Our group is aiming to characterize host responses to bacterial pore forming toxins (PFT). These proteins may kill target cells, weaken host defense, and help bacteria to gain access to sterile tissues, intracellular compartments and nutrients. The prime focus of our work is on function or failure of cell-autonomous defense against PFT. We propose that these processes are crucial for the maintenance of epithelial and endothelial barrier functions. Consequently, we consider them an important aspect of innate immunity against bacteria. The group has identified mechanisms which enable mammalian cells to recover from perforation of their membrane, or to confer a priori cellular tolerance to PFT. Endocytic removal of membrane lesions, autophagy and metabolic homeostasis emerge as mainstays of defense. Ca2+-influx-dependent membrane repair, the default mechanism responsible for resealing of torn membranes, also protects cells against large pore forming toxins, like streptolysin O. By contrast, the small b-pore forming S. aureus a-toxin or Vibrio cholerae cytolysin subvert this process. Whereas S. aureus a-toxin triggers an alternative, Ca2+-influx independent, MAPK-dependent salvage pathway, Vibrio cholerae cytolysin appears to cause sustained damage. Because efficiency, kinetics and mode of repair depend on the PFT, we strive to explore new members of this toxin-family. A recent addition is a small b-PFT of P. damselae subsp. damselae, an emerging marine pathogen, which causes hyper-aggressive soft tissue infections in humans. Specific features of different PFT shall help us to elucidate various aspects of cell autonomous defense; a range of technical approaches is being applied. To sum, we aim to understand the function of bacterial pore forming toxins, and of mechanisms conferring host tolerance against these abundant virulence factors. Ultimately this may aid in designing strategies to control infectious diseases and autoimmune conditions.
von Hoven, G., M. Meyenburg, C. Neukirch, D. Siedenschnur and M. Husmann. 2022. Glutamine 666 renders murine ADAM10 an inefficient S. aureus a-toxin receptor. BioRxiv doi: https://doi.org/10.1101/2022.05.11.491455
von Hoven, G., and M. Husmann. 2019. Staphylococcus aureus alpha-Toxin's Close Contacts Ensure the Kill. Trends Microbiol 27:89-90.
von Hoven, G., Q. Qin, C. Neukirch, M. Husmann, and N. Hellmann. 2019. Staphylococcus aureus alpha-toxin: small pore, large consequences. Biol Chem 400:1261-1276.
von Hoven, G., A.J. Rivas, and M. Husmann. 2019. Phobalysin: Fisheye View of Membrane Perforation, Repair, Chemotaxis and Adhesion. Toxins (Basel) 11:
von Hoven, G., C. Neukirch, M. Meyenburg, S. Schmidt, A. Vences, C.R. Osorio, M. Husmann, and A.J. Rivas. 2018. Cytotoxin- and Chemotaxis-Genes Cooperate to Promote Adhesion of Photobacterium damselae subsp. damselae. Front Microbiol 9:2996.
Schwiering, M., M. Husmann, and N. Hellmann. 2017. P2X-Receptor Antagonists Inhibit the Interaction of S. aureus Hemolysin A with Membranes. Toxins (Basel) 9:
Vences, A., A.J. Rivas, M.L. Lemos, M. Husmann, and C.R. Osorio. 2017. Chromosome-Encoded Hemolysin, Phospholipase, and Collagenase in Plasmidless Isolates of Photobacterium damselae subsp. damselae Contribute to Virulence for Fish. Appl Environ Microbiol 83:
von Hoven, G., A.J. Rivas, C. Neukirch, M. Meyenburg, Q. Qin, S. Parekh, N. Hellmann, and M. Husmann. 2017. Repair of a Bacterial Small beta-Barrel Toxin Pore Depends on Channel Width. mBio 8:
von Hoven, G., A.J. Rivas, C. Neukirch, S. Klein, C. Hamm, Q. Qin, M. Meyenburg, S. Fuser, P. Saftig, N. Hellmann, R. Postina, and M. Husmann. 2016. Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus alpha-toxin action. Biochem J 473:1929-1940.
Rivas, A.J., A. Vences, M. Husmann, M.L. Lemos, and C.R. Osorio. 2015. Photobacterium damselae subsp. damselae major virulence factors Dly, plasmid-encoded HlyA, and chromosome-encoded HlyA are secreted via the type II secretion system. Infect Immun 83:1246-1256.
Rivas, A.J., G. von Hoven, C. Neukirch, M. Meyenburg, Q. Qin, S. Fuser, K. Boller, M.L. Lemos, C.R. Osorio, and M. Husmann. 2015. Phobalysin, a Small beta-Pore-Forming Toxin of Photobacterium damselae subsp. damselae. Infect Immun 83:4335-4348.
von Hoven, G., C. Neukirch, M. Meyenburg, S. Fuser, M.B. Petrivna, A.J. Rivas, A. Ryazanov, R.J. Kaufman, R.V. Aroian, and M. Husmann. 2015. eIF2alpha Confers Cellular Tolerance to S. aureus alpha-Toxin. Front Immunol 6:383.
Husmann, M. 2013. Vital dyes and virtual deaths. Cell Death Differ 20:963.
