Kinetics of monocyte subpopulations during experimental cerebral malaria and its resolution in a model of late chloroquine treatment

International audienceCerebral malaria (CM) is one of the most severe forms of malaria and is a neuropathology that can lead to death. Monocytes have been shown to accumulate in the brain microvasculature at the onset of neurological symptoms during CM. Monocytes have a remarkable ability to adapt their function to their microenvironment from pro-inflammatory to resolving activities. This study aimed to describe the behavior of monocyte subpopulations during infection and its resolution. C57BL/6 mice were infected with the Plasmodium berghei ANKA strain and treated or not with chloroquine (CQ) on the first day of the onset of neurological symptoms (day 6) for 4 days and followed until day 12 to mimic neuroinflammation and its resolution during experimental CM. Ly6C monocyte subpopulations were identified by flow cytometry of cells from the spleen, peripheral blood, and brain and then quantified and characterized at different time points. In the brain, the Ly6C int and Ly6C low monocytes were associated with neuroinflammation, while Ly6C hi and Ly6C int were mobilized from the peripheral blood to the brain for resolution. During neuroinflammation, CD36 and CD163 were both involved via splenic monocytes, whereas our results suggest that the low CD36 expression in the brain during the neuroinflammation phase was due to degradation. The resolution phase was characterized by increased expressions of CD36 and CD163 in blood Ly6C low monocytes, a higher expression of CD36 in the microglia, and restored high expression levels of CD163 in Ly6C hi monocytes localized in the brain. Thus, our results suggest that increasing the expressions of CD36 and CD163 specifically in the brain during the neuroinflammatory phase contributes to its resolution

Patterns of selection on Plasmodium falciparum erythrocyte-binding antigens after the colonization of the New World.

Pathogens, which have recently colonized a new host species or new populations of the same host, are interesting models for understanding how populations may evolve in response to novel environments. During its colonization of South America from Africa, Plasmodium falciparum, the main agent of malaria, has been exposed to new conditions in distinctive new human populations (Amerindian and populations of mixed origins) that likely exerted new selective pressures on the parasite's genome. Among the genes that might have experienced strong selective pressures in response to these environmental changes, the eba genes (erythrocyte-binding antigens genes), which are involved in the invasion of the human red blood cells, constitute good candidates. In this study, we analysed, in South America, the polymorphism of three eba genes (eba-140, eba-175, eba-181) and compared it to the polymorphism observed in African populations. The aim was to determine whether these genes faced selective pressures in South America distinct from what they experienced in Africa. Patterns of genetic variability of these genes were compared to the patterns observed at two housekeeping genes (adsl and serca) and 272 SNPs to separate adaptive effects from demographic effects. We show that, conversely to Africa, eba-140 seemed to be under stronger diversifying selection in South America than eba-175. In contrast, eba-181 did not show any sign of departure from neutrality. These changes in the patterns of selection on the eba genes could be the consequence of changes in the host immune response, the host receptor polymorphisms and/or the ability of the parasite to silence or express differentially its invasion proteins

adsl_sequences

Sequences alignment of adsl gen

Data from: Patterns of selection on Plasmodium falciparum erythrocyte binding antigens after the colonisation of the New World

Pathogens, which have recently colonized a new host species or new populations of the same host, are interesting models for understanding how populations may evolve in response to novel environments. During its colonization of South America from Africa Plasmodium falciparum, the main agent of malaria, has been exposed to new conditions in distinctive new human populations (Amerindian and populations of mixed origins), that likely exerted new selective pressures on the parasite's genome. Among the genes that might have experienced strong selective pressures in response to these environmental changes, the eba genes (erythrocyte binding antigens genes), which are involved in the invasion of the human red blood cells, constitute good candidates. In this study, we analyzed, in South America, the polymorphism of three eba genes (eba-140, eba-175, eba-181) and compared it to the polymorphism observed in African populations. The aim was to determine whether these genes faced selective pressures in South America distinct from what they experienced in Africa. Patterns of genetic variability of these genes were compared to the patterns observed at two housekeeping genes (adsl and serca) and 272 SNPs to separate adaptive effects from demographic effects. We show that, conversely to Africa, eba-140 seemed to be under stronger diversifying selection in South America than eba-175. In contrast, eba-181 did not show any sign of departure from neutrality. These changes in the patterns of selection on the eba genes could be the consequence of changes in the host immune response, the host receptor polymorphisms, and / or the ability of the parasite to silence or express differentially its invasion proteins

Patterns of selection on Plasmodium falciparum erythrocyte-binding antigens after the colonization of the New World.

International audiencePathogens, which have recently colonized a new host species or new populations of the same host, are interesting models for understanding how populations may evolve in response to novel environments. During its colonization of South America from Africa, Plasmodium falciparum, the main agent of malaria, has been exposed to new conditions in distinctive new human populations (Amerindian and populations of mixed origins) that likely exerted new selective pressures on the parasite's genome. Among the genes that might have experienced strong selective pressures in response to these environmental changes, the eba genes (erythrocyte-binding antigens genes), which are involved in the invasion of the human red blood cells, constitute good candidates. In this study, we analysed, in South America, the polymorphism of three eba genes (eba-140, eba-175, eba-181) and compared it to the polymorphism observed in African populations. The aim was to determine whether these genes faced selective pressures in South America distinct from what they experienced in Africa. Patterns of genetic variability of these genes were compared to the patterns observed at two housekeeping genes (adsl and serca) and 272 SNPs to separate adaptive effects from demographic effects. We show that, conversely to Africa, eba-140 seemed to be under stronger diversifying selection in South America than eba-175. In contrast, eba-181 did not show any sign of departure from neutrality. These changes in the patterns of selection on the eba genes could be the consequence of changes in the host immune response, the host receptor polymorphisms and/or the ability of the parasite to silence or express differentially its invasion proteins

eba181_sequences

Sequences alignment of eba-181 gen

Multiple independent introductions of Plasmodium falciparum in South America.

The origin of Plasmodium falciparum in South America is controversial. Some studies suggest a recent introduction during the European colonizations and the transatlantic slave trade. Other evidence--archeological and genetic--suggests a much older origin. We collected and analyzed P. falciparum isolates from different regions of the world, encompassing the distribution range of the parasite, including populations from sub-Saharan Africa, the Middle East, Southeast Asia, and South America. Analyses of microsatellite and SNP polymorphisms show that the populations of P. falciparum in South America are subdivided in two main genetic clusters (northern and southern). Phylogenetic analyses, as well as Approximate Bayesian Computation methods suggest independent introductions of the two clusters from African sources. Our estimates of divergence time between the South American populations and their likely sources favor a likely introduction from Africa during the transatlantic slave trade