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Credit: St Jude
Children’s Research Hospital
A new study has shown that malaria parasites can rapidly change proteins on the surface of human red blood cells (RBCs) during the course of a single infection, which helps the parasites evade the immune system.
The findings, which overturn previous thinking about the Plasmodium falciparum parasite’s lifecycle, could explain why so many attempts to create an effective malaria vaccine have failed and how the parasites are able to survive in the human body for such long periods of time.
Investigators described this research in PLOS Genetics.
The team kept P falciparum parasites dividing in human blood in the lab for over a year and sequenced the full parasite genome regularly. This provided snapshots of the parasite’s genome at multiple time points, allowing them to track evolution as it unfolded in the lab.
They found that the 60 or so genes that control proteins on the surface of infected human RBCs, known as var genes, swapped genetic information regularly, creating around a million new and unrecognizable surface proteins in every infected human every 2 days.
“These genes are like decks of cards constantly being shuffled,” explained study author William Hamilton, a graduate student at the Wellcome Trust Sanger Institute in Cambridge, UK.
“The use of whole-genome sequencing and the sheer number of samples we collected gave us a detailed picture of how the var gene repertoire changes continuously within red blood cells.”
The results showed, for the first time, that recombination does not occur when the malaria parasite is inside the mosquito, as previously thought. Instead, it occurs during the asexual stage of the parasite’s lifecycle inside human RBCs. This finding may help explain how chronic asymptomatic infection, a crucial problem for malaria elimination, is possible.
“It’s very likely that mosquitos are re-infected with Plasmodium falciparum parasites at the beginning of each wet season by biting humans who have carried the parasites, often asymptomatically, for up to 8 months during the dry season,” said study author Antoine Claessens, PhD, of the Wellcome Trust Sanger Institute.
“During those months, the parasite’s var genes are busy recombining to create millions of different versions—cunning disguises that mean they remain safe from the immune system and ready for the new malarial season.”
While further work will be required to fully understand the mechanism driving the recombination of P falciparum’s var genes, the investigators were able to calculate the rate at which it happens. They found that var gene recombination takes place in about 0.2% of parasites after each 48-hour life cycle in the RBC.
With about a billion parasites living inside a typical infected human, there is huge potential for the parasite to create new, recombined var genes inside each person with malaria. This pace of change far exceeds that of genes in any other region of the parasite’s genome.
“When you consider that 200 million people across the world are infected with malaria, and each of them is harboring parasites that are continually generating millions of antigenic variants, it becomes apparent why our fight against malaria is so challenging,” said study author Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“This study is a great example of how genome sequence analysis is enriching our understanding of malaria biology. By learning the genetic tricks that the parasite uses to evade the human immune system, we will be in a much better position to eliminate this deadly disease.” 
Credit: St Jude
Children’s Research Hospital
A new study has shown that malaria parasites can rapidly change proteins on the surface of human red blood cells (RBCs) during the course of a single infection, which helps the parasites evade the immune system.
The findings, which overturn previous thinking about the Plasmodium falciparum parasite’s lifecycle, could explain why so many attempts to create an effective malaria vaccine have failed and how the parasites are able to survive in the human body for such long periods of time.
Investigators described this research in PLOS Genetics.
The team kept P falciparum parasites dividing in human blood in the lab for over a year and sequenced the full parasite genome regularly. This provided snapshots of the parasite’s genome at multiple time points, allowing them to track evolution as it unfolded in the lab.
They found that the 60 or so genes that control proteins on the surface of infected human RBCs, known as var genes, swapped genetic information regularly, creating around a million new and unrecognizable surface proteins in every infected human every 2 days.
“These genes are like decks of cards constantly being shuffled,” explained study author William Hamilton, a graduate student at the Wellcome Trust Sanger Institute in Cambridge, UK.
“The use of whole-genome sequencing and the sheer number of samples we collected gave us a detailed picture of how the var gene repertoire changes continuously within red blood cells.”
The results showed, for the first time, that recombination does not occur when the malaria parasite is inside the mosquito, as previously thought. Instead, it occurs during the asexual stage of the parasite’s lifecycle inside human RBCs. This finding may help explain how chronic asymptomatic infection, a crucial problem for malaria elimination, is possible.
