Malaria has evolved throughout human existence and
therefore has some potent immune evasion strategies. Generating protective immunity against the early liver stage of
malaria infection is feasible but has been difficult to achieve in
regions with high rates of malaria infection.
Researchers at the
University of Washington (UW) School of Medicine reveal one potential
reason for this difficulty in Cell Reports
study demonstrates that exposure to the latter blood stage of malaria
infection inhibits the formation of the protective immune cells (and
their antibodies) that can prevent the early liver stage infection.
‘Exposure to the latter blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent the early liver stage infection.’
"The blood stage of malaria infection has a very profound impact on
the liver stage immune response, and that impact had never been
dissected and visualized at this level," says co-author Marion Pepper,
UW Medicine researcher and assistant professor of immunology at the UW
School of Medicine. "These studies really suggest that you need a
vaccine that is protective against both stages of infection to
effectively prevent malaria."
To track how the blood stage of malaria infection overpowers the
liver stage immune response, Pepper and her collaborators infected two
groups of mice with different forms of the malaria parasite. One of
these was engineered by their collaborators in the lab of Stefan Kappe,
UW affiliate professor of global health and investigator, Center for
Infectious Disease Research in Seattle, to stop at the liver stage of
infection, while the other progressed to the blood stage of infection.
Six days after infection, the researchers found that the levels of
antibodies were significantly lower in the mice with the blood stage
infection than in mice that only had the parasite targeted to the liver.
To understand this discrepancy, the team tracked the differentiation
of Plasmodium liver stage-specific B cells. B cells can differentiate
into antibody-secreting early effector cells or long-lived memory cells,
both of which contribute to protection against malaria.
that 14 days after infection, the B cells in the blood stage infected
mice never went through the necessary changes to make rapidly responsive
memory cells. However, in the mice that received the liver-stage
attenuated version of the parasite, the B cells were still able to
differentiate and create the necessary antibodies and memory cells for
an effective immune response.
"This work really highlights the importance of looking at
antigen-specific B cells," says Pepper. "These data also suggest that if
you're getting a vaccine while you have an ongoing blood stage
infection, there is a chance that the vaccine will not generate good
memory cells because the blood stage disrupts all the processes that are
involved in making that immunological memory."
Pepper and her collaborators are now looking into the possibility of
a drug treatment to solve this problem, as they were able to show that
when you treat the second stage of the infection with a drug, the B
cells are able to create the optimally responsive memory cells. But for
now, the researchers are hopeful that their work can be used to answer
immediate questions about the efficacy of malaria vaccines in regions
that are most significantly affected by the disease.
"We really tried to
tease apart some of the factors that could be driving the loss of
protective immunity during natural infection and with current vaccine
strategies in areas of high malaria transmission," says Pepper. "Our
next step is to compare malaria-specific B cells after vaccination or
natural infection in humans so we can translate these findings and start
to determine how to solve this problem."