Catching malaria evolution in the act

Date:
October 13, 2021
Source:
Texas Biomedical Research Institute
Summary:
Researchers can now detect brand new mutations in individual
malaria parasites infecting humans. Such high resolution could
help us understand how parasites develop drug resistance and evade
immune responses, and suggest potential treatment targets.



FULL STORY ========================================================================== Understanding how malaria parasites evolve after a human is bitten by an infected mosquito is very difficult. There can be billions of individual parasites in a patient's bloodstream and traditional genetic sequencing techniques can't identify the raw material for evolution: new mutations.


==========================================================================
"If you want to understand if the parasites are related to each other,
if they are all from one mosquito or multiple mosquito bites, and what
novel mutations are emerging in an infection, then you have to bring
it down to the individual genome level," says Assistant Professor Ian Cheeseman, Ph.D., and Co-lead of the Host-Pathogen Interactions Program
at Texas Biomedical Research Institute.

Thanks to a combination of advanced techniques, Cheeseman and his
collaborators are now able to sequence the genomes of individual parasites found in the blood of infected patients. Notably, they can now do this
even when the infection burden is very low, which can occur during
asymptomatic infections. They describe their approach this month in the
journal Cell Host & Microbe. Gaining this incredibly detailed view of
malaria parasite genetics and evolution is expected to give researchers
and drug companies ammunition to develop more effective treatments,
vaccines or therapies.

Malaria infects more than 200 million people a year, killing more than
400,000 in 2019 -- most of them young children. Of the five malaria
parasite species that infect humans, two are the most widespread:
Plasmodium falciparum, which is the deadliest; and Plasmodium vivax,
which is the leading cause of recurring malaria infections because it
can lie dormant in the liver and reemerge later.

"We were really excited to understand how this dormant liver stage
might impact genetic variation and evolution in a P. vivax infection,"
says co-first paper author Aliou Dia, Ph.D., a postdoctoral researcher
in Cheeseman's lab who is now at the University of Maryland School
of Medicine.

The challenge is that when P. vivax does emerge, it only infects very
young red blood cells, so parasites are rare in the blood. Analyzing
such low levels of infection is the microbiology equivalent of finding
a needle in a haystack.



==========================================================================
The scientists start with red blood cells, which become slightly magnetic
when infected with malaria parasites. They used a high-powered magnet
to separate the infected red blood cells from uninfected cells. The
infected cells were then run through a machine called a flow cytometer,
which uses a laser and fluorescent tags to detect if there is indeed
parasite DNA present. Cells with parasite DNA are plopped one by one
into test wells and ultimately run through a genetic sequencing machine
to decode each individual parasite genome.

Single cell sequencing enables the scientists to precisely compare
individual parasite genomes to one another to determine how related they
are to each other. They can also really dig down and pinpoint single differences in the genetic code -- say an A is changed to a T -- to see
what happened since the parasite infected that patient.

"We would expect these brand-new mutations to be scattered randomly
throughout the genome," Cheeseman says. "Instead, we find they are
often targeting a gene family that controls transcription in malaria."
But that's not the only notable thing about the results. What really
excites Cheeseman is that when the team compared single cell sequencing
data for P.

vivax and P. falciparum, the same transcription gene family contained
the majority of new mutations for both species.

"We have two different species of malaria from two different parts of
the world, Thailand and Malawi," he says. "When we see the same thing
happening independently in different species, this is an example of
convergent evolution." In other words, similar processes might be
shaping similar mutation patterns in both species, even though their
last common ancestor was millions of years ago.

The team does not know yet what impact the mutations have on the parasite
and its ability to persist and cause damage in human hosts. The mutations
may be critical for survival, or something like drug resistance, or may
reveal those genes are unimportant.

"We don't know what these mutations are doing," Cheeseman
says. "But the fact that they are targeting what is
seen to be a fairly fundamental part of the parasite
lifecycle is interesting and worthy of a lot of follow up." ========================================================================== Story Source: Materials provided by
Texas_Biomedical_Research_Institute. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Aliou Dia, Catherine Jett, Simon G. Trevino, Cindy S. Chu, Kanlaya
Sriprawat, Timothy J.C. Anderson, Franc,ois Nosten, Ian
H. Cheeseman.

Single-genome sequencing reveals within-host evolution of
human malaria parasites. Cell Host & Microbe, 2021; DOI:
10.1016/j.chom.2021.08.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211013122728.htm

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