Acquired Resistance to the Acute Phase


Although human hosts have no natural resistance to the acute phase of Chagas’ disease, infected humans usually acquire resistance to the severe pathology of the acute phase from subsequent infections, either of the same or different strains. Acquired resistance (partial immunity) is an immunity that slowly develops after the establishment of the acute phase and is antibody dependent. Acquired resistance primarily protects hosts from the mortality associated with initial contact with the parasite (acute phase) and from consequences of future acute phases by a quick and vigorous immune response. But acquired resistance remains only as long as T. cruzi is present.

An important consideration for doctors is whether or not to completely kill all the parasites in the body of someone living in an endemic area, where that person is at high risk of being reinfected and possibly subject to the acute pathology. An alternative is to help the immune system manage the number of parasites throughout the chronic phase. Paradoxically, the one bonus T. cruzi provides to infected individuals is protection from the frequently deadly attacks of parasitemia in the acute phase. However, even this resistance wanes and waxes, as evidenced by exacerbations of the infection with repeat acute attacks in some individuals throughout life.

Parasites have many strategies for evading host immunity. Some evasive strategies are less refined, such as destruction of T4 cells by HIV, while others are more fine‑tuned, such as getting inside cells and hiding, acquiring or synthesizing hostlike surface components, modulating the immune system so that it doesn’t destroy them, or developing antigenic variation. Trypanosoma cruzi can incorporate certain host plasma proteins onto its surface to escape immune recognition. It can also cleave antibody molecules attached to its surface, rendering them ineffective as markers for immune cells and complement. As already discussed, T. cruzi are unable to antigenically vary their surfaces as effectively as their African counterparts. Rather than face the immune system, T. cruzi runs for cover, employing an evasive strategy of quickly entering into host cells, where it hides and reproduces as amastigotes (an intracellular, nonflagellated form; see Figure 5). Thus, T. cruzi uses intracellular localization to evade immunity, a strategy that appears important during the chronic phase of infection when the majority of parasites are intracellular. Post‑mortem examinations indicate that chronic patients have amastigotes within their heart cells years after the initial infection.

The human immune system is as sophisticated, perplexing, and capable as are the parasites against which it acts. The human immune system is how the host defends itself against nonself entities (viruses, bacteria, protozoa, etc.). It also serves as an internal janitor, assigned the job of cleaning up self components that have been altered. The immune system also preserves body integrity, monitors internal changes, attacks foreign organisms, degrades and passes on information about nonself intruders, and remembers the information for future attacks. The human immune system is broadly classified into cellular and humoral components, which can act independently as well as interact in varying degrees of complexity. Cellular response depends on the action of cells, whereas humoral immunity depends on antibody molecules, which are present in the blood and body fluids. Both cellular and humoral responses are mounted during T. cruzi infection.

The basic components of the humoral immune system are immunoglobulins, which are closely related but not identical proteins that interact with the specific antigens promoting their production. Out of five major types, immunoglobulin M (IgM) and immunoglobulin G (IgG) are featured in the host response to T. cruzi. IgM is the body’s first reaction to the parasite and is relatively ineffective in Chagas’ disease. Appearing later and being more effective against blood‑form trypomastigotes, IgG is the principal antibody in the blood. T. cruzi‑ specific IgG and IgM are crucial to driving the parasite into an intracellular existence, terminating the acute phase of the disease. This antibody attack is T‑cell‑dependent. That is, T cells recognizing T. cruzi antigen stimulate B cell proliferation and differentiation into plasma cells, actively producing parasite‑specific antibodies. Among activated lymphocytes are long‑lived memory cells which respond rapidly to secondary infection with T. cruzi, producing quick and effective humoral and cellular responses against the parasite.

