The parasites' presence in the lymph nodes almost certainly has implications
for the mammalian immune response, said Robert Mnard, a Howard Hughes Medical
Institute (HHMI) international research scholar who led the study.
Mnard and colleagues report their findings in the February issue of the
journal Nature Medicine, published online on January 22, 2006.
When a mosquito infected with Plasmodium bites a mammal, the immature parasites
travel to the animal's liver, which, until now, scientists thought was the only
place they could develop, Mnard said. Once they have fully developed, the
parasites burst out of the liver cells and infect red blood cells, beginning the
onset of malaria.
Although researchers understand this life cycle, no one has measured directly
how many parasites a mosquito bite transmits or where else in a mammal's body
they travel, said Mnard. To find out, he and his colleagues infected
mosquitoes with fluorescently tagged Plasmodium parasites, and then allowed the
mosquitoes to bite a mouse. From each mosquito bite, they found an average of 20
fluorescent parasites embedded in the animal's skin. Mnard found that the
parasites moved through the skin in a random, circuitous path at a speed that is
amongst the fastest recorded for any migrating cell. After leaving the skin, the
parasites frequently invaded blood vessels. That was no surprise to Mnard,
since they need to travel through blood vessels to get to the liver. However,
many of the parasites also invaded lymphatic vessels. About 25 percent of the
parasites injected by the mosquito bites were drained by lymphatic vessels and
ended up in lymph nodes close to the site of the bite. Their journey seemed to
stop there, as the malaria parasites almost never appeared in lymph nodes
Within about four hours of the mosquito bite, many of the lymph-node parasites
appeared degraded. They were also seen interacting with key mammalian immune
cells, suggesting that the immune cells were destroying them.
A small number of the parasites in the lymph nodes, however, escaped degradation
and began to develop into forms usually found only in the liver. Up to now,
researchers believed that, although both blood and lymphatic vessels take up
Plasmodium parasites, they all end up in the liver, Mnard said. "Nobody
had proposed that they actually might stop" in the lymph nodes and develop
there, he observed.
By 52 hours after the mosquito bites, no parasites remained in the lymph nodes,
which suggests that they can't develop completely there, Mnard said. Only
fully developed parasites can infect red blood cells and cause malaria, so the
lymph-node parasites probably don't contribute to the appearance of malaria
symptoms, he added. But even partially developed or destroyed parasites could
significantly affect how the immune system responds to infection, he noted.
Another unexpected finding adds even more complexity to the mammalian immune
response to the malaria parasite. An hour after a mouse was bitten, nearly half
of the parasites remained in the animal's skin, and some were detected there
even after seven hours. "That's really surprising," Mnard said.
Although he cautions that those numbers may be specific to mice and the species
of Plasmodium the scientists used, it's likely that at least some parasites
remain in the skin of any mammal bitten by a malarial mosquito until immune
cells come along to sweep them out, Mnard said. This second influx of
parasites could prompt a somewhat different immune response in the host, and
those parasites might have different fates. Parasites developing in the lymph
nodes could have two opposite effects on the body's immune response, he
explained. They might alert the body that an invader is present and activate a
protective immune response. On the other hand, their presence in the lymph nodes
might desensitize the body to the parasites, blunting the immune system's
response to liver and blood-cell infection.
"We have to integrate all these new data into something that makes sense
from the immune standpoint," the researcher observed. Understanding the
intricacies of the mammalian immune response to Plasmodium infection might help
scientists create better vaccines, including vaccines that target parasites
before they develop in the liver, Mnard said. Parasite development in lymph
nodes could even be one reason there is so much tolerance to these parasites, he
Howard Hughes Medical Institute