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Credit: Swiss TPH
Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.
It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.
Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.
Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.
The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.
Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.
With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.
Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.
Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.
Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.
“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”
The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.
However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.
“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”
Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.
“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.
“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”
This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission. 
Credit: Swiss TPH
Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.
It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.
Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.
Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.
The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.
Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.
With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.
Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.
Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.
Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.
“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”
The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.
However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.
“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”
Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.
“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.
“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”
This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission.
Credit: Swiss TPH
Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.
It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.
Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.
Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.
The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.
Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.
With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.
Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.
Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.
Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.
“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”
The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.
However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.
“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”
Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.
“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.
“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”
This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission.