<i>Leishmania</i>expressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce anti-leishmanial responses

Srivastava, Sunit K.; Pandey, Surya Prakash; Jha, Mukesh Kumar; Chandel, Himanshu Singh; Saha, Bhaskar

doi:10.1111/cei.12074

Cited by 76 publications

(73 citation statements)

References 24 publications

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“…Macrophages were treated with different doses of TLR ligands or left untreated for 60 h. Macrophages were fixed with chilled methanol and stained with Giemsa stain. Amastigotes were counted under the microscope, as reported earlier (11).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, TLR2-TLR6 heterodimer is shown to induce IL-12 (16), a cytokine known for promoting IFN-g-predominated host-protective response in L. major infection (22). In contrast, TLR2 was found to promote L. major (11) and L. donovani (23) infections. Although TLR1-TLR2 and TLR2-TLR6 heterodimers are known for recognition of triacylated lipopeptides or diacylated lipopeptides, respectively (4,5), whether they function differently is not known.…”

mentioning

confidence: 88%

“…cDNA from each sample was amplified with Taq DNA polymerase (Invitrogen Life Technologies) in 25 ml reaction mix, under the following conditions: 94˚C for 1 min, annealing for 1 min at a temperature between 53 and 60˚C depending upon the gene-specific primers (Table I), and 72˚C for 1 min for a total of 28-30 cycles. Each sample was amplified for mouse GAPDH or b-actin to ensure equal cDNA input, as described earlier (11). Amplified PCR products were run in 1.2% agarose gel.…”

Section: Rt-pcr and Real-time Pcrmentioning

confidence: 99%

“…Whereas recognition of Leishmania by a TLR may be followed by macrophage activation and parasite control (8), the protozoan devises immune evasion strategies either by indirect interference of the IFN-g-secreting host-protective Th1 cell generation (9) or by direct interference through lipophosphoglycanmediated deactivation of macrophages (10). Lipophosphoglycan-TLR2 interaction diminishes the antileishmanial response by reducing TLR9 expression (11). By contrast, TLR2-deficient mice on a resistant C57BL/6 background and the wild-type controls are equally resistant to Leishmania braziliensis infection (12), suggesting that TLR2 may not play a role in Leishmania infection.…”

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confidence: 99%

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Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Pandey

Chandel

Srivastava

et al. 2014

The Journal of Immunology

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TLRs recognize pathogen-expressed Ags and elicit host-protective immune response. Although TLR2 forms heterodimers with TLR1 or TLR6, recognizing different ligands, differences in the functions of these heterodimers remain unknown. In this study, we report that in Leishmania major-infected macrophages, the expression of TLR1 and TLR2, but not TLR6, increased; TLR2–TLR2 association increased, but TLR2–TLR6 association diminished. Lentivirus-expressed TLR1–short hairpin RNA (shRNA) or TLR2–shRNA administration reduced, but TLR6–shRNA increased L. major infection in BALB/c mice. Corroboratively, Pam3CSK4 (TLR1–TLR2 ligand) and peptidoglycan (TLR2 ligand) increased L. major infection but reduced TLR9 expression, whereas pegylated bisacycloxypropylcysteine (BPPcysMPEG; TLR2–TLR6 ligand) reduced L. major number in L. major-infected macrophages, accompanied by increased TLR9 expression, higher IL-12 production, and inducible NO synthase expression. Whereas MyD88, Toll/IL-1R adaptor protein, and TNFR-α–associated factor 6 recruitments to TLR2 were not different in Pam3CSK4-, peptidoglycan-, or BPPcysMPEG-treated macrophages, only BPPcysMPEG enhanced p38MAPK and activating transcription factor 2 activation. BPPcysMPEG conferred antileishmanial functions to L. major-infected BALB/c-derived T cells in a macrophage–T cell coculture and in BALB/c mice; the protection was TLR6 dependent and IL-12 dependent, and it was accompanied by reduced regulatory T cell number. BPPcysMPEG administration during the priming with fixed L. major protected BALB/c mice against challenge L. major infection; the protection was accompanied by low IL-4 and IL-10, but high IFN-γ productions and reduced regulatory T cells. Thus, BPPcysMPEG, a novel diacylated lipopeptide ligand for TLR2–TLR6 heterodimer, induces IL-12–dependent, inducible NO synthase–dependent, T-reg–sensitive antileishmanial protection. The data reveal a novel dimerization partner-dependent duality in TLR2 function.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 88%

Section: Rt-pcr and Real-time Pcrmentioning

confidence: 99%

mentioning

confidence: 99%

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Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Pandey

Chandel

Srivastava

et al. 2014

The Journal of Immunology

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“…Blockade of TLR2 or LPG reduced L. major parasite number in infected macrophages (13,14). Therefore, we tested whether TLR2 silencing reversed the L. major-modulated Ras expression.…”

Section: Tlr2 Upregulates N-ras Expression But Reduces K-ras Expressionmentioning

confidence: 99%

Inhibition of CD40-Induced N-Ras Activation Reduces Leishmania major Infection

Chakraborty

Srivastava

Jha

et al. 2015

The Journal of Immunology

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Leishmania major is a parasite that resides and replicates in macrophages. We previously showed that the parasite enhanced CD40-induced Raf-MEK-ERK signaling but inhibited PI3K-MKK-p38MAPK signaling to proleishmanial effects. As Raf and PI3K have a Ras-binding domain but exert opposite effects on Leishmania infection, we examined whether Ras isoforms had differential roles in Leishmania infection. We observed that L. major enhanced N-Ras and H-Ras expression but inhibited K-Ras expression in macrophages. L. major infection enhanced N-Ras activity but inhibited H-Ras and K-Ras activity. TLR2 short hairpin RNA or anti-TLR2 or anti-lipophosphoglycan Abs reversed the L. major–altered N-Ras and K-Ras expressions. Pam3CSK4, a TLR2 ligand, enhanced N-Ras expression but reduced K-Ras expression, indicating TLR2-regulated Ras expression in L. major infection. Whereas N-Ras silencing reduced L. major infection, K-Ras and H-Ras silencing enhanced the infection both in macrophages in vitro and in C57BL/6 mice. BALB/c-derived macrophages transduced with lentivirally expressed N-Ras short hairpin RNA and pulsed with L. major–expressed MAPK10 enhanced MAPK10-specific Th1-type response. CD40-deficient mice primed with these macrophages had reduced L. major infection, accompanied by higher IFN-γ but less IL-4 production. As N-Ras is activated by Sos, a guanine nucleotide exchange factor, we modeled the N-Ras–Sos interaction and designed two peptides from their interface. Both the cell-permeable peptides reduced L. major infection in BALB/c mice but not in CD40-deficient mice. These data reveal the L. major–enhanced CD40-induced N-Ras activation as a novel immune evasion strategy and the potential for Ras isoform–targeted antileishmanial immunotherapy and immunoprophylaxis.

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Pathogen-associated Molecular Patterns

Cavaillon

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Leishmaniaexpressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce anti-leishmanial responses

Cited by 76 publications

References 24 publications

Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Inhibition of CD40-Induced N-Ras Activation Reduces Leishmania major Infection

Pathogen-associated Molecular Patterns

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