Leishmania species: models of intracellular parasitism

Leishmania species are obligate intracellular parasites of cells of the macrophage-dendritic cell lineage. Indeed, the ability to survive and multiply within macrophages is a feature of a surprising number of infectious agents of major importance to public health, including Mycobacterium tuberculosis, Mycobacterium leprae, Listeria monocytogenes, Salmonella typhimurium, Toxoplasma gondii and Trypanosoma cruzi. The relationship between such organisms and their host cells is particularly intriguing because, not only are macrophages capable of potent microbicidal activity, but in their antigen-presenting capacity they can orchestrate the developing immune response. Thus, to initiate a successful infection parasites must gain entry into macrophages, and also withstand or circumvent their killing and degradative functions. However, to sustain a chronic infection, parasites must also subvert macrophage-accessory-cell activities and ablate the development of protective immunity. The leishmanias produce a wide spectrum of disease in mice, and as such they have provided excellent models for studying problems associated with intracellular parasitism. In recent years, largely using these organisms, we have made enormous progress in elucidating the mechanisms by which successful intracellular infection occurs. Furthermore, characterization of immunological pathways that are responsible for resistance or susceptibility to Leishmania has given rise to the Th1/Th2 paradigm of cellular/humoral dominance of the immune response.

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Macrophage Polarization in the Skin Lesion Caused by Neotropical Species of Leishmania sp

Journal of Immunology Research ◽

10.1155/2021/5596876 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Carmen M. Sandoval Pacheco ◽

Gabriela V. Araujo Flores ◽

Kadir Gonzalez ◽

Claudia M. de Castro Gomes ◽

Luiz F. D. Passero ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Macrophage Polarization ◽

Leishmania Species ◽

Skin Lesions ◽

Host Cells ◽

M2 Macrophage ◽

M2 Macrophages ◽

Intracellular Parasites ◽

Skin Biopsies ◽

Acquired Immune Responses

Macrophages play important roles in the innate and acquired immune responses against Leishmania parasites. Depending on the subset and activation status, macrophages may eliminate intracellular parasites; however, these host cells also can offer a safe environment for Leishmania replication. In this sense, the fate of the parasite may be influenced by the phenotype of the infected macrophage, linked to the subtype of classically activated (M1) or alternatively activated (M2) macrophages. In the present study, M1 and M2 macrophage subsets were analyzed by double-staining immunohistochemistry in skin biopsies from patients with American cutaneous leishmaniasis (ACL) caused by L. (L.) amazonensis, L. (V.) braziliensis, L. (V.) panamensis ,and L. (L.) infantum chagasi. High number of M1 macrophages was detected in nonulcerated cutaneous leishmaniasis (NUCL) caused by L. (L.) infantum chagasi ( M 1 = 112 ± 12 , M 2 = 43 ± 12 cells/mm2). On the other side, high density of M2 macrophages was observed in the skin lesions of patients with anergic diffuse cutaneous leishmaniasis (ADCL) ( M 1 = 195 ± 25 , M 2 = 616 ± 114 ), followed by cases of localized cutaneous leishmaniasis (LCL) caused by L. (L.) amazonensis ( M 1 = 97 ± 24 , M 2 = 219 ± 29 ), L. (V.) panamensis ( M 1 = 71 ± 14 , M 2 = 164 ± 14 ), and L. (V.) braziliensis ( M 1 = 50 ± 13 , M 2 = 53 ± 10 ); however, low density of M2 macrophages was observed in NUCL. The data presented herein show the polarization of macrophages in skin lesions caused by different Leishmania species that may be related with the outcome of the disease.

