Leishmania donovani: Action of excreted factor on hydrolytic enzyme activity of macrophages from mice with genetically different resistance to infection

El‐On, Joseph; Bradley, David J.; Freeman, Joan

doi:10.1016/0014-4894(80)90114-9

Cited by 67 publications

(15 citation statements)

References 16 publications

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“…However, we and others have provided previously compelling evidence that Leishmania promastigotes are perfectly well adapted for survival in acidic environments. Promastigotes grow normally at pH 5.5 [42], and their surface glycocalyx confers resistance to lysosomal hydrolases in insect and vertebrate hosts [43]–[46]. We previously showed that intracellular survival of attenuated lpg − mutants was restored to wild-type levels in oxidant-deficient phox −/− host cells, although extensive fusion of parasite-containing phagosomes with host cell lysosomes occurred [18].…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major

et al. 2009

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Intracellular parasites of the genus Leishmania generate severe diseases in humans, which are associated with a failure of the infected host to induce a protective interferon γ (IFNγ)-mediated immune response. We tested the role of the JAK/STAT1 signaling pathway in Leishmania pathogenesis by utilizing knockout mice lacking the signal transducer and activator of transcription 1 (Stat1) and derived macrophages. Unexpectedly, infection of Stat1-deficient macrophages in vitro with promastigotes from Leishmania major and attenuated LPG1 knockout mutants (lpg −) specifically lacking lipophosphoglycan (LPG) resulted in a twofold increased intracellular growth, which was independent of IFNγ and associated with a substantial increase in phagosomal pH. Phagosomes in Stat1−/− macrophages showed normal maturation as judged by the accumulation of the lysosomal marker protein rab7, and provided normal vATPase activity, but were defective in the anion conductive pathway required for full vesicular acidification. Our results suggest a role of acidic pH in the control of intracellular Leishmania growth early during infection and identify for the first time an unexpected role of Stat1 in natural anti-microbial resistance independent from its function as IFNγ-induced signal transducer. This novel Stat1 function may have important implications to studies of other pathogens, as the acidic phagolysosomal pH plays an important role in antigen processing and the uncoating process of many viruses.

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Section: Discussionmentioning

confidence: 99%

A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major

et al. 2009

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“…One of the first biological activities of EF to be described was the promotion of growth of leishmania strains in non-permissive hosts (Handman & Greenblatt 1977). El-On, Bradley & Freeman (1980) have shown that EF inhibits /?-galactosidase of mouse macrophages, a result suggesting that a leishmania1 factor may modify the activity of lysosomal enzymes produced by the host and therefore be partially responsible for the macrophage-parasite relationship during the disease. Handman, Ceredig & Mitchell (1979) found that crude EF taken up in uitro by macrophages may be presented in a faulty fashion to T-lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Action of leishmanial excreted factor (EF) on human lymphocyte blast transformation

Londner

Frankenburg

Slutzky

et al. 1983

Parasite Immunology

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The effect of Leishmania tropica major excreted factor (EF) on human immune and normal mononuclear peripheral blood cells has been studied. The response of lymphocytes to stimulation either specifically with leishmanial antigens or non-specifically with phytohemagglutinin (PHA) in the presence of EF was tested by the uptake of 3 [H]thymidine. The results showed that EF inhibits the response of cells from immune donors to leishmanial antigens and from normal donors to PHA or PPD. Adherent and non-adherent cells were separated and the effect of EF on both populations was analysed. The results showed that EF inhibited blast transformation if both EF and antigen were presented to each of the separate populations. The inhibition of the adherent cells (mainly monocytes) was more marked than the inhibition of the non-adherent population (mainly lymphocytes).

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“…In that regard, such extracellular factors have been demonstrated with the amastigote stage of the life cycle [68] and in vitro promastigote-generated factors have been used to render normally resistant macrophages susceptible to parasite infection [69]. Further, such factors have been implicated both as a lymphocyte inhibitor [70] and as an inhibitor of murine 0-galactosidase but not several other murine macrophage lysosom-a1 hydrolases [71].…”

Section: Additional Surface Membrane Factorsmentioning

confidence: 99%

The surface membrane chemistry of Leishmania: Its possible role in parasite sequestration and survival

Dwyer

Gottlieb

1983

J of Cellular Biochemistry

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Species of the parasitic protozoan genus Leishmania are the causative agents of a wide variety of human cutaneous, mucocutaneous, and visceral diseases. These organisms reside throughout their digenetic life cycles in hydrolytic environs, ie, as extracellular, flagellated promastigote forms in the alimentary tract of their sandfly vector hosts and as obligate intracellular amastigote forms within the phagolysosomal system of macrophages in their mammalian hosts. In the latter hosts, cutaneous (eg L tropica, L major, and L mexicana) and mucocutaneous (eg, L braziliensis) species reside within, and are generally restricted to, macrophages of the skin and/or the mucous membranes, whereas viscerotropic species (eg, L donovani, L aethiopica, L infantum, and L chagasi) inhabit tissue macrophages of the spleen, liver (ie, Kupffer cells), and bone marrow [l-141.How these organisms transform, survive, and respond to signals within their infected hosts is unknown. However, considering that all physiologic and biochemical interactions between host and parasite occur, at least temporally, at or across such membranes (eg, they are in direct confrontation with both host immune and nonimmune responses, and all of an organism's nutrient requirements, as well as its secretory and metabolic excretory products, must traverse them), they must obviously play a central role in the survival and maintenance of the parasite within the infected host. Therefore, knowledge of the chemical, enzymatic, and antigenic composition of surface membranes are of import in defining the mechanisms by which Leishmania survive. Further, the identification of unique parasite surface membrane constituents may prove useful as adjuncts in the clinical diagnosis of leishmania1 infections in addition to serving as potential targets for the design of new and more effective chemotherapeutic agents and/or immunoprophylactic therapies.

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Leishmania donovani: Action of excreted factor on hydrolytic enzyme activity of macrophages from mice with genetically different resistance to infection

Cited by 67 publications

References 16 publications

A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major

A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major

Action of leishmanial excreted factor (EF) on human lymphocyte blast transformation

The surface membrane chemistry of Leishmania: Its possible role in parasite sequestration and survival

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