Imre, G., J. Heering, A.N. Takeda, M. Husmann, B. Thiede, D.M. zu Heringdorf, D.R. Green, F.G. van der Goot, B. Sinha, V. Dotsch, and K. Rajalingam. 2012. Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis. EMBO J 31:2615-2628.
Kloft, N., C. Neukirch, G. von Hoven, W. Bobkiewicz, S. Weis, K. Boller, and M. Husmann. 2012. A subunit of eukaryotic translation initiation factor 2alpha-phosphatase (CreP/PPP1R15B) regulates membrane traffic. J Biol Chem 287:35299-35317.
Usmani, S.M., J. von Einem, M. Frick, P. Miklavc, M. Mayenburg, M. Husmann, P. Dietl, and O.H. Wittekindt. 2012. Molecular basis of early epithelial response to streptococcal exotoxin: role of STIM1 and Orai1 proteins. Cell Microbiol 14:299-315.
von Hoven, G., N. Kloft, C. Neukirch, S. Ebinger, W. Bobkiewicz, S. Weis, K. Boller, K.D. Janda, and M. Husmann. 2012. Modulation of translation and induction of autophagy by bacterial exoproducts. Med Microbiol Immunol 201:409-418.
Kao, C.Y., F.C. Los, D.L. Huffman, S. Wachi, N. Kloft, M. Husmann, V. Karabrahimi, J.L. Schwartz, A. Bellier, C. Ha, Y. Sagong, H. Fan, P. Ghosh, M. Hsieh, C.S. Hsu, L. Chen, and R.V. Aroian. 2011. Global functional analyses of cellular responses to pore-forming toxins. PLoS Pathog 7:e1001314.
Reiss, K., I. Cornelsen, M. Husmann, G. Gimpl, and S. Bhakdi. 2011. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. J Biol Chem 286:26931-26942.
Kloft, N., C. Neukirch, W. Bobkiewicz, G. Veerachato, T. Busch, G. von Hoven, K. Boller, and M. Husmann. 2010. Pro-autophagic signal induction by bacterial pore-forming toxins. Med Microbiol Immunol 199:299-309.
Husmann, M., E. Beckmann, K. Boller, N. Kloft, S. Tenzer, W. Bobkiewicz, C. Neukirch, H. Bayley, and S. Bhakdi. 2009. Elimination of a bacterial pore-forming toxin by sequential endocytosis and exocytosis. FEBS Lett 583:337-344.
Kloft, N., T. Busch, C. Neukirch, S. Weis, F. Boukhallouk, W. Bobkiewicz, I. Cibis, S. Bhakdi, and M. Husmann. 2009. Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium. Biochem Biophys Res Commun 385:503-506.
Lux, C.A., A. Koschinski, K. Dersch, M. Husmann, and S. Bhakdi. 2009. Hypersusceptibility of neutrophil granulocytes towards lethal action of free fatty acids contained in enzyme-modified atherogenic low density lipoprotein. Atherosclerosis 207:116-122.
Fenske, D., K. Dersch, C. Lux, L. Zipse, P. Suriyaphol, Y. Dragneva, S.R. Han, S. Bhakdi, and M. Husmann. 2008. Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells. Thromb Haemost 100:1146-1154.
Schwarz, M., L. Spath, C.A. Lux, K. Paprotka, M. Torzewski, K. Dersch, C. Koch-Brandt, M. Husmann, and S. Bhakdi. 2008. Potential protective role of apoprotein J (clusterin) in atherogenesis: binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity. Thromb Haemost 100:110-118.
Spoden, G., K. Freitag, M. Husmann, K. Boller, M. Sapp, C. Lambert, and L. Florin. 2008. Clathrin- and caveolin-independent entry of human papillomavirus type 16--involvement of tetraspanin-enriched microdomains (TEMs). PLoS One 3:e3313.
Yarovinsky, T.O., M.M. Monick, M. Husmann, and G.W. Hunninghake. 2008. Interferons increase cell resistance to Staphylococcal alpha-toxin. Infect Immun 76:571-577.
Haugwitz, U., W. Bobkiewicz, S.R. Han, E. Beckmann, G. Veerachato, S. Shaid, S. Biehl, K. Dersch, S. Bhakdi, and M. Husmann. 2006. Pore-forming Staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation. Cell Microbiol 8:1591-1600.
Husmann, M., K. Dersch, W. Bobkiewicz, E. Beckmann, G. Veerachato, and S. Bhakdi. 2006. Differential role of p38 mitogen activated protein kinase for cellular recovery from attack by pore-forming S. aureus alpha-toxin or streptolysin O. Biochem Biophys Res Commun 344:1128-1134.
Walev, I., M. Hombach, W. Bobkiewicz, D. Fenske, S. Bhakdi, and M. Husmann. 2002. Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events. FASEB J 16:237-239.
Dragneva, Y., C.D. Anuradha, A. Valeva, A. Hoffmann, S. Bhakdi, and M. Husmann. 2001. Subcytocidal attack by staphylococcal alpha-toxin activates NF-kappaB and induces interleukin-8 production. Infect Immun 69:2630-2635.
Walev, I., M. Palmer, E. Martin, D. Jonas, U. Weller, H. Hohn-Bentz, M. Husmann, and S. Bhakdi. 1994. Recovery of human fibroblasts from attack by the pore-forming alpha-toxin of Staphylococcus aureus. Microb Pathog 17:187-201.