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Sex-Related Differences in Immune Response and Symptomatic Manifestations to Infection with Leishmania Species

Journal of Immunology Research ◽

10.1155/2019/4103819 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 11

Author(s):

Ryan D. Lockard ◽

Mary E. Wilson ◽

Nilda E. Rodríguez

Keyword(s):

Immune Response ◽

Visceral Leishmaniasis ◽

Healthcare Access ◽

Leishmania Species ◽

Biological Sex ◽

Intracellular Parasites ◽

Progression Of Disease ◽

Current Therapies ◽

Experimental Findings ◽

New Treatments

Worldwide, an estimated 12 million people are infected with Leishmania spp. and an additional 350 million are at risk of infection. Leishmania are intracellular parasites that cause disease by suppressing macrophage microbicidal responses. Infection can remain asymptomatic or lead to a spectrum of diseases including cutaneous, mucocutaneous, and visceral leishmaniasis. Ultimately, the combination of both pathogen and host factors determines the outcome of infection. Leishmaniasis, as well as numerous other infectious diseases, exhibits sex-related differences that cannot be explained solely in terms of environmental exposure or healthcare access. Furthermore, transcriptomic evidence is revealing that biological sex is a variable impacting physiology, immune response, drug metabolism, and consequently, the progression of disease. Herein, we review the distribution, morbidity, and mortality among male and female leishmaniasis patients. Additionally, we discuss experimental findings and new avenues of research concerning sex-specific responses in cutaneous and visceral leishmaniasis. The limitations of current therapies and the emergence of drug-resistant parasites underscore the need for new treatments that could harness the host immune response. As such, understanding the mechanisms driving the differential immune response and disease outcome of males versus females is a necessary step in the development of safer and more effective treatments against leishmaniasis.

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RNA-Based Vaccines in Cancer Immunotherapy

Journal of Immunology Research ◽

10.1155/2015/794528 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 60

Author(s):

Megan A. McNamara ◽

Smita K. Nair ◽

Eda K. Holl

Keyword(s):

Immune Response ◽

Cancer Immunotherapy ◽

Rna Structure ◽

Messenger Rna ◽

Host Cells ◽

Translational Efficiency ◽

Tumor Associated Antigen ◽

Antigen Presenting ◽

Template Dna

RNA vaccines traditionally consist of messenger RNA synthesized byin vitrotranscription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy.

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Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

Frontiers in Chemistry ◽

10.3389/fchem.2021.711346 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rosa Ester Forgione ◽

Cristina Di Carluccio ◽

Francesco Milanesi ◽

Marie Kubota ◽

Ferran Fabregat Nieto ◽

...

Keyword(s):

Wide Spectrum ◽

Mumps Virus ◽

Host Cells ◽

Neuraminidase Inhibitors ◽

Acetylneuraminic Acid ◽

Design And Synthesis ◽

Molecular Features ◽

Viral Hemagglutinin ◽

Viral Glycoproteins

The inhibition of surface viral glycoproteins offers great potential to hamper the attachment of viruses to the host cells surface and the spreading of viral infection. Mumps virus (MuV) is the etiological agent of the mumps infectious disease and causes a wide spectrum of mild to severe symptoms due to the inflammation of the salivary glands. Here we focus our attention on the hemagglutinin-neuraminidase (HN) isolated from MuV SBL-1 strain. We describe the molecular features of host sialoglycans recognition by HN protein by means of NMR, fluorescence assays and computational studies. Furthermore, we also describe the synthesis of a N-acetylneuraminic acid-derived thiotrisaccharide targeting the viral protein, and the corresponding 3D-complex. Our results provide the basis to improve the design and synthesis of potent viral hemagglutinin-neuraminidase inhibitors.

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Quantitative proteomic analysis and functional characterization of Acanthamoeba castellanii exosome-like vesicles

Parasites & Vectors ◽

10.1186/s13071-019-3725-z ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Wei-Chen Lin ◽

Chia-Yun Tsai ◽

Jian-Ming Huang ◽

Shang-Rung Wu ◽

Lichieh Julie Chu ◽

...

