HIV-1 Promotes Intake of Leishmania Parasites by Enhancing Phosphatidylserine-Mediated, CD91/LRP-1-Dependent Phagocytosis in Human Macrophages

Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec-CHUL, Université Laval, Québec, Canada.
PLoS ONE (Impact Factor: 3.53). 03/2012; 7(3):e32761. DOI: 10.1371/journal.pone.0032761
Source: PubMed

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.

Download full-text


Available from: Michel Ouellet, Jul 05, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The outcomes of Leishmania infection are determined by host immune and nutrition status, parasite species, and co-infection with other pathogens. While subclinical infection and self-healing cutaneous leishmaniasis (CL) are common, uncontrolled parasite replication can lead to non-healing local lesions or visceral leishmaniasis (VL). It is known that infection control requires Th1-differentiation cytokines (IL-12, IL-18, and IL-27) and Th1 cell and macrophage activation. However, there is no generalized consensus for the mechanisms of host susceptibility. The recent studies on regulatory T cells and IL-17-producing cells help explain the effector T cell responses that occur independently of the known Th1/Th2 cell signaling pathways. This review focuses on the immunopathogenesis of non-healing American CL and progressive VL. We summarize recent evidence from human and animal studies that reveals the mechanisms of dysregulated, hyper-responses to Leishmania braziliensis, as well as the presence of disease-promoting or the absence of protective responses to Leishmania amazonensis and Leishmania donovani. We highlight immune-mediated parasite growth and immunopathogenesis, with an emphasis on the putative roles of IL-17 and its related cytokines as well as arginase. A better understanding of the quality and regulation of innate immunity and T cell responses triggered by Leishmania will aid in the rational control of pathology and the infection.
    Seminars in Immunopathology 10/2012; DOI:10.1007/s00281-012-0350-8 · 6.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leishmania amazonensis parasites can cause diverse forms of leishmaniasis in humans and persistent lesions in most inbred strains of mice. In both cases, the infection is characterized by a marked immunosuppression of the host. We previously showed that amastigote forms of the parasite make use of surface-exposed phosphatidylserine (PS) molecules to infect host cells and promote alternative macrophage activation, leading to uncontrolled intracellular proliferation of the parasites. In this study, we demonstrated that treatment of infected mice with an PS-targeting monoclonal antibody ameliorated parasite loads and lesion development, which correlated with increased proliferative responses by lymphocytes. In addition, we observed an enhanced dendritic cell (DC) activation and antigen presentation in vitro. Our data imply that the recognition of PS exposed on the surface of amastigotes plays a role in down-modulating DC functions, in a matter similar to that of apoptotic cell clearance. This study provides new information regarding the mechanism of immune suppression in Leishmania infection. © 2012 Blackwell Publishing Ltd.
    Parasite Immunology 11/2012; 35(3-4). DOI:10.1111/pim.12019 · 1.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE OF REVIEW: HIV infection profoundly impairs the immune mechanisms needed to control and clear Leishmania infection, and outcomes in patients with HIV-associated visceral leishmaniasis are poor. This review summarizes recent work describing the epidemiology, presentation and outcomes of HIV-associated visceral leishmaniasis and discusses advances in diagnosis and management. RECENT FINDINGS: Studies have shown that serological tests can effectively diagnose HIV-associated visceral leishmaniasis, with a sensitivity of 98% if direct agglutination test and rK39 assays are used in combination. Few data exist to guide treatment recommendations. Observational data show high rates of toxicity and treatment failure with pentavalent antimonials, and their use is no longer recommended. Liposomal amphotericin B (L-AmB) is better tolerated, but outcomes are suboptimal, with mortality rates of 7-12%, and parasitological failure rates of up to 32%. Initial reports suggest that L-AmB and miltefosine in combination may be effective in HIV-associated visceral leishmaniasis; however, clinical trial data are lacking. Secondary prophylaxis reduces the rate of relapse, but optimal regimens have not been defined, and optimal timing of antiretroviral therapy initiation in patients with visceral leishmaniasis is unknown. SUMMARY: Recent studies have demonstrated the inadequacy of current treatments for HIV-associated visceral leishmaniasis. Clinical trials are needed to improve early diagnosis, develop combination therapies and define effective secondary prophylaxis regimens.
    Current Opinion in Infectious Diseases 12/2012; DOI:10.1097/QCO.0b013e32835c2198 · 5.03 Impact Factor