelial cells, which form the linings of blood vessels, as the likely middlemen in this process. “We’ve found that once they come into extended contact with falciparum-infected red blood cells, these endothelial cells lining cerebral vessels start to release numerous inflammatory compounds,” she says.

It had been thought that these compounds are released only into the bloodstream. But with a new model of this endothelial borderland between the bloodstream and the brain, Stins has found that these compounds also are released in significant amounts into the brain. “There they can activate astrocytes, microglial cells and even neurons,” she says, and in humans this might contribute to the development of brain inflammation and coma.

If the work pans out, she adds, it could lead to therapies that block specific signals released from these endothelial cells, thereby preventing coma while the malaria infection is treated.

Mapping Hidden Reservoirs

Hospitalization rates for malaria are declining in Africa, but the disease is still far from being eliminated. Malaria parasites have been co-evolving with humans in Africa for millions of years, and, as Tamaki Kobayashi, PhD, MPH, explains, “in endemic areas, people who are repeatedly exposed to malaria develop a partial immunity, so they don’t feel sick even though they still harbor the parasites.”

To track these hidden reservoirs of malaria, Kobayashi, an Epidemiology research associate, has been sampling asymptomatic populations in Zambia using a blood test for antibodies against Plasmodium falciparum. Steadily declining levels of these antibodies in a person or a community indicate that malaria transmission has dropped off—and immunity has declined—while a sudden rise from lower levels indicates a recent exposure.

“In areas where malaria exposure is no longer so frequent, we think we can use this technique to develop a finely detailed map of its spread in asymptomatic people over time and across geography,” she says.

Kobayashi, who won a 2009 Young Investigator Award from the American Society of Tropical Medicine and Hygiene, works closely with Molecular Microbiology and Immunology Professor Greg Glass, PhD, and research associate Tim Shields, MA. The experts in geographic information systems prepare maps of target areas using satellite imagery. “They help us to identify which households to include in our studies, and also help with spatial analysis,” she says.

Kobayashi has taken samples from more than 1,500 people over the past few years. In principle, those communities in which malaria is revealed to be quietly smoldering would become the focus of antimalarial drug treatment efforts. Even communities where antibody levels have fallen steadily would be encouraged to tighten their malaria control programs because, as Kobayashi says, “their falling immunity would indicate an increased susceptibility to disease resurgence."