How are antibodies involved in the protective mechanism of susceptible mice infected with T. cruzi?

Umekita, L.F.; Mota, I.

doi:10.1590/S0100-879X2000000300001

Abstract

Host resistance to Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the acute phase of the infection the presence of IFN-<FONT FACE=Symbol>g</font>, TNF-<FONT FACE=Symbol>a</font>, IL-12 and GM-CSF has been closely associated with resistance, whereas TGF-ß and IL-10 have been associated with susceptibility. Several investigators have demonstrated that antibodies are responsible for the survival of susceptible animals in the initial phase of infection and for the maintenance of low levels of parasitemia in the chronic phase. However, how this occurs is not yet understood. Our results and other data in the literature support the hypothesis that the protective role of antibodies in the acute phase of infection is dependent mostly on their ability to induce removal of bloodstream trypomastigotes from the circulation in addition to other concomitant cell-mediated events.

Trypanosoma cruzi; chronic mouse antibodies; clearance; cytokines; acute phase; susceptible mice

How are antibodies involved in the protective mechanism of susceptible mice infected with T. cruzi?

L.F. Umekita and I. Mota

Laboratório de Imunopatologia, Instituto Butantan, São Paulo, SP, Brasil

^Text

References

^{Correspondence and Footnotes} Correspondence and Footnotes

Host resistance to Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the acute phase of the infection the presence of IFN-g, TNF-a, IL-12 and GM-CSF has been closely associated with resistance, whereas TGF-ß and IL-10 have been associated with susceptibility. Several investigators have demonstrated that antibodies are responsible for the survival of susceptible animals in the initial phase of infection and for the maintenance of low levels of parasitemia in the chronic phase. However, how this occurs is not yet understood. Our results and other data in the literature support the hypothesis that the protective role of antibodies in the acute phase of infection is dependent mostly on their ability to induce removal of bloodstream trypomastigotes from the circulation in addition to other concomitant cell-mediated events.

Key words: Trypanosoma cruzi, chronic mouse antibodies, clearance, cytokines, acute phase, susceptible mice

Trypanosoma cruzi, the causative agent of Chagas' disease, is a protozoan parasite that affects millions of people in Latin America. The parasite assumes different morphological, physiological and biochemical characteristics during its life cycle. Ingested trypomastigotes differentiate in the insect gut into epimastigotes, the replicative form, which will then differentiate into metacyclic trypomastigotes, the infecting form, inside the insect. Once in the vertebrate host, infective trypomastigote forms readily enter cells where they replicate as amastigotes and differentiate into bloodstream trypomastigotes which are released and can either infect other cells, other mammalian hosts or new insects when they suck infected blood.

After experimental infection of normal mice the parasites are able to survive and replicate in a variety of nucleated cells and are easily detected in peripheral blood during the acute phase. This is followed by a considerable reduction of parasitemia with the establishment of an apparent equilibrium between the parasite and the host in the chronic phase of the infection. Animals in the chronic phase of the infection do not present a new acute phase even when re-infected with a very large infective dose of parasites. Susceptible mice do not survive the acute phase. To control infection in the acute and chronic phase several components of the innate and acquired immune responses are required simultaneously through still unclear mechanisms.

Many strains of mice have been studied and different experimental approaches have been used to obtain a better understanding of the immune response to T. cruzi. Evidence has accumulated over the years that cytokines play key roles in the control of the acute infection. IFN-g, TNF-a, IL-12 (1) and GM-CSF (2) seem to be the cytokines most closely associated with the control of the parasitemia and mortality of resistant mice in the acute phase of the disease. This occurs due to an increase of oxidative metabolism (3,4), stimulation and proliferation of cells involved in the production of IFN-g and TNF-a (5), and an increase of the cytotoxic activity of lymphocytes (6), although a direct nitric oxide-mediated killing of Trypanosoma cruzi has also been suggested (7). Other investigators have suggested that GM-CSF and TNF-a have a direct trypanocidal effect independent of nitric oxide liberation (8). Furthermore, transgenic mice with high levels of soluble TNF-a receptors that neutralize the in vivo effect of TNF-a are highly susceptible to T. cruzi infection (9). Class I MHC-restricted CD8+ T cells have been added to the list of critical effector mechanisms in immunity to T. cruzi (10-12). Furthermore, results of experiments in mice with induced defects in the cytolytic function of CD8+ T cells suggest that the control of T. cruzi infection by this population of T cells is not dependent on the granzyme perforin cytolytic pathway (11). However, there is also experimental evidence suggesting that TGF-ß (13) and IL-10 (14) increase the susceptibility to the infection by inhibiting the cytokines induced by macrophage activation and suppressing the production of reactive oxygen and nitrogen intermediates (15). Nitric oxide has also been shown to be involved in suppression of host immunity by participating in the modulation of the immune response by mediating apoptosis (16).

