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Wednesday, November 21, 2012 10:54:05 AM
infected mice, and another which tests PGN401 (bavituximab) in guinea pigs infected with Ebola Zaire virus.
This is a great indication of how anti-PS antibodies have potential in anti-viral and anti-parasite uses.
The authors on the Leishmania paper include Dr. Phil Thorpe and Dr. Lynn Soong, who holds a joint appointment at
Department of Microbiology and Immunology, Institute for Human Infections and Immunity, and
Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Sealy Center for
Vaccine Development, University of Texas Medical Branch, Galveston, TX
Phosphatidylserine exposure on the surface of Leishmania amazonensis amastigotes modulates
in vivo infection and dendritic cell function
Parasite Immunolgy http://onlinelibrary.wiley.com/doi/10.1111/pim.12019/abstract
From the Introduction
[snip]
We have previously reported that amastigotes of L. amazonensis employ a unique strategy to
infect and regulate MF activity via the externalization of phosphatidylserine (PS) molecules (16,
17). PS is a phospholipid located in the inner leaflet of the plasma membrane that is translocated
transiently by some cell types during cell activation and differentiation (18-20) and permanently
during apoptotic cell death (21). Externalized PS molecules become targets for receptors
involved in apoptotic cell clearance and for triggering anti-inflammatory responses by
phagocytes, mainly characterized by the production of TGF-ß1 (19). We found that lesionderived
amastigotes make use of PS molecules in a similar way, maintaining those molecules on
their surface which serve as ligands for parasite endocytosis and MF modulation, in a
mechanism that we termed apoptotic mimicry (16, 17). PS exposure on intracellular pathogens
operates in several different infection models to facilitate infection and avoid the immune
system. Apoptotic mimicry is relevant for the infection of organisms such as Trypanosoma cruzi
and Toxoplasma gondii, in which their respective infective stages expose PS as a strategy to
silently invade host cells (22, 23). Viral particles that carry enveloped membranes from their
previous host cells also make use of exposed PS molecules to invade new cells (24-27). In
addition, by inducing transient PS exposure on the surface of host cells, viral infections can
spread signals derived from PS recognition, such as TGF-ß1 and IL-10 production by
neighboring phagocytes, to avoid full activation of the immune system (24). In fact, in viral
infection models, administration of an PS-targeting monoclonal antibody can cure about 35% of
guinea pigs infected with a lethal dose of Pichinde virus (a model for the human Lassa fever).
The efficiency of cure can reach up to 65% of the animals when PS-targeting mAb is combined
with standard anti-viral drugs. Furthermore, PS-targeting mAb treatment was also effective at
rescuing BALB/c mice with lethal murine cytomegalovirus infections (24).
Now, we demonstrate that PS-targeting treatment of mice infected with L. amazonensis parasites
decreases tissue parasite loads and lesion development. The in vivo effect of the antibody-based
treatment correlates both with increased T cell proliferation and increased DC activation in vitro.
DCs infected with lesion-derived amastigotes treated with PS-targeting mAb become more
efficient APCs, both for exogenous antigens, such as OVA, or for parasite antigens. PS-targeting
treatment could be employed, in co-administration with leishmanicidal drugs, as a therapeutic
strategy for the most severe clinical forms associated with L. amazonensis infection. Our
findings lead us to suggest that PS exposure by intracellular amastigotes of L. amazonensis acts
as a novel mechanism to down-modulate host immune responses
[snip]
From the Discussion section
[snip]
In this cutaneous leishmaniasis model, we found decreased tissue parasite loads and attenuated
lesions in mice receiving PS-targeting mAb, but not control mAb (Fig. 1). In contrast to the viral
infection models, PS-targeting treatment was not sufficient to clear leishmanial infection. Our
findings that PS-targeting treatment was able to restrain the kinetics of lesion progression (Fig.
1B) open a future research possibility for co-administering PS-targeting Ab and anti–leishmanial
drugs (42) for better control of non-healing New World leishmaniasis associated with L.amazonensis infection
[snip]
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