Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

Cezário, Glaucia Aparecida Gomes; Oliveira, Larissa Ragozo Cardoso de; Peresi, Eliana; Nicolete, Vanessa C; Polettini, Jossimara; Lima, Carlos Roberto Gonçalves de; Gatto, Mariana; Calvi, Sueli Aparecida

doi:10.1590/s0074-02762011000500010

Cited by 40 publications

(40 citation statements)

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“…Previous studies showed that Leishmania spp. presented the ability to regulate TLR expression (33). Here, we found that L. infantum infection positively modulated the expression of TLR9 on the surface of DCs, suggesting that this receptor may be involved in the recognition of parasites and may orchestrate the immune response against this parasite.…”

Section: Discussionmentioning

confidence: 72%

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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Section: Discussionmentioning

confidence: 72%

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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“…found that L. donovani suppresses TLR2-mediated p38 mitogenactivated protein kinase (MAPK) activation, which results in decreased IL-12 and upregulated IL-10 production through extracellular signal-regulated kinase 1 and 2 (ERK1/2)-MAPK activation that eventually leads to disease pathogenesis (32). It has been also reported that TLR4 mRNA in the spleen correlates with the parasitic load in Leishmania infantum-infected BALB/c mice (33). The previous reports indicated that the prophylactic and/or therapeutic administration of TLR2 (34,35), TLR4 (36), or TLR9 agonists (37-39) enhances resistance in L. donovani-infected hamsters or BALB/c mice.…”

Section: Astrakurkurone-induced Nitric Oxide Caused the Inhibition Ofmentioning

confidence: 99%

“…4). As CD40, IL-12, and TLRs modulate each other in initiation of cellular activation leading to parasite clearance (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), we next attempted to explore the involvement of TLRs in astrakurkurone-mediated immunomodulation (Fig. 4).…”

Section: Astrakurkurone-induced Nitric Oxide Caused the Inhibition Ofmentioning

confidence: 99%

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Mallick

Dutta

Chaudhuri

et al. 2016

Antimicrob Agents Chemother

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eIn our previous report, we showed that astrakurkurone, a triterpene isolated from the Indian mushroom Astraeus hygrometricus (Pers.) Morgan, induced reactive oxygen species, leading to apoptosis in Leishmania donovani promastigotes, and also was effective in inhibiting intracellular amastigotes at the 50% inhibitory concentration of 2.5 g/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone, leading to effective antileishmanial activity in vitro and in vivo. Astrakurkurone-mediated antileishmanial activity was evaluated by real-time PCR and flow cytometry. The involvement of Toll-like receptor 9 (TLR9) was studied by in vitro assay in the presence of a TLR9 agonist and antagonist and by in silico modeling of a three-dimensional structure of the ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression of L. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that a TLR9 agonist (CpG, ODN 1826) in combination with astrakurkurone enhanced the amastigote killing, while a TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing, which could be further justified by in silico evidence of docking between mouse TLR9 and astrakurkurone. Astrakurkurone was found to reduce the parasite burden in vivo by inducing protective cytokines, gamma interferon and interleukin 17. Moreover, astrakurkurone was nontoxic toward peripheral blood mononuclear cells of immunocompromised patients with visceral leishmaniasis. Astrakurkurone, a nontoxic antileishmanial, enhances the immune efficiency of host cells, leading to parasite clearance in vitro and in vivo.

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“…The same group later showed that there was an increased parasite growth and delayed healing of cutaneous lesions resulting from a lack of TLR4 (Kropf et al 2004 b ). In a L. infantum mouse model study, it was revealed that L. infantum infection resulted in increased transcription of TLR4 along with TLR2 (Cezario et al 2011). This increased transcription could have been due to an influx of inflammatory cells into the spleen, in particular at the beginning of the infection, and a decrease seen at the chronic stage of infection could possibly have been due to partial control of the infection (Cezario et al 2011).…”

Section: Tlrsmentioning

confidence: 99%

Insights on adaptive and innate immunity in canine leishmaniosis

2016

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SUMMARYCanine leishmaniosis (CanL) is caused by the parasite Leishmania infantum and is a systemic disease, which can present with variable clinical signs, and clinicopathological abnormalities. Clinical manifestations can range from subclinical infection to very severe systemic disease. Leishmaniosis is categorized as a neglected tropical disease and the complex immune responses associated with Leishmania species makes therapeutic treatments and vaccine development challenging for both dogs and humans. In this review, we summarize innate and adaptive immune responses associated with L. infantum infection in dogs, and we discuss the problems associated with the disease as well as potential solutions and the future direction of required research to help control the parasite.

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Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

Cited by 40 publications

References 57 publications

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

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

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Insights on adaptive and innate immunity in canine leishmaniosis

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