On the other hand, it has been known for many years that antibodies are very important in the control of the chronic phase of infection. Several investigators have shown that protection induced by adoptive transfer of spleen cells from chronically infected mice is prevented by depletion of B cells and that passive transfer of serum or IgG antibody isotypes collected from chronically infected mice protects naive recipients (17-19).

Two biological activities of T. cruzi antibodies are their ability to 1) induce in vitro lysis of the parasites (19) and 2) induce clearance of the parasites when injected together with trypomastigote forms into normal mice (20).

Attempts to characterize the parasite antigens, target of lytic antibodies, have identified a wide range of membrane polypeptides from 72 to 160 kDa (21-23). However, the mechanism by which these antigens participate in the lytic process is not well known. It has been suggested that some antigens may be molecules that prevent the interaction of C3b with factor B suppressing C3 convertase formation (24,25). In this case specific antibodies may inhibit this activity rendering the trypomastigotes susceptible to lysis.

Studies from our laboratory have demonstrated that trypomastigotes are easily removed from the mouse circulation in the presence of antibodies collected during the chronic phase of the infection and complement. In this situation the Fc fragment of the antibody molecule plus the C3 factor of the complement system are essential for parasite clearance (20). However, C5 is not involved, suggesting that lysis by complement activation is not implicated in parasite clearance (26).

An interesting biological aspect observed during the immune clearance of trypomastigotes is a significant decrease in platelet number (27). In addition, animals previously depleted of platelets show significantly decreased immune parasite clearance. In this respect, it is important to point out that platelets are involved in the antibody activity against Schistosoma mansoni larvae (28), Brugia malayi (29), sheep erythrocytes (30), and Trypanosoma musculi (31) and in chagasic cardiomyopathy (32).

Experiments performed in our laboratory by incubating opsonized trypomastigotes and platelets showed an immediate adherence of platelets to the parasites, but 4 h were required to produce lysis (33). This observation seems to rule out the possibility that platelet-induced lysis is involved in the clearance of bloodstream trypomastigotes since this is a very rapid phenomenon in vivo. Platelet adhesion to bloodstream trypomastigotes was only observed in the presence of antibody and complement.

Considering data reported by Norris et al. (22) suggesting that epimastigote forms of T. cruzi are not infective due to the absence of a 160-kDa membrane complement regulatory protein (CRP), it was interesting to determine the role of mouse platelets in epimastigote clearance. Curiously, the incubation of epimastigotes with fresh mouse whole blood, serum or plasma in the presence of platelets results in the immediate adherence of platelets to the parasites through a mechanism dependent on the C3 component of complement, although no lysis was induced. However, epimastigote forms are cleared from the circulation of mice at an extremely rapid rate (34).

The ultrastructural characterization of the fate of parasites 15 min after intravenous injection of an epimastigote suspension (1-2 x 10⁸) into normal mice showed clumps of parasites and platelets in direct contact with phagocytes in the lumen of capillaries. Parasites which were intact or in different stages of disintegration inside phagocytic cells were observed mostly in the pulmonary microvasculature (35).

Recent advances in the genetic manipulation of trypanosomes have shown that epimastigotes may be transfected with a plasmid encoding the trypomastigote-specific CRP, inducing conversion from a complement-sensitive to a complement-resistant state (36). These studies showed the critical function of this membrane protein in protecting the parasite from the effect of complement. Anti-CRP antibodies with the capacity to inhibit the C3b-CRP interaction were capable of supporting high levels of complement-mediated lysis of trypomastigotes and were also protective when adoptively transferred to mice prior to a lethal Trypanosoma cruzi challenge (36). On the other hand, Franchin et al. (37) showed that a sialylated epitope on the surface of bloodstream trypomastigotes is the target of a protective monoclonal antibody. This mAb did not lyse trypomastigotes in vitro in the presence of human complement or mouse spleen cells. The precise mechanism of action of this antibody is unknown.

When monitoring the appearance of lytic and clearance antibodies during the course of the infection, it can be seen that, whereas lytic antibodies appear early in the acute phase, clearance antibodies are detected later in the acute phase and in the chronic phase. Krettli et al. (38) showed that lytic antibodies present in trypomastigotes collected in the acute phase can be completely eluted when the parasites are incubated at 37^oC for 2 h (further incubation of the parasites in the presence of complement does not induce lysis). Similar results were obtained by De Gaspari et al. (39) who were also able to elute antibodies from trypomastigotes collected in the acute phase. Garcia et al. (40) showed that in the acute phase most antibodies on the membrane of trypomastigotes are of the IgM class, which is very efficient in inducing lysis (38,39) but very inefficient in inducing clearance (40,41).

