Leishmania: Current Biology and Control
"an excellent reference" (Doodys)
"a useful guide" (Fungal Diversity)
Caister Academic Press
Subrata Adak and Rupak Datta
CSIR - Indian Institute of Chemical Biology, Kolkata, India and Indian Institute of Science Education and Research, Kolkata, Mohanpur, India; respectively
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With an estimated 1.3 million new cases and causing more than 20,000 deaths every year, Leishmaniasis continues to be a menace in countries across the globe. The absence of an anti-Leishmania vaccine, the toxicity of current anti-parasite drugs, coupled with the rapid emergence of drug resistant Leishmania strains remain significant challenges for disease control. This has spurred a plethora of research initiatives into the parasite biology, parasite-host interaction, mechanisms of disease pathogenesis, drug development and molecular mechanism of drug resistance. Insights obtained from various such studies are essential for the development of novel anti-Leishmania treatment strategies.
In this timely book respected Leismania experts distil the important current research highlighting the most insightful discoveries in the field. Topics covered include: modulation of host miRNA; heat shock proteins; Iron in the Leishmania-macrophage interaction; oxidative and nitrosative stress response; cell death; strategies for immune evasion; STAT signalling; parasite modulation of toll-like receptors in macrophages; T cells in Leishmania infection; vaccine biology; inhibitors of Leishmania DNA topoisomerases; and mechanism of drug resistance in visceral Leishmaniasis.
An essential text for everyone in the Leishmania community and recommended for researchers working in related fields.
"a comprehensive summary of the most recent advances in Leishmania biology and disease control ... an excellent reference not only for the Leishmania community, but also for investigators in related fields, in particular, graduate and undergraduate students and physicians in the field of parasitology in general. " from Doodys
"Written by expert authors ... a useful guide for anyone in the field of studying Leishmania and its related researches." from Fungal Diversity
Table of contents
1. Modulation of Host Cell miRNA Expression During Leishmania Infection and Emergence of miRNA as a New Therapeutic Molecule
Suvendra N.Bhattacharyya, June Ghosh and Sudarshana Basu
The kinetoplastid protozoan Leishmania donovani infects liver and spleen of the mammalian hosts and resides inside the tissue macrophages. The pathogen resides within the parasitophorous vacuoles, the specialized subcellular structures in the infected macrophage cells, and affects gene expression in infected and also the non-parasitized neighboring cells. Expression of miRNAs, the tiny regulatory RNA of eukaryotic cells, also gets altered in Leishmania infected macrophages and also in the hepatocytes of infected mouse liver. Restoration of expression of miR-122, a hepatic miRNA that regulate serum cholesterol and get reduced upon Leishmania infection in liver, is associated with increase in serum cholesterol level and lowering of liver parasite load. In this chapter we have discussed the importance of host cell miRNA alteration and its mechanism in the context of visceral leishmaniasis.
2. Heat Shock Proteins of Leishmania: Chaperones in the Driver's Seat
Joachim Clos and Antje Hombach
The roles of so-called heat shock proteins (HSPs) in Leishmania was long assumed to revolve around protective functions against temperature and adverse milieu inside macrophages. In recent years, however, a picture has emerged that shows heat shock proteins and co-chaperone proteins as effectors and regulators of signal transduction and immune evasion pathways, possibly compensating for the lack of regulated gene expression and regulatory factors in Leishmania spp.
3. Role of Iron in Leishmania-Macrophage Interaction
Kavita Bharati, Saswat Kumar Bal, Shalini Saini, Vikash Bhardwaj and Chinmay K. Mukhopadhyay
Iron is an essential micronutrient for most forms of life because of its vital role as a redox cofactor of proteins requiring for critical cellular processes. Being equally essential for survival of the host and pathogen, iron has taken its justified role in the immune status of the former and the virulence capacity of the later. Acquiring iron is a fundamental step in the development of a pathogen within the host, while host cells are known to implement several iron sequestration policies to encounter the different invasion strategies of pathogens. These illustrate the longstanding and ongoing battle for iron between host and pathogen in the evolution. This chapter describes the understanding of the role of iron in interaction between Leishmania and its mammalian host.
4. Oxidative and Nitrosative Stress Response in Leishmania
Swati Pal and Subrata Adak
The generation of reactive oxygen and reactive nitrogen species, in response to pathogen attacks, play a central role in host defense mechanism. Leishmania pathogens cleverly evade the assault by evolving several defense strategies to protect themselves against the toxic effects of these reactive species. In the arthropod host, reactive oxygen species (ROS) in Leishmania are generated as a result of cellular metabolism, uncoupled electron transfer in mitochondria, endoplasmic reticulum stress as well as unfavourable environment (limited nutrient and oxygen). In the human host, the parasite additionally encounters both the oxidative and nitrosative stress response; yet they remain successful in establishing and maintaining productive acute and persistent infections in the host. This chapter assembles the current knowledge regarding reactive oxygen and nitrogen species, and compares the adaptive mechanisms utilized by Leishmania species to resist the toxic effects resulting from exposure to various environmental stresses.
