Immune Response to Parasitic Infections

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Parasites interact with different B cell compartments triggering, in most cases, a vigorous antibody response. Unfortunately, this response is not necessarily protective; indeed, it can be harmful for the host. In this chapter we describe how protozoan parasites and helminths induce mature B cell responses and how B cells influence the characteristics of T cell response involved in parasite control. To protect themselves, the parasites develop unique ways to evade B cell responses, including changes in their antigenic coat and induction of immunosuppression and apoptosis of B cells. We discuss how parasites elude B cell immunity establishing a favourable balance that drives the infection to chronicity.

Trypanosoma cruzi is a blooded-flagellated protozoan transmitted to humans either by blood-sucking triatomine vectors, by blood transfusion or by congenital transmission causing the Chagas’ disease or American Trypanosomiasis. Serologic testing for specific antibodies to T. cruzi antigens is the most common employed approach for diagnosing chronic infection with this protozoan parasite in clinical patients as well as in blood donors. No assay has been universally accepted as the gold standard for the serologic diagnosis of T. cruzi infection, and likewise no assay is viewed as a definitive confirmatory test. Therefore, the antigen fractions (antigenic extract form, recombinant antigens and/or synthetic peptides) may have different affinities for both specific and non-specific antibodies and can produce variable sensitivities. To date, excreted-secreted antigens by the parasites have been proposed as antigen fractions for the detection of this parasite: Trypomastigote Excretory-Secretory Antigens (TESA), composed mainly of surface components such as SAPA, Gala1-3Gal, Tc-85 and T-DAF epitopes and excreted dismutase (SODe) appears to provide good sensitivity and specificity as reagents for the diagnosis of Chagas’ disease. This chapter revises the research on excreted/secreted antigens and their utility to establish an ideal diagnostic confirmatory Chagas test.

This review critically examines the development of malaria vaccine candidates and the results obtained in phase IIa and IIb efficacy evaluations since the first human trial till date. It is restricted only to proteins or protein fragments produced by peptide synthesis or DNA recombinant technology, for the simple reason that these are the only products that could be structurally evaluated. It is meant to make the scientific community aware of the shortcomings of some of these constructs with regard to their 3-dimensional structure and the need for more stringent biological/functional requirements to be met before field evaluations are initiated. Both of these factors are largely responsible for most of the failures witnessed in the past 20 years.

It is currently estimated that a total of 2.6 billion people live at a permanent risk of suffering malaria infection worldwide, and that 80-300 million experience Plasmodium vivax infections every year mostly in areas outside Africa. The increasing P. vivax drug resistance and recent reports of severe and lethal cases, the relapsing parasite behavior and the existence of Plasmodium spp. co-infections must prompt more investment and greater efforts for the development of a P. vivax vaccine. Because of funding shortage and technical difficulties, currently there are only two P. vivax vaccine candidates being tested in clinical trials and few others are being assessed in preclinical studies which contrast with the numerous P. falciparum vaccine candidates under evaluation. However, the recent availability of the P. vivax genome and ongoing proteomic analysis are likely to accelerate P. vivax vaccine development. Additionally, recent development of human sporozoite-challenge models would contribute to move clinical development forward and to identify mechanisms of immunity.

Amebiasis caused by the enteric protozoan parasite Entamoeba histolytica is among the three top causes of death from parasitic infections worldwide, as a result of amebic colitis (dysentery) and liver or brain abscess. The protective host factors as well as those that contribute to the onset of pathology remain poorly understood. E. histolytica uses a variety of strategies to suppress local and systemic host immune responses, thus allowing the parasite to persist in immunocompetent hosts. During invasive disease there is a marked down-regulation of macrophage functions rendering the cells incapable of antigen presentation and unresponsive to cytokine stimulation. Furthermore, during infections there are decreased levels of helper CD4+ T cells that are unable to proliferate with a corresponding increased level of CD8+ T cells. Not only are cell-mediated immune responses impaired during amebic infection, but humoral defenses also fail to eliminate the parasite. The relative ineffectiveness of anti-amebic antibodies during a primary infection is correlated with cysteine proteases secreted by the parasites, which can degrade human intestinal IgA and cleave the heavy chains of IgG. Moreover, E. histolytica trophozoites can internalize and degrade immunoglobulin fragments bound on their surface. As the complexity of the interactions between E. histolytica and the host is increasingly understood, it provides the tools required for the development of successful vaccines against amebiasis.

Giardia duodenalis is the most common protozoan cause of diarrhea in the world. A hallmark of this infection is the variation in clinical responses which are observed, ranging from asymptomatic, self-limited infections to chronic infections with persistent severe diarrhea, cramps, nausea and weight loss. Some of this variation likely derives from differences in the parasites themselves, while the remainder is likely due to differences in host immune responses. This chapter will focus on the role of immune responses in determining the outcome of infections with Giardia, both in eradicating parasites from the intestinal lumen and in contributing to the symptoms of infection.

Toxoplasma gondii and other apicomplexan parasites are widely distributed obligate intracellular protozoa. A critical host mediator produced in response to T. gondii infection is IL-12. This cytokine is synthesized by dendritic cells, macrophages and neutrophils and plays a pivotal role in the production of IFN-gamma, which in turn activates antimicrobial effector cells. In the past several years, many of the receptors and signaling pathways that link pathogen detection to induction of IL-12 have been identified and characterized. Among these receptors the Toll-like Receptor (TLR) family can recognize all classes of pathogens and induce different types of immune responses. In the following review, the evidence for specific TLR function in host resistance to T. gondii is summarized.

Apoptosis play a crucial role in the interaction between hosts and parasites. Apoptotic response includes innate and adaptive immunities to restrict intracellular parasite replication and regulatory functions to modulate host immune responses. The obligate intracellular protozoan Toxoplasma gondii extensively modifies apoptosis of its own host cell or of uninfected bystander cells. Upon infection with T. gondii, apoptosis is triggered in T lymphocytes, macrophages and other leukocytes, thereby suppressing immune responses against the parasite. On the other hand, T. gondii inhibits hostcell apoptosis by direct or indirect mechanisms in the infected cells to facilitate parasite survival. The dual activity of T. gondii to both promote and inhibit apoptosis requires tight regulation to stabilize host and parasite interaction and establish toxoplasmosis. Here, molecular mechanisms behind the inhibition or induction of apoptosis by T. gondii infection and their pathogenesis are focused on.

The tropical disease leishmaniasis is initiated by flagellated parasites of the genus Leishmania (L.), which are inoculated into the skin during the blood meal of a sandfly vector. A broad spectrum of clinical manifestations in humans, ranging from a self-limiting cutaneous infection to disseminating visceral leishmaniasis, are described with respect to the transmitted Leishmania species. During the last decades the experimental model of leishmaniasis, in which mice are infected with stationary phase promastigote parasites, allowed the examination of many immunological details of the hostparasite interaction. For instance, it is shown that the obligatory intracellular Leishmania parasites need phagocytic cells for replication as soon as the parasites are located in the dermal compartment. In this regard, neutrophils and macrophages play a pivotal role as host cells for Leishmania replication. On the other hand, infected macrophages produce leishmanicidal molecules after appropriate activation by antigen-specific T helper (h) cells. Thus, healing of leishmaniasis is associated with a protective Th1-type response, characterized by an early interferon-γ production by CD4+ T cells and the expression of inducible nitric oxide synthase by activated macrophages. In this context, it is generally accepted that professional antigen presenting cells are crucial for the induction of the protective Th1-type response in skin-draining lymph nodes. Due to the fact that L. major parasites enter the body via the skin, epidermal Langerhans Cells (LCs) were thought to be responsible for the initiation of the adaptive T cell-mediated immunity. More recent data indicate that dermal Dendritic Cells (DCs), rather than epidermal LCs, might be important for the initiation of the adaptive immune response. However, an indirect role for migratory skin-derived epidermal LCs in T cell-mediated immunity, possibly in delivering skin-derived antigens to cutaneous lymph node-resident DCs, could not be excluded in general. Based on the current knowledge about the role of DC subsets in experimental leishmaniasis, it is feasible that distinct DC subtypes interact with particular T cell populations: LCs with “regulatory” T cells, Langerin+ DCs with CD8+ T cells, and Langerin- DCs with CD4+ T cells.

In this chapter, we address the relationship between Leishmania and its host macrophage at the molecular level. Parasites of the genus Leishmania are able to secure their survival and propagation within their host by altering key signalling pathways involved in the ability of macrophages to directly kill pathogens or to activate cells of the adaptive immune system. One important step in this immune evasion process is the Leishmania-induced activation of host protein tyrosine phosphatase SHP-1. The latter has been shown to directly inactivate JAK2 and Erk1/2, and to play a role in the negative regulation of several transcription factors involved in macrophage activation such as: NF-kB, STAT1α, and AP- 1. These signalling alterations contribute to the inactivation of critical macrophage functions such as the production of IFN-γ-induced nitric oxide (NO), a free radical associated with parasite killing and clearance. In addition to interfering with IFN-γ receptor signalling, Leishmania is able to alter several LPS-mediated responses (e.g. IL-12, TNF-α, NO production) through mechanisms not yet fully understood. However, recent findings from our laboratory revealed a pivotal role for SHP-1 in the inhibition of TLR-induced macrophage activation through binding to and inactivating IL-1 receptor-associated kinase 1 (IRAK-1). Furthermore, we identified the binding site as an evolutionarily conserved ITIMlike motif, which we named Kinase Tyrosine-based Inhibitory Motif (KTIM). This accumulating knowledge helps us better understand evasion mechanisms employed by promastigotes and/or amastigotes of Leishmania which could help in the development of more efficient anti-leishmanial therapies in the near future.

Cutaneous Leishmaniasis caused by Leishmania guyanensis parasites is endemic in the North-East South America. There is, however, little information available concerning L. guyanensis infectivity and the immune response associated with different stages of the disease. In the following chapter we discuss the results obtained in human research with regard to the involvement of different types of immune cells and their roles during the development of infection with L. guyanensis parasites. We also provide a resume on the status of animal models of L. guyanensis infection and emphasize how essential these models are so as to increase our knowledge of immunopathogenesis in the host and thus provide an indispensable tool to test new therapeutic strategies.

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