Antibodies bound to the surface of T. cruzi trigger contact killing of bloodstream forms of T. cruzi by host cells, a process referred to as antibodydependent, cell‑mediated cytotoxicity (ADCC). ADCC elicits response by eosinophils, macrophages, and neutrophils, when antibodies are present, against bloodstream forms of T. cruzi (Kierszenbaum 1979; Kierszenbaum, Ackerman, and Gleich 1981). Macrophages phagocytize the parasite, and granules in the eosinophils and neutrophils fuse with the phagosome and kill T. cruzi (Okabe et al. 1980:344‑53). When macrophages are not activated by IgG antibodies specific to T. cruzi, then macrophagic engulfment works to the parasites’ benefit in that trypomastigotes are not killed but rather multiply within the macrophages and spread throughout other parts of the body. In fact, certain strains of T. cruzi prefer macrophages as first cellular sites for reproduction for the very reason that macrophages are mobile and ineffective until IgG antibodies are produced against them several weeks after the first infection.

When T. cruzi infects humans, it frequently invades monocytes, which are circulating macrophages important in phagocytosis. Phagocytosis is a process of engulfment of the invading particle within a vacuole created from the white blood cell’s membrane. The cell then empties digestive enzymes from organelles called lysosomes into the vacuole to destroy the particle (Schmidt and Roberts 1989:21). When blood monocytes move into the tissue, they differentiate into macrophages. As already discussed, macrophages are effective in destroying T. cruzi only in the presence of specific antibodies. Until the T cells are able to orchestrate the antibodies and macrophages, T. cruzi multiplies and spreads to other cells.

The dual role of macrophages makes them metaphorically similar to the fox guarding the hen house. Monocytes and macrophages first serve as host cells which support the parasites’ intracellular multiplication as amastigotes and differentiation into infective trypomastigotes. Macrophages are very mobile cells, so T. cruzi spreads throughout the body until macrophages are told to stay where they are; but this takes the assistance of T helper cells, which elaborate chemical messages (cytokines) that instruct macrophages to destroy the parasite. By this time, T. cruzi has entered many other types of cells and become ensconced within these other cells.

The belief that macrophages need ADCC to kill T. cruzi has been supported with naive (immunosuppressed) mice that were deprived of immunoglobulin production and infected with T. cruzi. These mice could not produce antibodies against the trypanosomes, and their macrophages engulfed but were unable to destroy the parasites. The parasites multiplied within the macrophages. With similarly immunosuppressed mice, trypanosomes were first exposed to immunoglobulin outside of the mice and then injected into the naive mice. Trypanosomes with antibodies were engulfed and destroyed by macrophages, so opsonization is an important process in phagocytosis of T. cruzi. Opsonization implies that antibodies mediate destruction of parasites by first binding the open end (FAB) of their Y‑shaped molecule to the parasite’s antigen. Phagocytic macrophages then recognize the projecting stem (Fc) of the antibody, engulf, and lyse the parasite.

However, it has not been established that antibodies on the parasite’s surface are the only factor involved in the opsonization process. In another experiment with immunocompetent mice, researchers stimulated the production of macrophages by injections of Bacillus Calmette‑Guerin (BCG), which is a protein similar to TB in its macrophage‑stimulating actions. This caused an activation of macrophages that were non‑specific for T. cruzi antigens. These macrophages engulfed T. cruzi, limited their multiplication, but did not kill them. This experiment indicated that BCG activates macrophages to at least the level of controlling reproduction but not to the top level as specific T. cruzi antibodies do. It takes cytokines, which are substances released by sensitized lymphocytes when they contact specific T. cruzi antigens, to reach that top level of macrophage activation. Cytokines help to produce cellular immunity by stimulating macrophages and monocytes. Cytokines cause macrophages to go one step farther and be trypanocidal.

A combination of T cells and macrophages is needed to destroy T. cruzi. Without this balance, problems arise: if a person has a lot of macrophages and fewer T cells, then this person will suffer a much more severe infection than one with a balance of the two or a surplus of T cells. One obvious conclusion is that immunosuppressed people, such as AIDS patients with depleted T cells, can suffer severe infections of Chagas’ disease.

Macrophage activation also demonstrates an important feature of the immune system: that there are different levels of macrophage activity, ranging from merely engulfing T. cruzi, which enables it to multiply and spread, to engulfing it and inhibiting its multiplication and spread, and, at the highest level, to involving T cells, with which the parasite is destroyed. It is not all or nothing in macrophage activation; rather, there are degrees of effectiveness and interacting processes.


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