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Immune adherence-mediated opsonophagocytosis: the mechanism of Leishmania infection.

Domínguez M, Toraño A - J. Exp. Med. (1999)

Bottom Line: We propose that adaptation to the immune adherence mechanism aids Leishmania survival, promoting rapid promastigote phagocytosis by leukocytes.This facilitates host colonization and may represent the parasite's earliest survival strategy.In light of this mechanism, it is unlikely that infection-blocking vaccines can be developed.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Inmunología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, E-28220 Madrid, Spain.

ABSTRACT
To mimic the sandfly pool feeding process and characterize the cellular and biochemical events that occur during the early stages of promastigote-host interaction, we developed an ex vivo model of human blood infection with Leishmania promastigotes. Within 30 s of blood contact, Leishmania promastigotes bind natural anti-Leishmania antibodies, which then activate the classical complement pathway and opsonization by the third component of complement. The opsonized promastigotes undergo an immune adherence reaction and bind quantitatively to erythrocyte CR1 receptors; opsonized Leishmania amastigotes also bind to erythrocytes. Progression of infection implies promastigote transfer from erythrocytes to acceptor blood leukocytes. After 10 min of ex vivo infection, 25% of all leukocytes contain intracellular parasites, indicating that blood cells are the early targets for the invading promastigotes. We propose that adaptation to the immune adherence mechanism aids Leishmania survival, promoting rapid promastigote phagocytosis by leukocytes. This facilitates host colonization and may represent the parasite's earliest survival strategy. In light of this mechanism, it is unlikely that infection-blocking vaccines can be developed.

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Kinetic profile of Leishmania IA reaction. The time course of  the opsonizing reactions involved in the Leishmania IA mechanism. IgM  binding (▪), C3 deposition (▴), and the promastigote–erythrocyte interaction (•) are taken from Fig. 3, B and A, and Fig. 2, respectively. Data  are expressed as a percentage of the point of maximum reaction.
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Figure 7: Kinetic profile of Leishmania IA reaction. The time course of the opsonizing reactions involved in the Leishmania IA mechanism. IgM binding (▪), C3 deposition (▴), and the promastigote–erythrocyte interaction (•) are taken from Fig. 3, B and A, and Fig. 2, respectively. Data are expressed as a percentage of the point of maximum reaction.

Mentions: IA plays a central role in the clearance of opsonized microorganisms and foreign particles from the circulation via their removal by phagocytes (57). Accordingly, we propose that Leishmania adaptation to the host IA mechanism aids parasite survival by promoting rapid promastigote phagocytosis and leukocyte colonization. During Leishmania opsonization in human blood, promastigotes undergo three continuous reactions: natural antibody binding, followed by C3 deposition, followed by subsequent adherence to erythrocytes. Each reaction proceeds at a different velocity (Fig. 7). Promastigote–IgM binding and erythrocyte–promastigote IA are very rapid, whereas promastigote C3 deposition by the classical pathway is a slower process. It is believed that IA proceeds faster than C3b deposition because erythrocyte CR1 receptors cluster on the cell surface and establish multipoint interactions with C3b ligands (58). This cooperative effect increases in such extent the overall CR1–C3b interaction avidity, that only very few C3b molecules (between 60 and 3,000 molecules/cell) are required to produce a positive IA reaction (59). A similar phenomenon appears to occur in Leishmania IA. Within 30 s of ex vivo infection, >80% of Leishmania epitopes recognized by IgM are occupied, the IA reaction is completed, and promastigotes are being shuttled to blood phagocytes. Complement lysis of parasites is still negligible at this time, as only ∼5% (10,000 molecules) of the total C3 promastigote acceptor capacity has been deposited. Since in the presence of 25% NHS, 50% [111In] cpm release from labeled promastigotes is registered by 90 s, the IA mechanism could substantially aid Leishmania survival through promotion of promastigote phagocytosis by leukocytes, which provide a safe haven for the parasite.