5. Cell Death in a Kinetoplastid Parasite, the Leishmania spp.
Radhika Mathur and Chandrima Shaha
Apoptosis is a distinct form of cell death that plays an important role in various physiological processes in mammals. Earlier it was thought that apoptosis evolved with multicellular organisms; however, studies over the past years have shown that single celled organisms such as Leishmania can also undergo programmed cell death. It is now believed that apoptosis plays an important role in the life cycle of Leishmania parasites. The process enables selection of fittest cells amongst the parasites within the sandfly vector and within the mammalian cells for necessary control of parasite numbers and for the evasion of immune responses. Like mammalian cells, Leishmania parasites also show typical features of apoptotic death, like cell shrinkage, nuclear condensation and DNA damage in response to heat stress, serum deprivation and a range of antileishmanial drugs. Understanding the molecular processes involved in apoptotic death in trypanosomatids might help in defining the cell death machinery and thus provide new targets for chemotherapeutic drug development.
6. Elucidating the Strategies of Immune Evasion by Leishmania
Supriya Srivastav, Anindita Ukil and Pijush K. Das
The protozoa Leishmania species are obligate intracellular parasites that harbour in the macrophages of their host. In order to inhabit an intracellular niche, they have evolved various means to attenuate and/or subvert how their host cell integrates signals from the external 'immune' environment. Since macrophages being the first line of defence in the immune system are specialized for the identification and destruction of invading pathogens by triggering an innate immune response, Leishmania have evolved a range of mechanisms for suppressing some critical macrophage activities. This is achieved either by employing strategies to inhibit proteins that play a positive role in immune cell activation or by activation of molecules that govern the negative regulation of immune cell signaling and function. This chapter highlights the strategies employed by Leishmania to suppress macrophage defence mechanism to create a favourable niche which aids the parasite in intracellular growth and virulence.
7. Role of STAT Signaling in Immunity to Leishmaniasis
Steve Oghumu, James Stock, Cesar Terrazzas, Gayathri Natarajan, Sanjay Varikuti and Abhay R Satoskar
The JAK/STAT signaling pathway is a principal mediator of the effects of cytokines on immune cells and therefore plays a major role in the orchestration of immunological responses to an infectious challenge. The STAT family is comprised of seven genes that code for STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6, and most of these STATs as well as their associated signaling mediators have been shown to be critical in immunity and/or pathogenesis of various forms of Leishmania infection. Leishmania are also known to exploit the JAK/STAT signaling pathway to favor parasite establishment, growth and replication. Understanding how Leishmania modulates this host intracellular pathway could lead to the development of more effective therapeutic approaches against leishmaniasis. In this chapter we will discuss the importance of STATs and their signaling ligands in various forms of Leishmania infection and how the parasite has exploited this intracellular network to evade anti-parasitic immune responses and facilitate survival within the host. We will also briefly address how our knowledge of these mechanisms can aid in the development of effective therapeutic strategies in the management of leishmaniasis.
8. Leishmania Modulates Toll-like Receptor Signaling in Macrophages
Soumya kanti Ghosh, Kalavati M. Lalsare and Bhaskar Saha
Toll-like receptors (TLRs) are essential pattern recognition receptors (PRR) of the innate immune system. Their sensitivity to variable types of ligand makes them appropriate immune receptors against most type of pathogens. Macrophages, the antigen presenting cells that play host to the protozoan parasite Leishmania, express the entire TLR family of receptors along with other PRRs. TLRs play vital roles during Leishmania infection via regulation of pro-inflammatory and anti-inflammatory cytokines. Leishmania interacts with host cells and invade them through surface molecules such as lipophosphoglycan (LPG), phosphoglycans and other pathogen molecules. Being ligands to several TLR receptors, these molecules can regulate TLR signalling and iNOS expression along with oxidative bursts following infection. Leishmanial survival techniques exploit TLR-TLR crosstalk and TLR signalling mechanisms for survival. This brings changes in signalling pattern and cytokine secretions. This chapter deals with the impact of leishmanial infection on TLR signalling, a major component of innate immunity and a trigger factor for adaptive immune system.
