Visual Universitätsmedizin Mainz

Host responses to bacterial pore forming toxins (PFT) (Husmann Laboratory)

Current Research

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.

Lab Members

Hamm
Christian Hamm
Function: Ph.D. Student

17-9364
17-9234
christian.hamm@unimedizin-mainz.de

Univ.-Prof. Dr. med. Husmann
Univ.-Prof. Dr. med. Matthias Husmann
Function: Principal Investigator

06131 17-9363
06131 17-9234
husmann@uni-mainz.de

Platzhalterbild
Stefan Klein
Function: Medical Doctoral Student

17-9124
17-9234
stklein@students.uni-mainz.de

Meyenburg
Martina Meyenburg
Function: Medical Technician

06131 17-9098
06131 17-9021
meyenbur@uni-mainz.de

Neukirch
Claudia Neukirch
Function: Medical Technician

06131 17-9124
06131 17-9021
neukircc@uni-mainz.de

Platzhalterbild
Qianqian Qin
Function: Ph.D. Student

17-9124
17-9234
qianqqin@uni-mainz.de

Dr. rer. nat von Hoven
Dr. rer. nat Gisela von Hoven
Function: Postdoc

17-9124
17-9234
vonhoven@uni-mainz.de

Publications

von Hoven Gisela, Rivas Amable J., Neukirch Claudia, Meyenburg Martina, Qin Qianqian, Parekh Sapun, Hellmann Nadja, Husmann Matthias Repair of a Bacterial Small beta-Barrel Toxin Pore Depends on Channel Width. MBIO. 2017; 8(1)   

von Hoven G, Rivas AJ, Neukirch C, Klein S, Hamm C, Qin Q, Meyenburg M, Füser S, Saftig P, Hellmann N, Postina R, Husmann M. Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action. Biochem J. 2016 Jul 1;473(13):1929-40.

Rivas AJ, von Hoven G, Neukirch C, Meyenburg M, Qin Q, Füser S, Boller K, Lemos ML, Osorio CR, Husmann M. Phobalysin, a Small β-Pore-Forming Toxin of Photobacterium damselae subsp. damselae. Infect Immun. 2015 Nov;83(11):4335-48.

von Hoven G, Neukirch C, Meyenburg M, Füser S, Petrivna MB, Rivas AJ, Ryazanov A, Kaufman RJ, Aroian RV, Husmann M. eIF2α Confers Cellular Tolerance to S. aureus α-Toxin. Front Immunol. 2015 Jul 27;6:383.

Rivas Amable J., Vences Ana, Husmann Matthias, Lemos Manuel L., Osorioa Carlos R. Photobacterium damselae subsp damselae Major Virulence Factors Dly, Plasmid-Encoded HlyA, and Chromosome-Encoded HlyA Are Secreted via the Type II Secretion System
INFECTION AND IMMUNITY. 2015; 83(4): 1246-1256.

Husmann M. Vital dyes and virtual deaths
CELL DEATH AND DIFFERENTIATION. 2013; 20(7): 963-963.

von Hoven G, Kloft N, Neukirch C, , Bobkiewicz W, Weis S, Boller K, Janda KD, Husmann. Modulation of translation and induction of autophagy by bacterial exoproducts. Medical Microbiology and Immunology. 2013: 201 (4): 409-418.

Kloft N, Neukirch C, von Hoven G, Ebinger S, Bobkiewicz W, Weis S, Boller K, Husmann M. A subunit of Eukaryotic Translation Initiation Factor 2a-Phosphatase, (CreP/PPP1R15B), regulates membrane traffic. JBC 2012; 287(42):35299-317.

Imre G, Heering J, Takeda AN, Husmann M, Thiede B, Heringdorf DMZ, Green DR, van der Goot FG, Sinha B, Dotsch V, Rajalingam K. Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis. EMBO Journal. 2012; 31 (11): 2615-2628.

Usmani SM, von Einem J, Frick M, Miklavc P, Mayenburg M, Husmann M, Dietl P, Wittekindt OH. Molecular basis of early epithelial response to streptococcal exotoxin: role of STIM1 and Orai1 proteins. Cellular Microbiology. 2012; 14 (3): 299-315.

Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S. Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity. Journal of Biological Chemistry. 2011; 286 (30): 26931-26942.

Gabriel M, Husmann M. Vom Nanobakterium zum kalzifizierenden Nanopartikel. Kinderärztliche Praxis. 2011: 1.

Kao CY, Los FCO, Huffman DL, Wachi S, Kloft N, Husmann M, Karabrahimi V, Schwartz JL, Bellier A, Ha C, Sagong Y, Fan H, Ghosh P, Hsieh M, Hsu CS, Chen L, Aroian RV. Global Functional Analyses of Cellular Responses to Pore-Forming Toxins. PLOS Pathogens. 2011; 7 (3).

Modulation of translation and induction of autophagy by bacterial exoproducts. Med Microbiol Immunol. 2012 Nov;201(4):409-18.

Kloft N, Neukirch C, Bobkiewicz W, Veerachato G, Busch T, von Hoven G, Boller K, Husmann M. Pro-autophagic signal induction by bacterial pore-forming toxins. MEDICAL MICROBIOLOGY AND IMMUNOLOGY. 2010; 199(4): 299-309.

Husmann M, Beckmann E, Boller K, Kloft N, Tenzer S, Bobkiewicz W, Neukirch C, Bayley H, Bhakdi S. Elimination of a bacterial pore-forming toxin by sequential endocytosis and exocytosis. FEBS Lett. 2009; 583(2): 337-44. 

Kloft N, Busch T, Neukirch C, Weis S, Boukhallouk F, Bobkiewicz W, Cibis I, Bhakdi S, Husmann M. Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium. Biochem Biophys Res Commun. 2009; 385(4): 503-6. 

Lux CA, Koschinski A, Dersch K, Husmann M, Bhakdi S. Hypersusceptibility of neutrophil granulocytes towards lethal action of free fatty acids contained in enzyme-modified atherogenic low density lipoprotein. Atherosclerosis. 2009; 207(1): 116-22. 

Fenske D, Dersch K, Lux C, Zipse L, Suriyaphol P, Dragneva Y, Han SR, Bhakdi S, Husmann M. Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells. Thromb Haemost. 2008; 100(6): 1146-54. 

Schwarz M, Spath L, Lux CA, Paprotka K, Torzewski M, Dersch K, Koch-Brandt C, Husmann M, Bhakdi S. Potential protective role of apoprotein J (clusterin) in atherogenesis: binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity Thromb Haemost. 2008; 100(1): 110-8. 

Spoden G, Freitag K, Husmann M, Boller K, Sapp M, Lambert C, Florin L. Clathrin 16--involvement of tetraspanin-enriched microdomains (TEMs). PLoS ONE. 2008; 3(10): e3313.

Yarovinsky TO, Monick MM, Husmann M, Hunninghake GW. Interferons increase cell resistance to Staphylococcal alpha-toxin. Infect Immun. 2008 Feb;76(2):571-7. Epub 2007 Dec 10.

Haugwitz U, Bobkiewicz W, Han SR, Beckmann E, Veerachato G, Shaid S, Biehl S, Dersch K, Bhakdi S, Husmann M. Pore-forming Staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation. Cell Microbiol. 2006 Oct;8(10):1591-600.

Husmann M, Dersch K, Bobkiewicz W, Beckmann E, Veerachato G, Bhakdi S. 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. 2006 Jun 16;344(4):1128-34. Epub 2006 Apr 21.
 

Walev I, Hombach M, Bobkiewicz W, Fenske D, Bhakdi S, Husmann M. Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events. FASEB J. 2002 Feb;16(2):237-9. Epub 2001 Dec 14.

Dragneva Y, Anuradha CD, Valeva A, Hoffmann A, Bhakdi S, Husmann M. Subcytocidal attack by staphylococcal alpha-toxin activates NF-kappaB and induces interleukin-8 production. Infect Immun. 2001 Apr;69(4):2630-5.

Walev I, Palmer M, Martin E, Jonas D, Weller U, Höhn-Bentz H, Husmann M, Bhakdi S. Recovery of human fibroblasts from attack by the pore-forming alpha-toxin of Staphylococcus aureus. Microb Pathog. 1994 Sep;17(3):187-201.