Investigating the Host Binding Signature on the PfEMP1 Protein Family
The Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1) family plays a central role in antigenic variation and cytoadhesion of
P. falciparum infected erythrocytes. PfEMP1
proteins/var genes are classified into three main
subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles
in binding and disease. To investigate whether these subfamilies have diverged
in binding specificity and test if binding could be predicted by adhesion domain
classification, we generated a panel of 19 parasite lines that primarily
expressed a single dominant var transcript and assayed binding
against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC
var genes were isolated, indicating that UpsA
var gene expression is rare under in vitro
culture conditions. Consequently, three UpsA variants were obtained by rosette
purification and selection with specific monoclonal antibodies to create a more
representative panel. Binding assays showed that CD36 was the most common
adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that
CD36 and ICAM-1 binding variants were highly predicted by adhesion domain
sequence classification. Binding to other host receptors, including CSA, VCAM-1,
HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor “X”, and
Fractalkine, was rare or absent. Our findings identify a category of larger
PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They
also support that the UpsA group, in contrast to UpsB and UpsC
var genes, has diverged from binding to the major
microvasculature receptor CD36 and likely uses other mechanisms to sequester in
the microvasculature. These results demonstrate that CD36 and ICAM-1 have left
strong signatures of selection on the PfEMP1 family that can be detected by
adhesion domain sequence classification and have implications for how this
family of proteins is specializing to exploit hosts with varying levels of
anti-malaria immunity.
Vyšlo v časopise:
Investigating the Host Binding Signature on the PfEMP1 Protein Family. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002032
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002032
Souhrn
The Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1) family plays a central role in antigenic variation and cytoadhesion of
P. falciparum infected erythrocytes. PfEMP1
proteins/var genes are classified into three main
subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles
in binding and disease. To investigate whether these subfamilies have diverged
in binding specificity and test if binding could be predicted by adhesion domain
classification, we generated a panel of 19 parasite lines that primarily
expressed a single dominant var transcript and assayed binding
against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC
var genes were isolated, indicating that UpsA
var gene expression is rare under in vitro
culture conditions. Consequently, three UpsA variants were obtained by rosette
purification and selection with specific monoclonal antibodies to create a more
representative panel. Binding assays showed that CD36 was the most common
adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that
CD36 and ICAM-1 binding variants were highly predicted by adhesion domain
sequence classification. Binding to other host receptors, including CSA, VCAM-1,
HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor “X”, and
Fractalkine, was rare or absent. Our findings identify a category of larger
PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They
also support that the UpsA group, in contrast to UpsB and UpsC
var genes, has diverged from binding to the major
microvasculature receptor CD36 and likely uses other mechanisms to sequester in
the microvasculature. These results demonstrate that CD36 and ICAM-1 have left
strong signatures of selection on the PfEMP1 family that can be detected by
adhesion domain sequence classification and have implications for how this
family of proteins is specializing to exploit hosts with varying levels of
anti-malaria immunity.
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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