Keyword(s):

Immune Response ◽

Proteomic Analysis ◽

Functional Characterization ◽

Acanthamoeba Castellanii ◽

Host Cells ◽

C6 Cells ◽

Proteomic Profiling ◽

Quantitative Proteomic Analysis ◽

Rat Glioma

Abstract Background Pathogenic protozoans use extracellular vesicles (EVs) for intercellular communication and host manipulation. Acanthamoeba castellanii is a free-living protozoan that may cause severe keratitis and fatal granulomatous encephalitis. Although several secreted molecules have been shown to play crucial roles in the pathogenesis of Acanthamoeba, the functions and components of parasite-derived EVs are far from understood. Methods Purified EVs from A. castellanii were confirmed by electron microscopy and nanoparticle tracking analysis. The functional roles of parasite-derived EVs in the cytotoxicity to and immune response of host cells were examined. The protein composition in EVs from A. castellanii was identified and quantified by LC-MS/MS analysis. Results EVs from A. castellanii fused with rat glioma C6 cells. The parasite-derived EVs induced an immune response from human THP-1 cells and a cytotoxic effect in C6 cells. Quantitative proteomic analysis identified a total of 130 proteins in EVs. Among the identified proteins, hydrolases (50.2%) and oxidoreductases (31.7%) were the largest protein families in EVs. Furthermore, aminopeptidase activities were confirmed in EVs from A. castellanii. Conclusions The proteomic profiling and functional characterization of EVs from A. castellanii provide an in-depth understanding of the molecules packaged into EVs and their potential mechanisms mediating the pathogenesis of this parasite.

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Lipid rafts and pathogens: the art of deception and exploitation

The Journal of Lipid Research ◽

10.1194/jlr.tr119000391 ◽

2019 ◽

Vol 61 (5) ◽

pp. 601-610 ◽

Cited By ~ 7

Author(s):

Michael I. Bukrinsky ◽

Nigora Mukhamedova ◽

Dmitri Sviridov

Keyword(s):

Immune Response ◽

Plasma Membrane ◽

Host Cell ◽

Lipid Rafts ◽

Therapeutic Approach ◽

Host Cells ◽

Infectious Agents ◽

Systematic Overview ◽

Intracellular Parasites ◽

A Cell

Lipid rafts, solid regions of the plasma membrane enriched in cholesterol and glycosphingolipids, are essential parts of a cell. Functionally, lipid rafts present a platform that facilitates interaction of cells with the outside world. However, the unique properties of lipid rafts required to fulfill this function at the same time make them susceptible to exploitation by pathogens. Many steps of pathogen interaction with host cells, and sometimes all steps within the entire lifecycle of various pathogens, rely on host lipid rafts. Such steps as binding of pathogens to the host cells, invasion of intracellular parasites into the cell, the intracellular dwelling of parasites, microbial assembly and exit from the host cell, and microbe transfer from one cell to another all involve lipid rafts. Interaction also includes modification of lipid rafts in host cells, inflicted by pathogens from both inside and outside the cell, through contact or remotely, to advance pathogen replication, to utilize cellular resources, and/or to mitigate immune response. Here, we provide a systematic overview of how and why pathogens interact with and exploit host lipid rafts, as well as the consequences of this interaction for the host, locally and systemically, and for the microbe. We also raise the possibility of modulation of lipid rafts as a therapeutic approach against a variety of infectious agents.

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Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major

Infection and Immunity ◽

10.1128/iai.72.4.1920-1928.2004 ◽

2004 ◽

Vol 72 (4) ◽

pp. 1920-1928 ◽

Cited By ~ 179

Author(s):

Pascale Kropf ◽

Marina A. Freudenberg ◽

Manuel Modolell ◽

Helen P. Price ◽

Shanti Herath ◽

...

Keyword(s):

Immune Response ◽

Leishmania Major ◽

Protozoan Parasite ◽

Parasite Growth ◽

Host Cells ◽

Effective Control ◽

Intracellular Parasites ◽

Oxide Synthase

ABSTRACT The essential role of Toll-like receptors (TLR) in innate immune responses to bacterial pathogens is increasingly recognized, but very little is known about the role of TLRs in host defense against infections with eukaryotic pathogens. For the present study, we investigated whether TLRs contribute to the innate and acquired immune response to infection with the intracellular protozoan parasite Leishmania major. Our results show that TLR4 contributes to the control of parasite growth in both phases of the immune response. We also addressed the mechanism that results in killing or growth of the intracellular parasites. Control of parasite replication correlates with the early induction of inducible nitric oxide synthase in TLR4-competent mice, whereas increased parasite survival in host cells from TLR4-deficient mice correlates with a higher activity of arginase, an enzyme known to promote parasite growth. This is the first study showing that TLR4 contributes to the effective control of Leishmania infection in vivo.