“It’s very likely that mosquitos are re-infected with Plasmodium falciparum parasites at the beginning of each wet season by biting humans who have carried the parasites, often asymptomatically, for up to 8 months during the dry season,” said study author Antoine Claessens, PhD, of the Wellcome Trust Sanger Institute.
“During those months, the parasite’s var genes are busy recombining to create millions of different versions—cunning disguises that mean they remain safe from the immune system and ready for the new malarial season.”
While further work will be required to fully understand the mechanism driving the recombination of P falciparum’s var genes, the investigators were able to calculate the rate at which it happens. They found that var gene recombination takes place in about 0.2% of parasites after each 48-hour life cycle in the RBC.
With about a billion parasites living inside a typical infected human, there is huge potential for the parasite to create new, recombined var genes inside each person with malaria. This pace of change far exceeds that of genes in any other region of the parasite’s genome.
“When you consider that 200 million people across the world are infected with malaria, and each of them is harboring parasites that are continually generating millions of antigenic variants, it becomes apparent why our fight against malaria is so challenging,” said study author Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“This study is a great example of how genome sequence analysis is enriching our understanding of malaria biology. By learning the genetic tricks that the parasite uses to evade the human immune system, we will be in a much better position to eliminate this deadly disease.”
Credit: St Jude
Children’s Research Hospital
A new study has shown that malaria parasites can rapidly change proteins on the surface of human red blood cells (RBCs) during the course of a single infection, which helps the parasites evade the immune system.
The findings, which overturn previous thinking about the Plasmodium falciparum parasite’s lifecycle, could explain why so many attempts to create an effective malaria vaccine have failed and how the parasites are able to survive in the human body for such long periods of time.
Investigators described this research in PLOS Genetics.
The team kept P falciparum parasites dividing in human blood in the lab for over a year and sequenced the full parasite genome regularly. This provided snapshots of the parasite’s genome at multiple time points, allowing them to track evolution as it unfolded in the lab.
They found that the 60 or so genes that control proteins on the surface of infected human RBCs, known as var genes, swapped genetic information regularly, creating around a million new and unrecognizable surface proteins in every infected human every 2 days.
“These genes are like decks of cards constantly being shuffled,” explained study author William Hamilton, a graduate student at the Wellcome Trust Sanger Institute in Cambridge, UK.
“The use of whole-genome sequencing and the sheer number of samples we collected gave us a detailed picture of how the var gene repertoire changes continuously within red blood cells.”
The results showed, for the first time, that recombination does not occur when the malaria parasite is inside the mosquito, as previously thought. Instead, it occurs during the asexual stage of the parasite’s lifecycle inside human RBCs. This finding may help explain how chronic asymptomatic infection, a crucial problem for malaria elimination, is possible.
“It’s very likely that mosquitos are re-infected with Plasmodium falciparum parasites at the beginning of each wet season by biting humans who have carried the parasites, often asymptomatically, for up to 8 months during the dry season,” said study author Antoine Claessens, PhD, of the Wellcome Trust Sanger Institute.
“During those months, the parasite’s var genes are busy recombining to create millions of different versions—cunning disguises that mean they remain safe from the immune system and ready for the new malarial season.”
While further work will be required to fully understand the mechanism driving the recombination of P falciparum’s var genes, the investigators were able to calculate the rate at which it happens. They found that var gene recombination takes place in about 0.2% of parasites after each 48-hour life cycle in the RBC.
With about a billion parasites living inside a typical infected human, there is huge potential for the parasite to create new, recombined var genes inside each person with malaria. This pace of change far exceeds that of genes in any other region of the parasite’s genome.
“When you consider that 200 million people across the world are infected with malaria, and each of them is harboring parasites that are continually generating millions of antigenic variants, it becomes apparent why our fight against malaria is so challenging,” said study author Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“This study is a great example of how genome sequence analysis is enriching our understanding of malaria biology. By learning the genetic tricks that the parasite uses to evade the human immune system, we will be in a much better position to eliminate this deadly disease.”