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HIV-1 promotes intake of Leishmania parasites by enhancing phosphatidylserine-mediated, CD91/LRP-1-dependent phagocytosis in human macrophages.

Lodge R, Ouellet M, Barat C, Andreani G, Kumar P, Tremblay MJ - PLoS ONE (2012)

Bottom Line: This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β).We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β.Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec-CHUL, Université Laval, Québec, Canada.

ABSTRACT
Over the past decade, the number of reported human immunodeficiency virus type-1 (HIV-1)/Leishmania co-infections has risen dramatically, particularly in regions where both diseases are endemic. Although it is known that HIV-1 infection leads to an increase in susceptibility to Leishmania infection and leishmaniasis relapse, little remains known on how HIV-1 contributes to Leishmania parasitaemia. Both pathogens infect human macrophages, and the intracellular growth of Leishmania is increased by HIV-1 in co-infected cultures. We now report that uninfected bystander cells, not macrophages productively infected with HIV-1, account for enhanced phagocytosis and higher multiplication of Leishmania parasites. This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β). Furthermore, we show for the first time that HIV-1 infection increases surface expression of phosphatidylserine receptor CD91/LRP-1 on human macrophages, thereby leading to a Leishmania uptake by uninfected bystander cells in HIV-1-infected macrophage populations. The more important internalization of parasites is due to interactions between the scavenger receptor CD91/LRP-1 and phosphatidylserine residues exposed at the surface of Leishmania. We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β. Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.

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HIV-1-mediated increase in Leishmania phagocytosis in uninfected bystander MDMs is inhibited by LRPAP/RAP.Mock-infected or 6 day HIV-1-infected MDMs were treated for 4 hours with the CD91/LRP-1-ligand antagonist, LRPAP/RAP, prior and during phagocytosis of Leishmania parasites (panel A) or zymosan particles (panel B), for 4 hours. MDMs were then fixed, stained and mounted for confocal microscopy analysis as described in Materials and Methods. The numbers of internalized targets were then determined. Results shown are the means of four distinct donors ± SEM.
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pone-0032761-g008: HIV-1-mediated increase in Leishmania phagocytosis in uninfected bystander MDMs is inhibited by LRPAP/RAP.Mock-infected or 6 day HIV-1-infected MDMs were treated for 4 hours with the CD91/LRP-1-ligand antagonist, LRPAP/RAP, prior and during phagocytosis of Leishmania parasites (panel A) or zymosan particles (panel B), for 4 hours. MDMs were then fixed, stained and mounted for confocal microscopy analysis as described in Materials and Methods. The numbers of internalized targets were then determined. Results shown are the means of four distinct donors ± SEM.

Mentions: In order to directly demonstrate the contribution of CD91/LRP-1-mediated phagocytosis in the HIV-1-dependent enhancement in Leishmania parasite uptake by uninfected bystander MDMs, we analyzed the effect of LRPAP/RAP, an antagonist of CD91/LRP-1-ligand interactions [26], on Leishmania or zymosan phagocytosis in HIV-1-infected MDM populations. Mock- or HIV-1-exposed macrophages were therefore treated with LRPAP/RAP prior and during phagocytosis of Leishmania parasites or zymosan particles. As shown in Figure 8A, a significant decrease in Leishmania parasite internalization was observed in uninfected bystander MDMs in presence of LRPAP/RAP when compared to the untreated counterpart (one tail, P = 0.038). Indeed, addition of the agonist brought down the numbers of internalized parasites in uninfected bystander cells to levels found in uninfected MDMs (P = 0.58). As shown in Figure 8B, the addition of LRPAP/RAP had no effect on zymosan phagocytosis, and thus was specific to CD91/LRP-1-mediated phagocytosis (P = 0.12).


HIV-1 promotes intake of Leishmania parasites by enhancing phosphatidylserine-mediated, CD91/LRP-1-dependent phagocytosis in human macrophages.

Lodge R, Ouellet M, Barat C, Andreani G, Kumar P, Tremblay MJ - PLoS ONE (2012)

HIV-1-mediated increase in Leishmania phagocytosis in uninfected bystander MDMs is inhibited by LRPAP/RAP.Mock-infected or 6 day HIV-1-infected MDMs were treated for 4 hours with the CD91/LRP-1-ligand antagonist, LRPAP/RAP, prior and during phagocytosis of Leishmania parasites (panel A) or zymosan particles (panel B), for 4 hours. MDMs were then fixed, stained and mounted for confocal microscopy analysis as described in Materials and Methods. The numbers of internalized targets were then determined. Results shown are the means of four distinct donors ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3295765&req=5

pone-0032761-g008: HIV-1-mediated increase in Leishmania phagocytosis in uninfected bystander MDMs is inhibited by LRPAP/RAP.Mock-infected or 6 day HIV-1-infected MDMs were treated for 4 hours with the CD91/LRP-1-ligand antagonist, LRPAP/RAP, prior and during phagocytosis of Leishmania parasites (panel A) or zymosan particles (panel B), for 4 hours. MDMs were then fixed, stained and mounted for confocal microscopy analysis as described in Materials and Methods. The numbers of internalized targets were then determined. Results shown are the means of four distinct donors ± SEM.
Mentions: In order to directly demonstrate the contribution of CD91/LRP-1-mediated phagocytosis in the HIV-1-dependent enhancement in Leishmania parasite uptake by uninfected bystander MDMs, we analyzed the effect of LRPAP/RAP, an antagonist of CD91/LRP-1-ligand interactions [26], on Leishmania or zymosan phagocytosis in HIV-1-infected MDM populations. Mock- or HIV-1-exposed macrophages were therefore treated with LRPAP/RAP prior and during phagocytosis of Leishmania parasites or zymosan particles. As shown in Figure 8A, a significant decrease in Leishmania parasite internalization was observed in uninfected bystander MDMs in presence of LRPAP/RAP when compared to the untreated counterpart (one tail, P = 0.038). Indeed, addition of the agonist brought down the numbers of internalized parasites in uninfected bystander cells to levels found in uninfected MDMs (P = 0.58). As shown in Figure 8B, the addition of LRPAP/RAP had no effect on zymosan phagocytosis, and thus was specific to CD91/LRP-1-mediated phagocytosis (P = 0.12).

Bottom Line: This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β).We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β.Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec-CHUL, Université Laval, Québec, Canada.

ABSTRACT
Over the past decade, the number of reported human immunodeficiency virus type-1 (HIV-1)/Leishmania co-infections has risen dramatically, particularly in regions where both diseases are endemic. Although it is known that HIV-1 infection leads to an increase in susceptibility to Leishmania infection and leishmaniasis relapse, little remains known on how HIV-1 contributes to Leishmania parasitaemia. Both pathogens infect human macrophages, and the intracellular growth of Leishmania is increased by HIV-1 in co-infected cultures. We now report that uninfected bystander cells, not macrophages productively infected with HIV-1, account for enhanced phagocytosis and higher multiplication of Leishmania parasites. This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β). Furthermore, we show for the first time that HIV-1 infection increases surface expression of phosphatidylserine receptor CD91/LRP-1 on human macrophages, thereby leading to a Leishmania uptake by uninfected bystander cells in HIV-1-infected macrophage populations. The more important internalization of parasites is due to interactions between the scavenger receptor CD91/LRP-1 and phosphatidylserine residues exposed at the surface of Leishmania. We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β. Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.

Show MeSH
Related in: MedlinePlus