User login
Image by Peter H. Seeberger
Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.
Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent 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,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.
“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, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.
One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.
The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.
Six days after infection, the researchers found 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.
The researchers discovered 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,” Dr Pepper said. “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.”
Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.
The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.
For now, the researchers hope 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.
“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “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.”
“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.” 
Image by Peter H. Seeberger
Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.
Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent 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,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.
“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, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.
One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.
The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.
Six days after infection, the researchers found 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.
The researchers discovered 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,” Dr Pepper said. “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.”
Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.
The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.
For now, the researchers hope 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.
“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “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.”
“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.”
Image by Peter H. Seeberger
Researchers say they have uncovered one potential reason why it has been difficult to generate protective immunity against the early liver stage of malaria infection in regions where the incidence of malaria is high.
Their research, conducted in mice and published in Cell Reports, suggests that exposure to the blood stage of malaria infection inhibits the formation of the protective immune cells (and their antibodies) that can prevent 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,” said study author Marion Pepper, PhD, of the University of Washington School of Medicine in Seattle.
“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, Dr Pepper and her colleagues infected 2 groups of mice with different forms of malaria parasites.
One group of mice was infected with Plasmodium yoelii wild-type sporozoites, which complete the pre-erythrocytic stage of infection and establish a blood-stage infection.
The other group was infected with a genetically attenuated Plasmodium yoelii parasite that arrests late in liver stage development and does not cause blood-stage infection.
Six days after infection, the researchers found 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.
The researchers discovered 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,” Dr Pepper said. “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.”
Dr Pepper and her colleagues are now looking into the possibility of treatment to solve this problem.
The team found that when they treated the second stage of the infection with the anti-malarial drug atovaquone, the B cells were able to create the optimally responsive memory cells.
For now, the researchers hope 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.
“Malaria has evolved with us throughout human existence and therefore has some potent immune evasion strategies,” Dr Pepper said. “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.”
“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.”