Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins
Danielle L Huffman1, Laurence Abrami, Roman Sasik
1Section of Cell and Developmental Biology, University of California at San Diego, La Jolla, 92093, USA.
Abstract:
Cytolytic pore-forming toxins are important for the virulence of many disease-causing bacteria. How target cells molecularly respond to these toxins and whether or not they can mount a defense are poorly understood. By using microarrays, we demonstrate that the nematode Caenorhabditis elegans responds robustly to Cry5B, a member of the pore-forming Crystal toxin family made by Bacillus thuringiensis. This genomic response is distinct from that seen with a different stressor, the heavy metal cadmium. A p38 mitogen-activated protein kinase (MAPK) kinase and a c-Jun N-terminal-like MAPK are both transcriptionally up-regulated by Cry5B. Moreover, both MAPK pathways are functionally important because elimination of either leads to animals that are (i) hypersensitive to a low, chronic dose of toxin and (ii) hypersensitive to a high, brief dose of toxin such that the animal might naturally encounter in the wild. These results extend to mammalian cells because inhibition of p38 results in the hypersensitivity of baby hamster kidney cells to aerolysin, a pore-forming toxin that targets humans. Furthermore, we identify two downstream transcriptional targets of the p38 MAPK pathway, ttm-1 and ttm-2, that are required for defense against Cry5B. Our data demonstrate that cells defend against pore-forming toxins by means of conserved MAPK pathways.
Insights
Cells defend against bacterial pore-forming toxins using conserved mitogen-activated protein kinase (MAPK) pathways. This defense mechanism involves specific MAPK pathways and downstream targets, crucial for survival against these toxins.
Area of Science:
- Microbiology
- Cell Biology
- Toxicology
Background:
- Cytolytic pore-forming toxins contribute to bacterial virulence.
- Cellular responses and defense mechanisms against these toxins are not well understood.
Purpose of the Study:
- To investigate the molecular response of Caenorhabditis elegans to the pore-forming toxin Cry5B.
- To identify conserved defense pathways against pore-forming toxins in both nematodes and mammalian cells.
Main Methods:
- Microarray analysis to study the genomic response of C. elegans to Cry5B.
- Genetic manipulation (elimination of specific genes) to assess functional importance of MAPK pathways.
- Inhibition of p38 MAPK in mammalian cells (baby hamster kidney cells) to test cross-species relevance.
Main Results:
- C. elegans mounts a robust genomic response to Cry5B, distinct from cadmium stress.
- p38 MAPK and c-Jun N-terminal-like MAPK pathways are transcriptionally upregulated by Cry5B and are essential for defense.
- Mammalian cells (baby hamster kidney cells) show hypersensitivity to aerolysin when p38 is inhibited.
- ttm-1 and ttm-2 were identified as downstream targets of the p38 MAPK pathway crucial for Cry5B defense.
Conclusions:
- Conserved MAPK pathways play a critical role in cellular defense against pore-forming toxins.
- The identified defense mechanisms are evolutionarily conserved across species, from nematodes to mammals.
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