Pore-forming toxins (PFTs) are the single largest class of bacterial protein toxins known and are employed by many pathogenic bacteria (e.g., Staphylococcus aureus and Streptococcus pyogenes) to cause disease. These toxins punch holes in cell membranes and disrupt normal cell functions. Despite their importance, how PFTs work, how host cells respond to them, and whether or not animal cells have a defense against this form of attack are poorly understood. Recently, the nematode Caenorhabditis elegans has emerged as an excellent system for studying PFTs. Using C. elegans, it has been demonstrated that the p38 MAP kinase pathway is activated by PFT and that the p38 pathway provides an innate defense for the animal against attack by PFTs. Furthermore, the p38 pathway was subsequently shown to also protect mammalian cells against PFTs, suggesting this defense is conserved between C. elegans and mammals and expanding the known immunological functions of this key pathway. This grant proposes to follow up these results and utilize the powerful genomic and genetic tools of C. elegans to globally dissect what host genes are needed to activate the p38 MAPK pathway in response to PFT, to uncover the downstream targets of the p38 MAPK pathway that execute the defensive program, to study the role of these C. elegans p38 defense pathway genes in the defense of mammalian cells against PFT, and to study the physiological mechanisms by which the p38 pathway defends animal cells against PFT. Understanding how the p38 pathway controls defense against PFTs is likely to suggest new therapeutic strategies for dealing with a range of important bacterial pathogens that use PFTs as key virulence factors. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071603-02
Application #
7225496
Study Section
Special Emphasis Panel (ZRG1-III-L (08))
Program Officer
Anderson, James J
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$264,612
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Dementiev, Alexey; Board, Jason; Sitaram, Anand et al. (2016) The pesticidal Cry6Aa toxin from Bacillus thuringiensis is structurally similar to HlyE-family alpha pore-forming toxins. BMC Biol 14:71
Franks, Sarah E; Ebrahimi, Celia; Hollands, Andrew et al. (2014) Novel role for the yceGH tellurite resistance genes in the pathogenesis of Bacillus anthracis. Infect Immun 82:1132-40
Los, Ferdinand C O; Randis, Tara M; Aroian, Raffi V et al. (2013) Role of pore-forming toxins in bacterial infectious diseases. Microbiol Mol Biol Rev 77:173-207
Los, Ferdinand C O; Ha, Christine; Aroian, Raffi V (2013) Neuronal Go? and CAPS regulate behavioral and immune responses to bacterial pore-forming toxins. PLoS One 8:e54528
Kao, Cheng-Yuan; Los, Ferdinand C O; Huffman, Danielle L et al. (2011) Global functional analyses of cellular responses to pore-forming toxins. PLoS Pathog 7:e1001314
Kho, Melanie F; Bellier, Audrey; Balasubramani, Venkatasamy et al. (2011) The pore-forming protein Cry5B elicits the pathogenicity of Bacillus sp. against Caenorhabditis elegans. PLoS One 6:e29122
Los, Ferdinand C O; Kao, Cheng-Yuan; Smitham, Jane et al. (2011) RAB-5- and RAB-11-dependent vesicle-trafficking pathways are required for plasma membrane repair after attack by bacterial pore-forming toxin. Cell Host Microbe 9:147-57
Chen, Chang-Shi; Bellier, Audrey; Kao, Cheng-Yuan et al. (2010) WWP-1 is a novel modulator of the DAF-2 insulin-like signaling network involved in pore-forming toxin cellular defenses in Caenorhabditis elegans. PLoS One 5:e9494
Bellier, Audrey; Chen, Chang-Shi; Kao, Cheng-Yuan et al. (2009) Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans. PLoS Pathog 5:e1000689
Bischof, Larry J; Kao, Cheng-Yuan; Los, Ferdinand C O et al. (2008) Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo. PLoS Pathog 4:e1000176