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Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity

Cancer Cell International ◽

10.1186/s12935-020-01598-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jing Cai ◽

Wenbo Zhu ◽

Yuan Lin ◽

Jun Hu ◽

Xincheng Liu ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Metabolic Reprogramming ◽

Host Cells ◽

Hexokinase 2 ◽

Antiviral Immune Response ◽

Successful Infection ◽

Mouse Xenograft Model ◽

Oncolytic Effect

Abstract Background Viruses are obligate parasites that depend on host cells to provide the energy and molecular precursors necessary for successful infection. The main component of virus-induced metabolic reprogramming is the activation of glycolysis, which provides biomolecular resources for viral replication. However, little is known about the crosstalk between oncolytic viruses and host glycolytic processes. Methods A MTT assay was used to detect M1 virus-induced cell killing. Flow cytometry was used to monitor infection of M1 virus expressing the GFP reporter gene. qPCR and western blotting were used to detect gene expression. RNA sequencing was performed to evaluate gene expression under different drug treatments. Scanning electron microscopy was performed to visualize the endoplasmic reticulum (ER). Caspase activity was detected. Last, a mouse xenograft model was established to evaluate the antitumor effect in vivo. Most data were analyzed with a two-tailed Student’s t test or one-way ANOVA with Dunnett’s test for pairwise comparisons. Tumor volumes were analyzed by repeated measures of ANOVA. The Wilcoxon signed-rank test was used to compare nonnormally distributed data. Results Here, we showed that the glucose analog 2-deoxy-d-glucose (2-DG) inhibited infection by M1 virus, which we identified as a novel type of oncolytic virus, and decreased its oncolytic effect, indicating the dependence of M1 replication on glycolysis. In contrast, lonidamine, a reported hexokinase 2 (HK2) inhibitor, enhanced the infection and oncolytic effect of M1 virus independent of HK2. Further transcriptomic analysis revealed that downregulation of the antiviral immune response contributes to the lonidamine-mediated potentiation of the infection and oncolytic effect of M1 virus, and that MYC is the key factor in the pool of antiviral immune response factors inhibited by lonidamine. Moreover, lonidamine potentiated the irreversible ER stress-mediated apoptosis induced by M1 virus. Enhancement of M1′s oncolytic effect by lonidamine was also identified in vivo. Conclusions This research demonstrated the dependence of M1 virus on glycolysis and identified a candidate synergist for M1 virotherapy.

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Transcription Factors Interplay Orchestrates the Immune-Metabolic Response of Leishmania Infected Macrophages

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.660415 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haifa Bichiou ◽

Cyrine Bouabid ◽

Imen Rabhi ◽

Lamia Guizani-Tabbane

Keyword(s):

Immune Response ◽

Transcription Factors ◽

Metabolic Response ◽

Wide Spectrum ◽

Clinical Manifestations ◽

Public Health Problem ◽

Host Cells ◽

Phagocytic Cells ◽

Important Public Health Problem ◽

Obligate Intracellular

Leishmaniasis is a group of heterogenous diseases considered as an important public health problem in several countries. This neglected disease is caused by over 20 parasite species of the protozoa belonging to the Leishmania genus and is spread by the bite of a female phlebotomine sandfly. Depending on the parasite specie and the immune status of the patient, leishmaniasis can present a wide spectrum of clinical manifestations. As an obligate intracellular parasite, Leishmania colonize phagocytic cells, mainly the macrophages that orchestrate the host immune response and determine the fate of the infection. Once inside macrophages, Leishmania triggers different signaling pathways that regulate the immune and metabolic response of the host cells. Various transcription factors regulate such immune-metabolic responses and the associated leishmanicidal and inflammatory reaction against the invading parasite. In this review, we will highlight the most important transcription factors involved in these responses, their interactions and their impact on the establishment and the progression of the immune response along with their effect on the physiopathology of the disease.

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