In contrast to the total elution of antibodies bound to parasites collected in the acute phase we found that antibodies can only be partially eluted from trypomastigotes sensitized with serum obtained during the chronic phase of the disease (42).

Two remarkable characteristics of anti-T. cruzi antibodies with lytic and clearance abilities are that they are induced mostly by live parasites and are specific for each parasite strain (17,18).

One pertinent question at this point involves the role of lysis and clearance in protection against T. cruzi infection. However, it is difficult to answer since clearance antibodies usually also have lytic ability, although these two abilities could be distinguished by the use of heterologous antisera (43). In this regard, it should be pointed out that antisera from the acute phase, in spite of their high lytic ability (38,39), have no clearance effect (40,41). Furthermore, the behavior of anti-T. cruzi antibodies after recurrence of acute infection also suggests a protective role for clearance antibodies (44).

Earlier studies by MacAskill et al. (45) have shown that the liver plays a major role in immune clearance of T. brucei from the circulation of mice. Similarly, Dempsey and Mansfield (46) and Scott and Moyes (47) reported that the liver was the primary organ of immune clearance of T. rhodesiense and T. cruzi, respectively. Gregory and Wing (48) suggested that the principal mechanism for clearing pathogens from the bloodstream and eliminating them from the liver depends upon the complex interaction of Kupffer cells with neutrophils that migrate into the liver following infection. However, in experiments on mice, in which Kupffer cells were excluded surgically from the circulation, the clearance of T. musculi was not affected (49).

In our recent study about the fate of bloodstream forms of T. cruzi in mouse tissues after immune clearance we observed that parasites were present more frequently in the lung (50), most of them interiorized by neutrophils, eosinophils and monocytes in various stages of degeneration. However, platelets, that are important in the clearance of both epimastigote and trypomastigote forms, were not found inside phagocytic cells although they were abundant in the capillaries, sometimes occluding them completely. Indeed the vascular endothelial cells, which are important targets for parasites, are among the cells that are first encountered by invading organisms, are closely associated with platelet function, and may also mediate parasite elimination (51). The fact that endothelial cells have both Fc and C3 receptors (52,53) and secrete nitric oxide following cytokine stimulation has important implications for the host defense mechanism dependent on antibody, complement and platelets (54). In this context, experiments of intravital microscopy performed during the clearance of epimastigote forms of T. cruzi (55) have confirmed the critical role of endothelial cells in the clearance of these parasite forms. Experiments with opsonized bloodstream trypomastigote forms are under way in our laboratory.

In summary, there is evidence that different cell populations may be responsible for the elimination of T. cruzi from the circulation, suggesting that the protective role of antibodies with clearance ability in vivo is dependent on the presence of concomitant cell-mediated events. As outlined previously, trypomastigote forms infect most nucleated cells, and thus susceptible mammalian hosts represent a favorable environment for the development and replication of the parasite. It is reasonable to suggest that clearance-inducing antibodies can change the course of infection of susceptible hosts by directing the parasites to cells that recognize the opsonized organisms and help to destroy them through intra- and extracellular events involving cytokine-activated cells or their secreted products.

Abstract

We are grateful to Dr. Harumi A. Takehara for a critical reading of the manuscript.

Acknowledgments

Address for correspondence: L.F. Umekita, Laboratório de Imunopatologia, Instituto Butantan, Av. Vital Brasil, 1500, 05503-900 São Paulo, SP, Brasil. Fax: +55-11-815-1505. E-mail: umekita@amcham.com.br

Research supported by FAPESP, FUNDAP and Fundação Butantan. Received April 9, 1999. Accepted December 8, 1999.

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Correspondence and Footnotes

Publication Dates

Publication in this collection
16 Mar 2000
Date of issue
Mar 2000

History

Accepted
08 Dec 1999
Received
09 Apr 1999

This work is licensed under a Creative Commons Attribution 4.0 International License.

[1] 1. Abrahamsohn IA & Coffman RL (1996). Trypanosoma cruzi: IL-10, TNF-a, IFN-g and IL-12 regulate innate and acquired immunity to infection. Experimental Parasitology, 84: 231-244.

[2] 2. Reed SG, Grabstein KH, Pihl DL & Morrissey PJ (1990). Recombinant granulocyte-macrophage colony stimulating factor restores deficient immune responses in mice with chronic Trypanosoma cruzi infections. Journal of Immunology, 145: 1564-1570.

[3] 3. Silva JS, Vespa GNR, Cardoso MAG, Aliberti JCS & Cunha FQ (1995). Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages. Infection and Immunity, 63: 4862-4867.

