title: Microarray analysis of differentially regulated genes in human neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin.
abstract: Among the seven serotypes (A-G), type A botulinum neurotoxin (BoNT/A) is the most prevalent etiologic agent and the most potent serotype to cause foodborne botulism, characterized by flaccid muscle paralysis. Upon ingestion, BoNT/A crosses epithelial cell barriers to reach lymphatic and circulatory systems and blocks acetylcholine release at the pre-synaptic cholinergic nerve terminals of neuromuscular junctions (NMJs) resulting in paralysis. One of the unique features of BoNT/A intoxication is its neuroparalytic longevity due to its persistent catalytic activity. The persistent presence of the toxin inside the cell can induce host cell responses. To understand the pathophysiology and host response at the cellular level, gene expression changes upon exposure of human HT-29 colon carcinoma (epithelial) and SH-SY5Y neuroblastoma cell lines to BoNT/A complex were investigated using microarray analysis. In HT-29 cells, 167 genes were up-regulated while 60 genes were down-regulated, whereas in SH-SY5Y cells about 223 genes were up-regulated and 18 genes were down-regulated. Modulation of genes and pathways involved in neuroinflammatory, ubiquitin-proteasome degradation, phosphatidylinositol, calcium signaling in SH-SY5Y cells, and genes relevant to focal adhesion, cell adhesion molecules, adherens and gap junction related pathways in HT-29 cells suggest a massive host response to BoNT/A. A clear differential response in epithelial and neuronal cells indicates that the genes affected may play a distinct role in BoNTs cellular mode of action, involving these two types of host cells.
authors.affiliation: Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Botulinum Research Center, 285 Old Westport Road, N Dartmouth, MA 02747, United States.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Thirunavukkarasusx
authors.forename: Koyel J
authors.initials: KJ
authors.lastname: Ghosal
authors.forename: Roshan
authors.initials: R
authors.lastname: Kukreja
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Alan
authors.initials: A
authors.lastname: Dombkowski
authors.forename: Shuowei
authors.initials: S
authors.lastname: Cai
authors.forename: Bal Ram
authors.initials: BR
authors.lastname: Singh
mesh_terms: D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics
chemical_list: D025801:Ubiquitin; D019274:Botulinum Toxins, Type A; D046988:Proteasome Endopeptidase Complex