A Malaria Mystery, Partly Solved: What Happens When the Rains End?

Each year malaria kills roughly 400,000 people, most of them children and pregnant women in Africa. Scientists have long known that most of those fevers and deaths occur during the rainy months, when mosquitoes abound. But how does the disease persist during the long dry seasons, when almost no one falls ill and there are few mosquitoes to carry the tiny malaria parasite from one human host to another?

That mystery has long bedeviled scientists. But a new study in Nature Medicine by researchers from Germany and Mali has provided at least a partial answer: The parasite enacts a genetic change that enables it to hide in an infected person’s bloodstream for months, undetected.

The researchers began by drawing blood at regular intervals from almost 600 children and young adults in Kalifabougou, a town in rural Mali with distinct wet and dry seasons. Blood tests revealed that, even when samples had too few parasites to be seen under a microscope, about 20 percent of the study participants still had very low levels of parasites hiding inside some of their red blood cells.

The malaria parasite is known to take over the protein-making machinery of some infected red blood cells, causing them to produce sticky proteins that then appeared on the surfaces of the cells. These cells adhere to the walls of the veins and arteries, instead of being swept downstream into the spleen, to be destroyed. The new study found that this activity varies with the season.

The spleen is something like a sieve, with narrow slits through which only young, flexible red blood cells can squeeze, said Sylvia Portugal, a malaria specialist at the Max Planck Institute for Infection Biology in Berlin and lead author of the study.

Stiff, older cells, as well as cells that are packed with multiplying parasites, are typically caught in the spleen and digested by patrolling large white blood cells called macrophages.

In much of Africa, the rainy season can be deadly. When malaria parasites are abundant and causing red blood cells to pump out sticky proteins, these cells can jam the tiny capillaries in the brain. “Cerebral malaria” is often fatal.

Credit...Omikron/Science Source

Each parasite has a long menu of proteins written into its genes, from which it can order selectively. It can produce up to 60 variants of the proteins that migrate to the surface of the cell. Normally, a parasite will shift to a new protein every few days, to escape the antibodies produced by the host’s immune response.

But during the dry season, the researchers found, the parasites in most red blood cells stopped making the sticky versions of that protein. They slipped away into the spleen to their destruction. But a few clingy survivors hung on, and appeared to slow down their metabolism, like microscopic bears hibernating for the winter.

This had two effects that protected them.

First, by measuring the inflammatory proteins produced by the immune system, Dr. Portugal showed that the reclusive parasites had somehow become too “quiet” to trigger the immune counterattack that might destroy them.

Second, too few sticky cells remained to clog brain capillaries, so even infected children survived.

“A parasite that kills its host during the dry season reaches a dead end,” Dr. Portugal said.

Sarah K. Volkman, a molecular biologist at Harvard’s T.H. Chan School of Public Health and a leading malaria expert, called the new study “important.” Dr. Volkman’s research in Senegal has found that parasite lineages persisted in villages for 10 years. She noted that understanding the importance of that small dry-season reservoir could reveal ways to destroy the parasites when they are at their weakest.

Dr. Miriam K. Laufer, a malaria specialist at the University of Maryland’s medical school, also praised the study, saying it “delivered concrete data about things we thought were the case, such as that the dry season infections do not elicit a big immune response.”

Dr. Nicholas J. White, director of a malaria research unit based at the University of Oxford and Mahidol University in Thailand, was more reserved, noting that researchers in Vietnam had previously shown that parasites persist in dry months.

Parasites might simply “change their clothes” every few cycles to avoid being recognized by the immune system, he argued, and the lower number of cells clinging to walls could be explained by a change in the host’s antibody response rather than by a change in the parasite.

But he conceded that he could not explain Dr. Portugal’s observation that infected red blood cells were more likely to be destroyed by the spleen during the dry season.

More research in the field is needed, all the experts agreed.

The discovery opens up an intriguing question: What triggers this shift? How do parasites deep inside a human body “know” when the dry season has begun and life for them is about to become perilous? Or when the rains have begun and good times have returned?

One theory is that something induces stress in the parasites. When parasites are under stress, Dr. Laufer said, they react by turning into gametocytes, the sexual life-cycle stage that allows them to be ingested by mosquitoes and carried to a new host. It is a risky move: They cannot change back, and if they are not carried off, they die.

Anti-malaria drugs are known to induce that stress and trigger the change to gametocytes. But so might an influx of new parasites — arriving with the rainy season, injected by mosquitoes and competing with the reclusive malarial parasites for juicy red blood cells, Dr. Laufer speculated.

Another possibility is that some protein in mosquito saliva — or in human allergic reactions to mosquito saliva, the histamines that cause bites to itch — alerts the malarial parasites to come out of hiding.

Some studies suggest that mosquitoes prefer to bite people who already have malaria. The parasites may somehow make those people smell tastier. It’s known that dogs can be trained to detect people with malaria, even by smelling socks that infected children have worn.

The idea that mosquitoes themselves are the wake-up alarm for the parasites is not unthinkable, the experts said, because the parasites exhibit a Darwinian genius for survival. But there is no proof yet.

“We don’t know yet,” Dr. Portugal said. “But I look forward to understanding it all better.”

The tenacious interdependence of host and parasite, Dr. Volkman said, reminded her of the poem “A New Year Greeting,” by W.H. Auden. In it, the poet welcomes predatory yeasts and bacteria to his skin, but warns them that they might be scalded to death in The Great Flood when he bathes. Their ultimate fate will conclude with his, he notes: “a Day of Apocalypse, when my mantle suddenly turns too cold, too rancid, for you, appetizing to predators of a fiercer sort.”

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