title: The role of a Brugia malayi p38 MAP kinase ortholog (Bm-MPK1) in parasite anti-oxidative stress responses.
abstract: Filariasis, caused by thread-like nematode worms, affects millions of individuals throughout the tropics and is a major cause of acute and chronic morbidity. Filarial nematodes effectively evade host immunological responses and are long lived within their hosts. Recently an emphasis has been placed on enzymatic and non-enzymatic anti-oxidant systems which counteract the generation of reactive oxygen species (ROS) by macrophages and granulocytes, a first line of defense against parasites. We have characterized an anti-oxidant pathway in the filarial parasite Brugia malayi related to the evolutionarily conserved human mitogen-activated p38 protein kinase and the Caenorhabditis elegans PMK-1 protein kinase stress pathways. We have expressed a recombinant p38/PMK-1 ortholog from B. malayi (Bm-MPK1) and have successfully activated the kinase with mammalian upstream kinases. In addition, we have demonstrated inhibition of Bm-MPK1 activity using a panel of known p38 inhibitors. Using the potent and highly selective allosteric p38 inhibitor, BIRB796, we have implicated Bm-MPK1 in a pathway which offers B. malayi protection from the effects of ROS. Our results, for the first time, describe a stress-activated protein kinase pathway within the filarial parasite B. malayi which plays a role in protecting the parasite from ROS. Inhibition of this pathway may have therapeutic benefit in treating filariasis by increasing the sensitivity of filarial parasites to ROS and other reactive intermediates.
authors.affiliation: Department of Chemistry and Biochemistry and The Herman and Margaret Sokol Institute for Pharmaceutical Life Sciences, Montclair State University, Montclair, NJ 07043, USA.
authors.forename: Akruti
authors.initials: A
authors.lastname: Patel
authors.forename: Agnieszka Nawrocka
authors.initials: AN
authors.lastname: Chojnowski
authors.forename: Katie
authors.initials: K
authors.lastname: Gaskill
authors.forename: William
authors.initials: W
authors.lastname: De Martini
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Goldberg
authors.forename: John J
authors.initials: JJ
authors.lastname: Siekierka
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017178:Brugia malayi / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans; D005260:Female; D005368:Filariasis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds
chemical_list: D015801:Helminth Proteins; D009281:Naphthalenes; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds