Editor: Emilio Jirillo

Immune Response to Parasitic Infections: Protozoa

Volume 1

eBook: US $79 Special Offer (PDF + Printed Copy): US $158
Printed Copy: US $119
Library License: US $316
ISSN: 2543-215X (Print)
ISSN: 1879-744X (Online)
ISBN: 978-1-60805-678-1 (Print)
ISBN: 978-1-60805-148-9 (Online)
Year of Publication: 2010
DOI: 10.2174/97816080514891100101


This Ebook provides an interesting and up-to-date overview of Parasite Immunology in terms of a survival battle between hosts and parasites, describing firstly how parasites interact with different B cell compartments and trigger a vigorous antibody response. An Interesting chapter deals with new insights into immune diagnosis in Trypanosoma cruzi infection, while another chapter on malaria vaccines critically reviews their development since the beginning, examining the basis for failures or successes encountered in clinical trials. Chapters on immunological aspects of amoebiasis, giardiasis, toxoplasmosis and leishmaniasis in humans are written by top researchers in the world working in this field. This Ebook should prove to be of interest to researchers and students wishing to familiarize themselves with the latest developments in this field. Therefore, this Ebook is considered essential for all researchers involved in Infectious Diseases, Parasitology, Microbiology, Immunology, and Vaccine design and discovery.

Indexed in: Chemical Abstracts, EBSCO, Ulrich's Periodicals Directory.


Diseases caused by parasitic protozoa are often emerging or uncontrolled, as in the case of human leishmaniasis, or have a heavy burden, persisting in spite of present control strategies, as for malaria. Therefore, knowledge of recent findings on host-parasite interaction is extremely important for the development of new relevant control tools, including novel vaccination strategies and possible antigenic targets of protective immune response.

In Chapter 1 by Carolina Montes et al. the full spectrum of B cell response toward parasite infections will elegantly be described. As parasites interact with different B cell compartments, they usually trigger an antibody response which can be protective but often harmful for the host.

Besides their major function of producing antibodies, parasite-induced B cells may act as antigen presenting cells and secretors of cytokines, which may contribute to host protection or susceptibility. B cells also function as regulatory cells, modulating anti-parasite immune response mediated by T cells, including unwanted autoaggressive T-cell responses.

The escape mechanisms of parasites from B cell response have also been highlighted. Variation of antigenic coat, molecular mimicry, induction of apoptosis of B cells, B cell fratricide, T cell apoptosis mediated by B cells and interference with the B cell signalling constitute the strategies adopted by parasites to elude B cell responses, which ultimately drive the infection to chronicity.

In Chapter 2 (by Clotilde Marín and Manuel Sánchez-Moreno), new insights into immune diagnosis of Trypanosoma cruzi infection (Chagas disease) are outlined.

Serologic testing for specific antibodies to T. cruziantigens is the most commonly employed approach for diagnosing T. cruzi chronic infection in clinical patients as well as in blood donors, but no assay has universally been accepted as the gold standard for the serologic diagnosis. This review will examine different antigenic preparations (parasite extracts, recombinant antigens and synthetic peptides), which may have different affinities for both specific and non-specific antibodies and can produce variable sensitivities. In particular, the review focuses on the usefulness of parasite excreted-secreted antigens in immunoblotting assays and ELISA as diagnostic confirmatory tests for Chagas disease. Nowadays, the trypomastigote excretory-secretory antigens (TESA) composed of surface components and excreted dismutase and purified by affinity chromatography seem to represent sensitive and specific reagents for diagnosis of Chagas disease by ELISA.

In Chapters 3 (by Antonio Verdini et al.) and 4 (by Sócrates Herrera and Myriam Arévalo-Herrera) the state of the art on malaria vaccine development is pointed out.

Chapter 3 critically covers malaria vaccine development since the beginning about twenty years ago, especially focusing on two mayor strategies, i.e. recombinant proteins and synthetic peptides, and examining the basis for failure or success encountered in clinical trials. In particular, the results obtained in phase IIa and IIb efficacy evaluation trials, by using Plasmodium falciparum proteins or protein fragments produced by peptide synthesis or DNA recombinant technology have been reported. The purpose is 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.

Chapter 4 illustrates present vaccination strategies against Plasmodium vivax. In spite of the high P.vivax malaria burden, the increasing drug resistance and possibility of severe and lethal cases, there are relatively only few vaccination trials, in comparison with P.falciparum vaccines under evaluation. Among P. vivax antigens, only two -CSP and Pvs25- have been already tested in Phase I trials, whereas two antigens from asexual blood stages -DBP and MSP-1- are likely to reach clinical testing within the next two years. In addition, a growing number of antigens, expressed on sporozoite surface, asexual blood stages or sexual stages, are being added to the list of potential candidates. However, the availability of P. vivax genome and proteomic studies will certainly accelerate the development of such new vaccines.

Finally, the authors report a recent development of successful sporozoite challenge models in malaria-naïve human volunteers with P. vivax strain derived from human donors, and underline the importance of these models for the understanding of mechanisms of immunity to P. vivax infection.

In Chapter 5 (by Leanne Mortimer and Kris Chadee) the immune responses elicited against Entamoeba histolytica are discussed.

The infected host is characterized by an impaired antigenic presentation and a dramatic reduction of cytokines produced by macrophages during the parasitic invasion. Furthermore, in the infective phase, CD4+ cells are decreased and CD8+ cells are increased. Moreover, cystein protease release by E. histolytica degrades human IgA and cleaves IgG heavy chains. When the parasite successfully subverts both the innate and adaptive immune response, the chronic disease ensues.

An important point in the study of very complex amoeba-host interactions is to understand why most people maintain asymptomatic infections while others succumb to acute illness. A determining factor may be the level of interleukin (IL)-10, which is crucial for the maintenance of gut homeostasis at the mucosal barrier. In a mouse model, IL-10 produced by haematopoietic cells is necessary for innate resistance to amoebic invasion, and also in humans an IL-10 deficiency could weaken the mucus layer, thus promoting parasite invasion.

Further chapter sections describe in detail intestinal and liver abscess pathogenesis, with data obtained from human biopsies that mark the progress of tissue destruction. Once beyond the epithelial barrier, trophozoites move into the mucosa and engorge on host tissue, while the invading trophozoites rapidly lyse any cells they encounter, including inflammatory cells which are abundantly produced.

The heavy burden of amebiasis in terms of incidence and mortality has prompted to vaccination studies. Some attempts to prepare an anti-E. histolytica vaccine are illustrated also in view of the evidence that only trophozoites need to be targeted and they express highly immunogenic proteins. The surface adhesin Gal-lectin enables amoeba to colonize via attachment to colonic mucus and has many functions that are central to the pathogenicity of E. histolytica. During invasion, it mediates adherence to host cells, apoptosis and phagocytosis, also triggers an inflammatory response and is involved in complement resistance. A recombinant version of the Gal-lectin cysteine rich region has experimentally been used for the preparation of a vaccine devoid of side effects. At the same time, the pentapeptide Monocyte Locomotion Inhibitory Factor and the surface antigen serin rich protein are other potential candidate for vaccination.

Giardia intestinalis is the most common protozoan cause of diarrhoea in the world. Chapter 6 by Aleksander Keselman and Steven Singer focuses on the role of immune responses in determining the outcome of infections with Giardia, both in eradicating parasites from the intestinal lumen and contributing to the symptoms of infection. Colonization of the small intestine elicits an immune response, both innate and adaptive, which plays an essential role in clearing infection and suggests that vaccination may be a promising and practical route of giardiasis control.

However, G. duodenalis has the capacity to suppress murine bone marrow derived dendritic cell (DC) antigen presentation, by blocking induction of MHC II proteins and co-stimulatory molecules. In addition, LPS-induced IL-12 secretion by DCs is significantly diminished, while ERK1/2-dependent IL-10 release is upregulated by coincubation with Giardia extract.

Furthermore, several mechanisms that contribute to pathogenesis of giardiasis are described. The recently discovered role for the neurotransmitter cholecystokinin (CCK) in mediating enhanced intestinal motility following Giardia infection is pointed out. CCK alters muscle function by activating mast cells, and also promotes parasite replication by stimulating the intestinal release of bile which is essential for trophozoite replication. Compromised molecular ultrastructural integrity in the intestinal epithelium, including changes of tight junction proteins, and caspase 3-dependent apoptosis of epithelial cells contribute to malabsorption by causing increased epithelial permeability. Moreover, Giardia produces excretory-secretory products that have enterotoxic properties and induces intestinal secretion of sodium and chloride.

Toxoplasma gondii and other Apicomplexa parasites are widely distributed obligate intracellular protozoa. In Chapters 7 and 8 the immune responses toward T. gondii are described.

In particular, in Chapter 7 Felix Yarovinsky reviews the evidence for specific Toll-like receptor (TLR) function in host resistance to T. gondii.

IL-12 is the critical host mediator in the initiation of adaptive immune response to T. gondii which culminates in the release of interferon (IFN)-γ#x03B3; deserving a protective function in the host. However, also this parasite can evade the host immune response by impairing DC antigen presentation, reducing release of IL-12 and interfering with IFN-γ signalling pathways in the infected cells.

