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

Pandey, Surya Prakash; Chandel, Himanshu Singh; Srivastava, Sunit K.; Selvaraj, Sathishkumar; Jha, Mukesh Kumar; Shukla, Divanshu; Ebensen, Thomas; Guzmán, Carlos A.; Saha, Bhaskar

doi:10.4049/jimmunol.1400672

Cited by 39 publications

(53 citation statements)

References 58 publications

(81 reference statements)

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“…In contrast, TLR2 agonist Pam3CSK4 led to conflicting results depending on the mouse model used. 63,98 These encouraging results support the idea that targeting the proper TLRs for vaccine development is a feasible strategy.…”

Section: Targeting Tlrs For Vaccine Developmentsupporting

confidence: 70%

Cutaneous Leishmaniasis: Update on Vaccine Development

Zufferey¹,

Whyte²

2017

HPD

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ABSTRACT:Leishmaniasis is an important disease mediated by the protozoan parasite Leishmania via the bite of the female sandfly insect vector. Leishmaniasis is endemic in the tropical and subtropical regions. The most common form of the disease is cutaneous leishmaniasis, which affects more than 10 million people worldwide and includes at least 1.5 million new cases every year. So far, treatment of the disease relies on unsatisfactory chemotherapy that can be complicated by the rising appearance of drug-resistant parasites. Furthermore, it is challenging to achieve solid control of the insect vector and animal reservoir. Therefore, the development of a safe and effective vaccine is urgently needed for the treatment and prevention of leishmaniasis. This review focuses on the recent advances in the development of a safe vaccine that could be used for prevention and treatment of cutaneous leishmaniasis. A short outlook for future research efforts is also presented.

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Section: Targeting Tlrs For Vaccine Developmentsupporting

confidence: 70%

Cutaneous Leishmaniasis: Update on Vaccine Development

Zufferey¹,

Whyte²

2017

HPD

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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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“…Interestingly, BPPcysMPEG has been shown to induce Th1-type immune responses in the context of allergens and parasite antigens363738. However, intramuscular immunization with hepatitis B surface antigen virus-like particles co-administered with BPPcysMPEG resulted in a Th2 dominated response39.…”

Section: Discussionmentioning

confidence: 99%

Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver

Volckmar

Gereke

Ebensen

et al. 2017

Sci Rep

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Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.

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

Cited by 39 publications

References 58 publications

Cutaneous Leishmaniasis: Update on Vaccine Development

Cutaneous Leishmaniasis: Update on Vaccine Development

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

Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver

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