Arabinosylated Lipoarabinomannan–Mediated Protection in Visceral Leishmaniasis through Up‐Regulation of Toll‐Like Receptor 2 Signaling: An Immunoprophylactic Approach

Bhattacharya, Pinaki; Bhattacharjee, Surajit; Gupta, Gaurav; Majumder, Saikat; Adhikari, Anupam; Mukherjee, Asok K.; Majumdar, S.; Saha, Bhaskar; Majumdar, Subrata

doi:10.1086/653210

Cited by 38 publications

(57 citation statements)

References 35 publications

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“…6) contrast directly with reports that treatment with this TLR1/2 agonist or arabinosylated lipoarabinomannan, a TLR2 agonist, enhances resistance to L. donovani (26,27). These studies, however, differed from ours in three ways: (i) BALB/c mice with a noncuring form of infection and different (19,21); and (iii) importantly, agonist treatment was not tested in the midst of initially provoked host responses to infection but given prophylactically, 2 to 7 days before challenge (26,27). The data shown in Fig.…”

Section: Discussionmentioning

confidence: 83%

“…At the same time, TLR2 signaling also promotes inflammatory, macrophage-activating, and immunizing responses (21,26,27,34,35,53,61,62,67), and TLR2 Ϫ/Ϫ mice are more susceptible to a diverse group of other pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, Salmonella Typhimurium, Francisella tularensis, Legionella pneumophila, Toxoplasma gondii, and various Mycobacterium spp. (20,34,35).…”

Section: Discussionmentioning

confidence: 99%

“…The latter have shown that expression of TLR2 and TLR4 mRNA in the spleen correlates with parasite load in L. infantum-infected BALB/c mice (25) and that prophylactic and/or therapeutic injections of TLR2 (26,27), TLR4 (28), or TLR9 agonists (29)(30)(31) enhance resistance in L. donovani-infected hamsters or BALB/c mice. Directly generated in vivo information is limited.…”

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confidence: 99%

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Regulatory Actions of Toll-Like Receptor 2 (TLR2) and TLR4 in Leishmania donovani Infection in the Liver

Murray

Zhang

et al. 2013

Infect Immun

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cIn livers of susceptible but self-curing C57BL/6 mice, intracellular Leishmania donovani infection enhanced Toll-like receptor 4 (TLR4) and TLR2 gene expression. In the liver, infected TLR4 ؊/؊ mice showed reduced gamma interferon (IFN-␥), tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS) mRNA expression, higher-level and slowly resolving infection, delayed granuloma formation, and little response to low-dose chemotherapy; in serum, the ratio of IFN-␥ to interleukin 10 (IL-10) activity was decreased by 50%. In contrast, in TLR2 ؊/؊ mice, control of liver infection, parasite killing, and granuloma assembly were accelerated and chemotherapy's efficacy enhanced. In livers of infected TLR2 ؊/؊ mice, mRNA expression was not increased for inflammatory cytokines or iNOS or decreased for IL-10; however, the serum IFN-␥/IL-10 ratio was increased 6.5-fold and minimal responses to IL-10 receptor blockade suggested downregulated IL-10. In established infection in wild-type mice, blockading TLR2 induced parasite killing and triggering TLR4 strengthened resistance and promoted chemotherapy's effect. Thus, in experimental L. donovani infection in the liver, TLR4 signaling upregulates and TLR2 signaling downregulates macrophage antileishmanial activity, making both receptors potential therapeutic targets in visceral leishmaniasis for engagement (TLR4) or blockade (TLR2).

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulatory Actions of Toll-Like Receptor 2 (TLR2) and TLR4 in Leishmania donovani Infection in the Liver

Murray

Zhang

et al. 2013

Infect Immun

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“…It has been described that resistance to Leishmania species infection is dependent on parasite lipophosphoglycan (LPG) recognition by TLR2 (8), the induction of IL-12, and the development of a Th1 immune response (12) together with NO production (13). Previous studies demonstrated a role for TLR2 and TLR3 in L. donovani recognition and killing by macrophages (14).…”