Concerning different host signalling pathways which contribute to innate recognition of T. gondii, MyD88 activation is clearly a critical step in the initiation of the IL-12-dependent response to this parasite. A potent stimulator of IL-12 production by DCs in a MyD88-dependent manner was isolated and identified as a T. gondii profilin, belonging to small, actin-binding proteins that regulate actin polymerization in eukaryotic cells. Profilin is required not only for parasite gliding, invasion, and egress from the host cell, but is also essential for the parasite virulence in vivo. Further investigations have identified TLR11 as an innate immune receptor for T. gondii profilin in mice, also required for DC IL-12 production. Interestingly, profilins isolated from Cryptosporidium parvum, Eimeria tenella, and Theileria parva induce TLR11 activation in a similar manner, thus establishing TLR11 as a common pattern-recognition receptor for apicomplexan protozoa.

Other TLRs also contribute to the host resistance to T. gondii. Macrophage activation strictly depends on TLR2 activation, acting on regulation of the chemokine CCL2 and Tumor Necrosis Factor production in response to the parasite. The definitive ligands for TLR2 are, as for P.falciparum, glycans and diacylglycerols isolated from purified T. gondii glycosylphosphatidylinositol (GPI).

Interestingly, intestinal cell damage triggered by parasitic infection allows an overgrowth of commensal bacteria in the ileum, which activate TLR2-, TLR4-, and TLR9-dependent host response and small intestine inflammation. Therefore, these TLRs are also involved in T. gondii-induced immunopathology.

Since apoptosis also plays a crucial role in the parasite-host interactions, the complex apoptosis processes that develop in Toxoplasma gondii-infected hostsare reviewed by Yoshifumi Nishikawa in Chapter 8.

Upon infection with T. gondii, apoptosis is triggered in T lymphocytes, macrophages and other leukocytes, thereby suppressing immune responses against the parasite. Among mechanisms of host immune suppression in the course of T. gondii infection, apoptosis of T cells should be taken into consideration even at regional level, as observed in the case of intestinal Peyer' patches lymphocytes.

On the other hand, T. gondii inhibits host-cell apoptosis by direct or indirect mechanisms in the infected cells to facilitate parasite survival. This dual activity of T. gondii to both promote and inhibit apoptosis requires tight regulation. Therefore, molecular mechanisms behind the inhibition or induction of apoptosisand their role in pathogenesis of the infection are clearly elucidated in this review. In this respect, in a mouse model abortion due to T. gondii infection seems to depend on the apoptotic reduction of T regulatory (Treg) cells at placenta and splenic levels.

Leishmaniasis is caused by flagellated parasites of the genus Leishmania, 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, is described.

Chapters 9, 10 and 11 deals with the host immune response against Leishmania antigens.

In mouse models, healing of leishmaniasis is associated with a protective Th1-type response, characterised by an early interferon-gamma production by CD4+ T cells and the expression of inducible nitric oxide synthase and other leishmanicidal molecules by activated macrophages.

It is well known that professional antigen presenting cells -such as DCs- are crucial for the induction of the protective immune response in skin-draining lymph nodes. In this context, presentation of skin-derived Leishmania antigens by DC subtypes is reviewed by Uwe Ritter (Chapter 9) in particular focusing the possible role of epidermal Langerhans cells and dermal dendritic cells in the presentation of skin-derived Leishmania antigens.

L. major parasites have the skin as portal of entry into the host, and, therefore, epidermal Langherans cells (LCs) should initiate adaptive immune response. However, recent findings attribute to dermal DCs a central role in the triggering of adaptive immune response. Consequently, LCs seems to play an indirect role in delivering skin-derived antigens to cutaneous lymph node-resident DCs. Moreover, based on the data from experimental leishmaniasis, it is feasible that distinct DC subtypes interact with particular T cell populations during the first days after infection: LCs with “regulatory” T cells, Langerin+ DCs with CD8+ T cells, and Langerin- DCs with CD4+ T cells, respectively.

Leishmania parasites need phagocytic cells for intracellular replication, and neutrophils and macrophages play a pivotal role as host cells for Leishmania. This parasite has the ability to enter host macrophages safely and replicate inside phagocytes that were recruited to destroy it.

The inability of macrophages to kill the parasite and activate cells of the adaptive immune system is a consequence of the parasite capacity to alter several key signalling pathways in the host, as reviewed by Issa Abu-Dayyeh and Martin Olivier in Chapter 10.

n infected macrophages, production of microbicidal molecules and activation of cytokines are inhibited, whereas secretion of immunosuppressive molecules, like PGE2, TGF-β, IL-10 and certain chemokines is increased. The main signalling molecules altered by Leishmania to survive inside host macrophages include PKC, JAK2, Mitogen-activated protein kinases ERK ½, JNK and p38, and several transcription factors.