9. Role of T Cells in Leishmania Infection
Chiranjib Pal and Sunil Martin
In Leishmaniasis, Th1-related cytokines production seems to be crucial for host control of parasite burden and clinical cure. Visceral and diffuse cutaneous Leishmaniasis are characterized by negative skin test for parasite antigens and failure to produce Th1 cytokines, whereas tegumentary leishmaniasis is characterized by positive skin test and the ability of peripheral blood mononuclear cells (PBMCs) to produce IL-12 and IFN-γ (Th1 cytokine). As a matter of fact, IL-4 and IL-13 (Th2 cytokines) promote disease progression in cutaneous Leishmaniasis, whereas IL-4 seems to enhance protective type-1 responses in visceral Leishmaniasis. Thus, immune response to intracellular parasites should dismiss the Th1/Th2 paradigm of resistance/susceptibility, embracing theory of a more biologically relevant network of regulatory/ counter regulatory interactions. Moreover, the presence of antigen specific regulatory T cell subsets may provide an environment that contributes to the balance between Th1 and Th2 cells. Finally, the involvement of CD8+ T cells has been described, but the modality of their role and function, in this kind of infection, has not been expanded so far. Recently discovered Th17, Th9 and Tfh subsets and related cytokines have been reported to perform diverse functions in the course of Leishmaniasis as a whole. Leishmania is one of the first microbes credited to employ T-reg cells for immunoevasion. IL-10 producing Foxp3+ and Foxp3- T-reg subtype perpetuate immunosuppression whereas inflammatory CD8+T cells counter the immunosuppression forcing the parasite to metastasize. Detailed understanding of this immune-regulatory check points may expose novel drug targets which may help in developing therapies against diseases with parallels molecular etiology.
10. Vaccine Biology of Leishmania Infection
Abdus Sabur and Nahid Ali
Leishmaniasis, a vector borne parasitic disease imposes devastating impact on global health. An impact making prophylactic measure against the disease is lacking. But promising prophylactic vaccine candidates are on the count, edging towards a successful vaccine for leishmanisis. This could be achieved by efforts put forward in understanding the immuno-biology associated with leishmaniasis, breakthroughs in search of antigenic components and advances in delivery system and adjuvant biology. The initial part of the chapter deals with the limitations and challenges in vaccine development against leishmaniasis pertaining to issues like less understood host parasite interaction during Leishmania infection and immunological requirements for protection. In the subsequent sections major advances in search of antigenic components and vaccine formulations are pointed. This section highlights various approaches and the developmental status of experimental vaccine for leishmaniasis. The limitations associated with each vaccine category are also pointed. An update of some impact making vaccine for canine leishmaniasis is briefed. The therapeutic potential of some of the vaccine candidates are also discussed. Finally the role played by various adjuvants and delivery system in vaccine development against leishmanisis is detailed. In a nutshell, the chapter sheds light on the developmental history, with recent updates and future prospects for a successful vaccine for leishmaniasis.
11. Inhibitors of DNA Topoisomerases as Potential Antileishmanial Agents
Sayan Chowdhury and Hemanta K. Majumder
Leishmaniasis is a dynamic disease which is gradually spreading, with the high mortality rates and involved in the economic loss resulting from morbidity. The disease is mainly prevalent in the tropical and subtropical areas. The enormous development of molecular and cellular biology in recent times have provided opportunities for discovering newer molecular targets for drug designing, which now forms a rational basis for the development of improved anti-parasitic therapy. The diversity found in the life cycle of these organisms must be directed by genetic events, wherein topoisomerases play an important role in cellular processes affecting the topology and organization of intracellular DNA. Recently, emergence of the bi-subunit topoisomerase I in the kinetoplastid family has brought a new twist in topoisomerase research related to evolution, functional conservation and as a potential target that can be exploited in drug designing and development of new intervention strategies. Therefore, understanding the biology of kinetoplastid topoisomerases and the components and steps involved in this intricate process provide opportunities for target based drug designing against protozoan parasitic diseases. This review summarizes the biology of kinetoplastid topoisomerases, which are the key molecular targets in antileishmanial chemotherapy.
12. Mechanism of Drug Resistance in Visceral Leishmaniasis
Shyam Sundar and Jaya Chakravarty
The treatment of visceral leishmaniasis is far from satisfactory. It is further complicated by the growing resistance of the parasites to antileishmanials. The exact mechanisms of resistance to various antileishmanials are not known. However, increased intracellular thiol levels, reduced uptake of the drug, sequestration and rapid drug efflux are some of the mechanism known for antimony resistance. Reduced uptake and increased efflux of pentamidine can lead to resistance. L. donovani miltefosine transporter (LdMT) and the protein LdRos3 has shown to play an important role in resistance to miltefosine. Paromomycin being an aminoglycoside is at an increased risk of developing resistance however clinical resistance to the drug has not been reported as yet. Unresponsiveness and relapses after amphotericin B (AmB) therapy is rare however with the increasing use of AmB in lipid formulations that have longer half-lives the risk for developing resistance can become a reality. Thus there is an urgent need to know the markers of drug resistance and to develop tools to determine the emergence of drug resistance in the field.
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(EAN: 9781908230522 9781908230539 Subjects: [microbiology] [medical microbiology] [parasitology] )