title: The host-protective effect of arabinosylated lipoarabinomannan against Leishmania donovani infection is associated with restoration of IFN-γ responsiveness.
abstract: Visceral leishmaniasis (VL), which is endemic as a major infectious disease in the tropical and subtropical countries, is caused by a protozoan parasite Leishmania donovani. At present, restricted treatment options and lack of vaccines intensify the problem of controlling VL. Therefore, finding a novel immunoprophylactic or therapeutic principle is a pressing need. Here, we report that arabinosylated lipoarabinomannan (Ara-LAM), a TLR2-ligand isolated from Mycobacterium smegmatis, exhibits a strong immunomodulatory property that conferred protection against L. donovani infection. Although, Ara-LAM modulates TLR2 and MAPK signaling, it is not known whether Ara-LAM involves IFN-γ signaling for effective parasite clearance. Because, it is reported that IFN-γ signaling, a principle mediator of NO generation and macrophage and Tcell activation, is hampered during leishmanial pathogenesis. Ara-LAM increases IFN-γ receptor expression and potentiates IFN-γ receptor signaling through JAK-STAT pathway. Moreover, Ara-LAM reciprocally modulates IRF4 and IRF8 expression and reinstates anti-leishmanial Th1 response that eventuates in significantly reduced parasite load in spleen and liver of L. donovani-infected BALB/c mice. IFN-γRα silencing resulted in the suppression of these host-protective mechanisms affected by Ara-LAM. Thus, Ara-LAM-mediated restoration of IFN-γ responsiveness is a novel immuno-modulatory principle for protection against L. donovani susceptible host.
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Bidisha Paul
authors: BP
authors: Chowdhury
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Syamdas
authors: S
authors: Bandyopadhyay
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Shibali
authors: S
authors: Das
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Saikat
authors: S
authors: Majumder
authors: Laboratory-V, National Centre for Cell Science (NCCS), Pune, Maharashtra, India.
authors: Mukesh Kumar
authors: MK
authors: Jha
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Suchandra Bhattacharyya
authors: SB
authors: Majumdar
authors: Laboratory-V, National Centre for Cell Science (NCCS), Pune, Maharashtra, India.
authors: Bhaskar
authors: B
authors: Saha
authors: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors: Subrata
authors: S
authors: Majumdar
mesh_terms: D000818:Animals; D001089:Arabinose / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000276:immunology*; D007893:Leishmania donovani / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D014157:Transcription Factors; C050016:lipoarabinomannan; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; D001089:Arabinose