One important step in this immune evasion process is the Leishmania-induced activation of protein tyrosine phosphatases (PTPs) such as SHP-1, which act as negative regulators of signal transduction. SHP-1 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-κβ, STAT-1α and AP-1. These signalling alterations contribute to an inactivation of critical macrophage functions such as the production of IFN-γ-induced nitric oxide associated with parasite killing. Moreover, recent findings also revealed a pivotal role for SHP-1 in the inhibition of TLR-induced macrophage activation through binding to a newly identified Kinase Tyrosine-based Inhibitory Motif (KTIM) and inactivating IL-1 receptor-associated kinase 1 (IRAK-1).

Finally, among the several Leishmania virulence factors involved in initial interaction and internalization, the glycoprotein 63 (γp63) plays a novel and important role in the cleavage and activation of several macrophage PTPs as well as in the cleavage and degradation of the key transcription factor AP-1.

There is limited information about the cytokine responses in different clinical forms of human leishmaniasis. It is generally considered that patients with cutaneous leishmaniasis present a heterogeneous cellular immune response with a predominant CD4+ Th1 type response upon healing. The subsets of T cells (CD4+ or CD8+), and their function within lesions is still, however, under debate. The presence of IFN-γ is most often associated with a cure of the infection and the presence of IL-4 and IL-13 are associated with non-healing lesions, analogous to results obtained in the murine model of infection with L. major. However, levels of IFN-γ do not always correlate with resistance and the preferential participation of Th1 or Th2 responses during human infection with Leishmania is not completely understood.

Therefore, the analysis by Catherine Ronet et al. (Chapter 11) of immune response in patients with localized American Cutaneous Leishmaniasis (LCL) due to Leishmania guyanensis, which is endemic in the North East of Latin America, is of particular interest.

The authors have investigated the role of cytokines during different phases of infection with L. guyanensis. Cytokine production has been determined in PBMCs and at the site of infection in: i. healthy subjects who have never been exposed to Leishmania, ii.healthy subjects exposed recently to Leishmania, and iii. patients developing the disease.

PBMCs from unexposed healthy subjects, following stimulation with live L. guyanensis, produce IFN-γ and TGF-β but not IL-4, IL-10 and IL-13. IFN-γ is generated from naïve CD8+ T cells and requires the presence of whole L. guyanensis parasites. Also stimulation of PBMCs with the antigen Leishmania homologue of Receptors of Activated C Kinase (LACK) induces IFN-γ production by CD8+ T cells. However, the picture is more complex, since LACK also induces IL-10 response in purified memory CD45RA- CD4+ T cells and, after neutralization of TGF-β, in CD4+ and CD8+ T cells.

In healthy exposed subjects, followed after their stay in the rain forest in French Guyana, IFN-g production by PBMCs originates from both CD4+ and CD8+ cells, also in response to Soluble Leishmania Antigen (SLA), in contrast to unexposed subjects. Interestingly, LACK-induced IFN-γ production by CD4+ T cells was detected in these subjects before SLA-induced IFN-γ production, suggesting that the former assay could be used as an early predictive immunological marker of exposure to Leishmania in healthy subjects.

In patients with LCL, peripheral blood mononuclear cells produce IFN-γ at high levels and IL-10, but not TGF-β following L. guyanensis stimulation. However, IFN-γ was produced in response to LACK stimulation only during the early phase of infection, probably due to recruitment of IFN-g-producing LACK-specific T cells in the inflamed skin during the late phase of infection. Indeed, at the site of infection in LCL patients Th2 responses predominate during the early phase and precede the development of a Th1 response.

In addition, in lesions of LCL patients Treg cells accumulate during the early phase of infection and their persistence is an index of a poor response to therapy. Interestingly, IL-13 is the main cytokine expressed within the lesion at the early phase and may be responsible for the maintenance of infection.

In conclusion, the bulk of data presented through the various chapters of this E-book emphasize the predominant as well as crucial role of the full spectrum of antiprotozoan immunity elicited by the host. Moreover, advances in the understanding of the mechanisms of immunity in the course of protozoan diseases have facilitated the development of novel vaccinal strategies, also in view of the emergent resistance of parasites to currently used antiparasitic drugs.

On these grounds, it appears clear that Immunoparasitology has enormously grown as an autonomous discipline, either didactically or scientifically. Therefore, this E-book also pursues the major goal to inform scientific community, clinicians and students about the progress of this hot sector of parasitic diseases.

This is the first of two eBooks on immune response to parasitic infections. The second volume of this series will deal with immune responses to helmithic infections.

Olga Brandonisio & Emilio Jirillo
University of Bari


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