Immune adherence-mediated opsonophagocytosis: the mechanism of Leishmania infection.

Domínguez M, Toraño A - J. Exp. Med. (1999)

Kinetic profile of Leishmania IA reaction. The time course of  the opsonizing reactions involved in the Leishmania IA mechanism. IgM  binding (▪), C3 deposition (▴), and the promastigote–erythrocyte interaction (•) are taken from Fig. 3, B and A, and Fig. 2, respectively. Data  are expressed as a percentage of the point of maximum reaction.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887685&req=5

Figure 7: Kinetic profile of Leishmania IA reaction. The time course of the opsonizing reactions involved in the Leishmania IA mechanism. IgM binding (▪), C3 deposition (▴), and the promastigote–erythrocyte interaction (•) are taken from Fig. 3, B and A, and Fig. 2, respectively. Data are expressed as a percentage of the point of maximum reaction.
Mentions: IA plays a central role in the clearance of opsonized microorganisms and foreign particles from the circulation via their removal by phagocytes (57). Accordingly, we propose that Leishmania adaptation to the host IA mechanism aids parasite survival by promoting rapid promastigote phagocytosis and leukocyte colonization. During Leishmania opsonization in human blood, promastigotes undergo three continuous reactions: natural antibody binding, followed by C3 deposition, followed by subsequent adherence to erythrocytes. Each reaction proceeds at a different velocity (Fig. 7). Promastigote–IgM binding and erythrocyte–promastigote IA are very rapid, whereas promastigote C3 deposition by the classical pathway is a slower process. It is believed that IA proceeds faster than C3b deposition because erythrocyte CR1 receptors cluster on the cell surface and establish multipoint interactions with C3b ligands (58). This cooperative effect increases in such extent the overall CR1–C3b interaction avidity, that only very few C3b molecules (between 60 and 3,000 molecules/cell) are required to produce a positive IA reaction (59). A similar phenomenon appears to occur in Leishmania IA. Within 30 s of ex vivo infection, >80% of Leishmania epitopes recognized by IgM are occupied, the IA reaction is completed, and promastigotes are being shuttled to blood phagocytes. Complement lysis of parasites is still negligible at this time, as only ∼5% (10,000 molecules) of the total C3 promastigote acceptor capacity has been deposited. Since in the presence of 25% NHS, 50% [111In] cpm release from labeled promastigotes is registered by 90 s, the IA mechanism could substantially aid Leishmania survival through promotion of promastigote phagocytosis by leukocytes, which provide a safe haven for the parasite.

Bottom Line: We propose that adaptation to the immune adherence mechanism aids Leishmania survival, promoting rapid promastigote phagocytosis by leukocytes.This facilitates host colonization and may represent the parasite's earliest survival strategy.In light of this mechanism, it is unlikely that infection-blocking vaccines can be developed.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Inmunología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, E-28220 Madrid, Spain.

ABSTRACT
To mimic the sandfly pool feeding process and characterize the cellular and biochemical events that occur during the early stages of promastigote-host interaction, we developed an ex vivo model of human blood infection with Leishmania promastigotes. Within 30 s of blood contact, Leishmania promastigotes bind natural anti-Leishmania antibodies, which then activate the classical complement pathway and opsonization by the third component of complement. The opsonized promastigotes undergo an immune adherence reaction and bind quantitatively to erythrocyte CR1 receptors; opsonized Leishmania amastigotes also bind to erythrocytes. Progression of infection implies promastigote transfer from erythrocytes to acceptor blood leukocytes. After 10 min of ex vivo infection, 25% of all leukocytes contain intracellular parasites, indicating that blood cells are the early targets for the invading promastigotes. We propose that adaptation to the immune adherence mechanism aids Leishmania survival, promoting rapid promastigote phagocytosis by leukocytes. This facilitates host colonization and may represent the parasite's earliest survival strategy. In light of this mechanism, it is unlikely that infection-blocking vaccines can be developed.

Show MeSH
Related in: MedlinePlus