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confidence: 99%

Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

et al. 2015

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Leishmania infantum is a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC)activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by different Leishmania species. We demonstrated that TLR9 is upregulated in vitro and in vivo during infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9 ؊/؊ mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9 ؊/؊ mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9 ؊/؊ mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore, L. infantum failed to activate both plasmacytoid and myeloid DCs from TLR9 ؊/؊ mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected both in vitro and in vivo when DCs were derived from TLR9 ؊/؊ mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response against L. infantum infection that could be associated with DC activation. L eishmania intracellular protozoan parasites cause a heterogeneous disease that can range from cutaneous lesions to visceral disease. Visceral disease can be caused by both Leishmania donovani and Leishmania infantum and is the most severe manifestation of this type of parasite infection. Therefore, Leishmania infections remain an important cause of human mortality and morbidity around the world (www.paho.org/english/ad/dpc/cd /res-dch-leish-priorities.pdf).Host defenses against Leishmania spp. depend on the activation of an inflammatory response initiated by the innate immune system (1), followed by specific immune responses mediated by gamma interferon (IFN-␥)-or interleukin-17 (IL-17)-producing CD4 ϩ T lymphocytes (2, 3). The innate immune system has specific mechanisms to rapidly recognize the parasite. A major component of pathogen recognition comprises a family of Toll-like receptors (TLRs) that detect common pathogen-associated molecular patterns (PAMPs) of various groups of microorganisms (4-7), including Leishmania spp. (8, 9).The role of TLRs in Leishmania infection control has been supported by the observations that mice lacking MyD88, an adaptor molecule required for TLR signaling, display enhanced susceptibility to infection (10, 11). It has been described that resistance to Leishmania species infection is dependent on parasite lipophosphoglycan (LPG) recognition by TLR2 (8), the induction of IL-12, and the development of a Th1 immune response (12) together with NO production (13). Previous studies demonstrated a role for TLR2 and TLR3 i...

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“…Upon ligand binding, the TLR gets activated leading to downstream signaling cascade activation leading to NF-κB-and MAPK (mitogen-activated protein kinase)-mediated proinflammatory cytokine production. The TLR2 agonists used to activate TLR2 signaling pathway showed host protective immune response resulting in parasite clearance from L. donovani infected macrophages [36]. To subvert this inflammatory response Leishmania either recruits suppressors of the cytokine signaling (SOCS) family proteins, SOCS-1/3 [37], or activates host de-ubiquitinating enzyme A20 to negatively regulate TLR2/4-induced host protective response [38,39].…”

Section: Downregulation Of Toll-like Receptor (Tlr) Pathwaysmentioning

confidence: 99%

Bioactive Component of Licorice as an Antileishmanial Agent

Gupta¹,

Ukil²,

Das³

2017

Biological Activities and Action Mechanisms of Licorice Ingredients

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The term leishmaniasis encompasses a spectrum of vector-borne protozoan parasitic diseases ranging from self-healing cutaneous to fatal visceral leishmaniasis. The disease affects 12 million people worldwide with 0.5 million new cases per annum. Present antileishmanial chemotherapeutic drugs project limitations because of severe toxicity, lengthy regime and occurrence of resistance, thereby making development of newer, gentler and efficacious therapeutics an urgent need for treatment of leishmaniasis. Application of medicinal plants in treatment of refractory diseases is valued for its clinical efficacy and nontoxicity. The biologically active components derived from them continue to play important roles as chemopreventive agents. Licorice has been known for its medicinal property from ancient times for treatment of various ailments. 18β-Glycyrrhetinic acid, glycyrrhizic acid and licochalcone A are the most extensively studied constituents of licorice in terms of antileishmanial agent. Overall, this chapter is dedicated to highlight the current understanding of the mechanism of these bioactive constituents of licorice, which potentiates them as antileishmanial agents. Furthermore, it also brings to light the importance of folk medicine in curing diseases and thereby gives impetus to explore ancient medicines and thier mode of actions to use them progressively to cure diseases.

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Arabinosylated Lipoarabinomannan–Mediated Protection in Visceral Leishmaniasis through Up‐Regulation of Toll‐Like Receptor 2 Signaling: An Immunoprophylactic Approach

Cited by 38 publications

References 35 publications

Regulatory Actions of Toll-Like Receptor 2 (TLR2) and TLR4 in Leishmania donovani Infection in the Liver

Regulatory Actions of Toll-Like Receptor 2 (TLR2) and TLR4 in Leishmania donovani Infection in the Liver

Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

Bioactive Component of Licorice as an Antileishmanial Agent

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