[4] 4. Christoph H, Kohler G, Muller U, Mossmann H, Schaub GA & Brombacher F (1998). Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase. Infection and Immunity, 66: 1208-1215.

[5] 5. Hunter CA, Slifer T & Araujo F (1996). Interleukin-12-mediated resistance to Trypanosoma cruzi is dependent on tumor necrosis factor alpha and IFN-g. Infection and Immunity, 64: 2381-2386.

[6] 6. Kagi D, Ledermann B, Burk K, Zinkernagel RM & Hengartner H (1996). Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogens in vivo Annual Review of Immunology, 14: 207-232.

[7] 7. Vespa GNR, Cunha FQ & Silva JS (1994). Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro Infection and Immunity, 62: 5177-5182.

[8] 8. Font EO, De Baetselier P, Heirman C, Thiclemans K, Lucas R & Vray B (1988). Effects of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha on Trypanosoma cruzi trypomastigotes. Infection and Immunity, 66: 2722-2727.

[9] 9. Lima ECS, Garcia I, Vicentelli MH, Vassalli P & Minoprio P (1997). Evidence for a protective role of tumor necrosis factor in the acute phase of Trypanosoma cruzi infection in mice. Infection and Immunity, 65: 457-465.

[10] 10. Nickell SP, Stryker GA & Arevalo C (1993). Isolation from Trypanosoma cruzi-infected mice of CD8+ MHC-restricted cytotoxic T cells that lyse parasite-infected target cells. Journal of Immunology, 150: 1446-1457.

[11] 11. Kumar S & Tarleton RL (1998). The relative contribution of antibody production and CD8+ T cell function to immune control of Trypanosoma cruzi Parasite Immunology, 20: 207-216.

[12] 12. Tarleton RL, Koller BH, Latour A & Postan M (1992). Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature, 356: 338-340.

[13] 13. Silva JS, Twardzik D & Reed SG (1991). Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor-ß. Journal of Experimental Medicine, 174: 539-545.

[14] 14. Reed SG, Brownell CE, Russo DM, Silva JS, Grabstein KH & Morrissey PJ (1994). IL-10 mediates susceptibility to Trypanosoma cruzi infection. Journal of Immunology, 153: 3135-3140.

[15] 15. Gazzinelli RT, Oswald IP, James SL & Sher A (1991). IL-10 inhibits parasite killing and nitrogen oxide production by IFN-g-activated macrophages. Journal of Immunology, 148: 1792-1796.

[16] 16. Martins GA, Cardoso MAG, Aliberti JCSA & Silva JS (1998). Nitric oxide-induced apoptotic cell death in the acute phase of Trypanosoma cruzi infection. Journal of Experimental Medicine, 175: 169-174.

[17] 17. Brener Z (1980). Immunity to Trypanosoma cruzi Advances in Parasitology, 18: 247-292.

[18] 18. Tarleton RL (1997). Immunity to Trypanosoma cruzi In: Haufmann SHE (Editor), Host Response to Intracellular Pathogens Landes Company, Austin, TX, 227-247.

[19] 19. Brener Z & Krettli AU (1990). Immunology of Chagas disease. In: David J & Wyler WH (Editors), Modern Parasite Biology. Cellular, Immunological and Molecular Aspects Freeman and Company, New York, 247-261.

[20] 20. Umekita LF, Takehara HA & Mota I (1988). Role of the antibody Fc in the immune clearance of Trypanosoma cruzi Immunology Letters, 17: 85-89.

[21] 21. Martins MS, Hudson L, Krettli AU, Cançado JR & Brener Z (1985). Human and mouse sera recognize the same polypeptide associated with immunological resistance to Trypanosoma cruzi infection. Clinical and Experimental Immunology, 61: 343-350.

[22] 22. Norris KA, Harth G & So M (1989). Purification of a Trypanosoma cruzi membrane glycoprotein which elicits lytic antibodies. Infection and Immunity, 57: 2372-2377.

[23] 23. Umezawa ES, Stolf AM & Zingales B (1993). Trypanosoma cruzi: different surface antigens of trypomastigotes are target of lytic antibodies. Acta Tropica, 54: 41-53.

[24] 24. Norris KA, Bradt B, Cooper N & So M (1991). Characterization of a Trypanosoma cruzi C3 binding protein with functional and genetic similarities to the complement regulatory protein, decay accelerating factor. Journal of Immunology, 147: 2240-2247.

[25] 25. Norris KA & Schrimph JE (1994). Biochemical analysis of the membrane and soluble forms of the complement regulatory protein of Trypanosoma cruzi Infection and Immunity, 62: 236-243.

[26] 26. Mota I & Umekita LF (1989). The effect of C3 depletion on the clearance of Trypanosoma cruzi induced by IgG antibodies. Immunology Letters, 21: 223-226.

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