Malaria parasites leave a trail of destruction in an infected person’s body. The microscopic invaders massacre red blood cells, produce harmful chemicals, and sometimes damage the brain. A new mouse study suggests that the parasites can also weaken bones. If they do the same in people, they could stunt the growth of children infected with the disease. But the study also provides some good news, identifying a potential way to prevent the skeletal decline with a compound similar to vitamin D.
“It’s important work,” says parasitologist Regina Joice Cordy of Emory University in Atlanta, who wasn’t connected to the study. “It’s taken us a step further,” she adds, in understanding the long-term effects of malaria infections.
Malaria parasites, which are transmitted through the bite of an infected mosquito, cause the most destruction during the part of their life cycle when they dwell in red blood cells circulating through the body. There, they reproduce and feast on oxygen-carrying hemoglobin proteins, releasing noxious byproducts. The parasites eventually explode from the blood cells, killing them in droves. Although researchers have also detected the parasites in bone marrow, where blood-forming stem cells reside, no one has known until now whether they damage the skeleton.
To find out, a team led by graduate student Michelle Lee and immunologist Cevayir Coban of Osaka University in Japan infected mice with either of two species of malaria parasites. The rodents’ immune systems fought off the parasites, but the animals’ skeletons showed the effects of the infection. “We found bone loss for both types of infections,” Coban says. In adult mice, the spongy material inside the bones began to break down. It contained more gaps, and support structures were thinner and less numerous. Similar changes occur in the bones of people with osteoporosis, Coban says.
In young mice, the bones also grew slower than normal. As a result, the animals’ thigh bones were about 10% shorter than those of their uninfected counterparts, the researchers report online today in Science Immunology.
The parasites might trigger these problems, the scientists hypothesized, by upsetting the normal balance between cells known as osteoclasts, which dissolve bone, and cells called osteoblasts, which build it back up. The researchers discovered that both types of cells shut down when the mice were infected with malaria. Once the animals had eliminated the parasites, both cell types started working again. But bone breakdown outpaced bone restoration, suggesting that osteoclasts were working harder.
Why do the mice’s bones deteriorate even after their immune system ousted the parasites? Lee, Coban, and colleagues suspected that the culprit was chemical waste released by the parasites, including the residue of digested hemoglobin, a molecule called hemozoin. In malaria-infected mice, the researchers found, hemozoin seeped into the bones, turning them black. It was still there 2 months after the parasites had been eliminated. To gauge the impact of hemozoin and other parasite wastes, the team cultured bone marrow cells in a cocktail of these substances. The mixture spurred the cells to release inflammation-promoting molecules known to spur osteoclast production.
That mechanism suggested a way to block the parasite’s bone-destroying effects. Coban and colleagues gave infected mice alfacalcidol, a derivative of vitamin D that treats osteoporosis by suppressing osteoclasts and stimulating osteoblasts. The drug prevented bone loss in the mice.
Cordy says the proposed bone-destroying mechanism is plausible. The key question, she says, is whether it occurs in humans. So far, Coban says, the researchers don’t have direct evidence that malaria triggers bone loss in people. Children in malaria-prone areas often grow abnormally slowly, but researchers aren’t sure whether malaria or other diseases that are prevalent in these areas are to blame. If further studies confirm the new findings, treating kids with alfacalcidol or related molecules, along with antimalarials, might lead to a growth spurt.