title: Leishmania donovani prevents oxidative burst-mediated apoptosis of host macrophages through selective induction of suppressors of cytokine signaling (SOCS) proteins.
abstract: One of the mechanisms for establishment of infection employed by intra-macrophage pathogen-like Leishmania is inhibition of oxidative burst-mediated macrophage apoptosis to protect their niche for survival and replication. We tried to elucidate the underlying mechanism for this by using H2O2 for induction of apoptosis. Leishmania donovani-infected macrophages were much more resistant to H2O2-mediated apoptosis compared with control. Although infected cells were capable of comparable reactive oxygen species production, there was less activation of the downstream cascade consisting of caspase-3 and -7 and cleaved poly(ADP)-ribose polymerase. Suppressors of cytokine signaling (SOCS) 1 and 3 proteins and reactive oxygen species scavenging enzyme thioredoxin, known to be involved in stabilization of protein-tyrosine phosphatases, were found to be induced during infection. Induction of SOCS proteins may be mediated by Egr1, and silencing of Socs1 and -3 either alone or in combination resulted in reduced thioredoxin levels, enhanced activation of caspases, and increased apoptosis of infected macrophages. The induction of protein-tyrosine phosphatases, thioredoxin, SOCS, and Egr1 in L. donovani-infected macrophages was found to be unaffected by H2O2 treatment. SOCS knocked down cells also displayed decreased parasite survival thus marking reduction in disease progression. Taken together, these results suggest that L. donovani may exploit SOCS for subverting macrophage apoptotic machinery toward establishing its replicative niche inside the host.
authors.affiliation: From the Infectious Diseases and Immunology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032 and.
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastav
authors.forename: Writoban
authors.initials: W
authors.lastname: Basu Ball
authors.forename: Purnima
authors.initials: P
authors.lastname: Gupta
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Giri
authors.forename: Anindita
authors.initials: A
authors.lastname: Ukil
authors.forename: Pijush K
authors.initials: PK
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D007893:Leishmania donovani / Q000254:growth & development* / Q000502:physiology; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010587:Phagocytosis / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D034622:RNA Interference; D016897:Respiratory Burst / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016877:Oxidants; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D020169:Caspases
keywords: Apoptosis; Host-Pathogen Interactions; Leishmania; Macrophages; Reactive Oxygen Species (ROS)