Avid Bioservices Inc (CDMO)

[jazzbeerman]

Leishmania Exploits Exposed PS ------



parasitic infection through "apoptotic mimicry"....






The Journal of Immunology, 2006, 176: 1834-1839
.


Mimicry of Apoptotic Cells by Exposing Phosphatidylserine Participates in the Establishment of Amastigotes of Leishmania (L) amazonensis in Mammalian Hosts

http://www.jimmunol.org/cgi/content/abstract/176/3/1834


João L. M. Wanderley*,{dagger}, Maria E. C. Moreira*, Aline Benjamin*,{dagger}, Adriana C. Bonomo*,{ddagger} and Marcello A. Barcinski2,*,§


Signaling through exposed phosphatidylserine (PS) is fundamental for the TGFbeta1-dependent, noninflammatory phagocytosis of apoptotic cells. This same mechanism operates in the internalization of amastigotes of Leishmania (L) amazonensis (L(L)a) in a process quoted as apoptotic mimicry. Now we show that the host modulates PS exposure by the amastigotes and, as a consequence, BALB/c mice-derived amastigotes expose significantly more PS than those derived from C57BL/6 mice. Due to this difference in the density of surface PS molecules, the former are significantly more infective than the latter, both in vivo, in F1 (BALB/c x C57BL/6) mice, and in vitro, in thioglycollate-derived macrophages from this same mouse strain. PS exposure increases with progression of the lesion and reaches its maximum value in amastigotes obtained at the time point when the lesion in C57BL/6 mice begins to decrease in size and the lesions in BALB/c mice are still growing in size. Synthesis of active TGFbeta1, induction of IL-10 message, and inhibition of NO synthesis correlate with the amount of surface PS displayed by viable (propidium iodide-negative) infective amastigote. Furthermore, we also show that, similar to what happens with apoptotic cells, amastigotes of L(L)a are internalized by macropinocytosis. This mechanism of internalization is consistent with the large phagolysosomes characteristic of L(L)a infection. The intensity of macrophage macropinocytic activity is dependent on the amount of surface PS displayed by the infecting amastigote.




------------------------


more Leishmania & PS



Braz J Med Biol Res. 2005 Jun;38(6):807-12. Epub 2005 Jun 1.

Apoptotic mimicry: an altruistic behavior in host/Leishmania interplay.


Wanderley JL, Benjamin A, Real F, Bonomo A, Moreira ME, Barcinski MA.

Instituto Nacional de Cancer, 20231-050 Rio de Janeiro, RJ, Brasil.



Apoptosis is the most common phenotype observed when cells die through programmed cell death. The morphologic and biochemical changes that characterize apoptotic cells depend on the activation of a diverse set of genes. Apoptosis is essential for multicellular organisms since their development and homeostasis are dependent on extensive cell renewal. In fact, there is strong evidence for the correlation between the emergence of multicellular organisms and apoptosis during evolution. On the other hand, no obvious advantages can be envisaged for unicellular organisms to carry the complex machinery required for programmed cell death. However, accumulating evidence shows that free-living and parasitic protozoa as well as yeasts display apoptotic markers. This phenomenon has been related to altruistic behavior, when a subpopulation of protozoa or yeasts dies by apoptosis, with clear benefits for the entire population. Recently, phosphatidylserine (PS) exposure and its recognition by a specific receptor (PSR) were implicated in the infectivity of amastigote forms of Leishmania, an obligatory vertebrate intramacrophagic parasite, showing for the first time that unicellular organisms use apoptotic features for the establishment and/or maintenance of infection. Here we focus on PS exposure in the outer leaflet of the plasma membrane--an early hallmark of apoptosis--and how it modulates the inflammatory activity of phagocytic cells. We also discuss the possible mechanisms by which PS exposure can define Leishmania survival inside host cells and the evolutionary implications of apoptosis at the unicellular level.





--------------------------------







Curr Biol. 2001 Nov 27;11(23):1870-3.

Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity.



de Freitas Balanco JM, Moreira ME, Bonomo A, Bozza PT, Amarante-Mendes G, Pirmez C, Barcinski MA.

Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil.

Programmed cell death by apoptosis of unnecessary or potentially harmful cells is clearly beneficial to multicellular organisms. Proper functioning of such a program demands that the removal of dying cells proceed without an inflammatory reaction. Phosphatidylserine (PS) is one of the ligands displayed by apoptotic cells that participates in their noninflammatory removal when recognized by neighboring phagocytes. PS ligation induces the release of transforming growth factor-beta (TGF-beta), an antiinflammatory cytokine that mediates the suppression of macrophage-mediated inflammation. In Hydra vulgaris, an organism that stands at the base of metazoan evolution, the selective advantage provided by apoptosis lies in the fact that Hydra can survive recycling apoptotic cells by phagocytosis. In unicellular organisms, it has been proposed that altruistic death benefits clonal populations of yeasts and trypanosomatids. Now we show that advantageous features of the apoptotic process can operate without death as the necessary outcome. Leishmania spp are able to evade the killing activity of phagocytes and establish themselves as obligate intracellular parasites. Amastigotes, responsible for disease propagation, similar to apoptotic cells, inhibit macrophage activity by exposing PS. Exposed PS participates in amastigote internalization. Recognition of this moiety by macrophages induces TGF-beta secretion and IL-10 synthesis, inhibits NO production, and increases susceptibility to intracellular leishmanial growth.





-----------------------------




Leishmaniasis

http://www.sbri.org/diseases/leishmaniasis.asp


Impact

Leishmaniasis is a parasitic disease transmitted by the bite of a sandfly that is infected with Leishmania parasites. Currently 350 million people in 88 countries around the world are threatened, and 12 million people are affected by leishmaniasis. Of the 1.5 – 2 million new cases of leishmaniasis estimated to occur annually, most occur in the tropics and subtropics, including the Middle East. In 2002, leishmaniasis reached epidemic levels in Afghanistan, with the World Health Organization calling for more funding and research for the disease. Leishmania/HIV co-infection is emerging as a serious new disease and it is increasingly frequent. It is considered a threat in southwestern Europe, such as Spain, Italy, France, and Portugal.


Symptoms

With the bite of an infected sandfly, Leishmania parasites are passed from one infected animal or human to others. Leishmaniasis is a spectrum of diseases, each distinctly manifested and all with potentially devastating consequences – disfigurement, damage to internal organs, death. Depending on the species of the infecting parasite, the spleen, liver, bone marrow, mucous membranes, and/or skin may be attacked. Leishmania donovani, the most dangerous of these, causes Kala azar, or visceral leishmaniasis, characterized by fever, severe weight loss and anemia. If left untreated, visceral leishmaniasis can lead to death.




--------------------------





j