Alessandra Bragonzi
e-mail: bragonzi.alessandra AT hsr.it
website: www.unisr.it/view.asp?id=6465
affiliation: San Raffaele Scientific Institute
research area(s): Immunity And Infection, Molecular Biology
Course:
Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
University/Istitution: Università Vita-Salute San Raffaele
Education
1997 Degree in Biological Sciences, University of Milan (Italy)
2006 Ph.D., Natural Sciences (magna cum laude), Eberhard Karls University Tübingen, Germany
Scientific career
1995-1998 Undergraduate Student and Fellow, Biotechnology Unit, San Raffaele Scientific Institute, Milano (Italy)
1998-2000 Predoctoral Fellow, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milano (Italy)
2000-2004 EU Marie Curie Postdoctoral Fellow, Eberhard Karls University Tübingen, Germany
2004-2009 Assistant Scientist, Institute for Experimental Treatment of Cystic Fibrosis, San Raffaele Scientific Institute, Milano, Italy
2006 Visiting fellow, Universitè Laval, Quebec, Canada
2009-today Researcher, Group Leader, Infections and Cystic Fibrosis Unit, San Raffaele Scientific Institute, Milano (Italy)
1997 Degree in Biological Sciences, University of Milan (Italy)
2006 Ph.D., Natural Sciences (magna cum laude), Eberhard Karls University Tübingen, Germany
Scientific career
1995-1998 Undergraduate Student and Fellow, Biotechnology Unit, San Raffaele Scientific Institute, Milano (Italy)
1998-2000 Predoctoral Fellow, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milano (Italy)
2000-2004 EU Marie Curie Postdoctoral Fellow, Eberhard Karls University Tübingen, Germany
2004-2009 Assistant Scientist, Institute for Experimental Treatment of Cystic Fibrosis, San Raffaele Scientific Institute, Milano, Italy
2006 Visiting fellow, Universitè Laval, Quebec, Canada
2009-today Researcher, Group Leader, Infections and Cystic Fibrosis Unit, San Raffaele Scientific Institute, Milano (Italy)
Persistent bacterial infections involving Pseudomonas aeruginosa pose serious problems for human health including Cystic Fibrosis patients. After causing an initial acute disease state, which is kept in check by an adaptive immune response, Pseudomonas aeruginosa establishes persistent infection and colonizes the host by evading immune surveillance. The goal of our program is to elucidate cellular and molecular mechanisms that are involved in the host-pathogen interactions during persistent infection with the aim of devising new therapeutic approaches to treat respiratory infections.
Research Program
Pseudomonas aeruginosa is the fourth most commonly isolated hospital pathogen, and one of the most recalcitrant, difficult-to-treat and potentially deadly causes of pneumonia. Individuals in intensive care units can develop ventilator-associated pneumonia and/or sepsis from this organism. P. aeruginosa is the cause of lung function deterioration leading to death in patients with Cystic Fibrosis (CF) who also suffer from infections caused by Staphylococcus aureus or Burkholderia cenocepacia. Our research program has been specifically designed to provide key answers to host-pathogen interaction and mobilize the relevant know-how to generate new antimicrobial drugs by bypassing current antimicrobial mechanisms of resistance in Gram-negative bacteria.
Cellular and molecular mechanisms involved in P. aeruginosa-host pathogen interactions. The ability of P. aeruginosa to cause a variety of serious acute and chronic infections can be traced to its great genetic adaptability to different and specific host conditions. Although P. aeruginosa is acquired from environmental sources the subsequent microevolution of the bacterial genome within the human body has been observed in chronically infected CF patients, but typically not in the acute process. In patients with CF, long term colonization of the respiratory tracts provides a selective environment for the emergence of pathoadaptive variants derived from the initially acquired strain. To pursue the understanding and dissection of the bacterial and host processes involved in the initiation of acute lung infections as well as the development and maintenance (persistence) of chronic infections (especially treatment-refractory biofilm infections), we have established a mouse model of chronic infection. Virulence of early and late clonally related CF isolates was assessed by monitoring acute mortality versus survival, and P. aeruginosa persistence versus clearance in mice of different genetic backgrounds, including CF. We found that chronic infection is established with P. aeruginosa pathogenic variants distinguished by initially acquired strains and attenuated in causing acute mortality. Of particular interest is the finding that P. aeruginosa virulence factors, relevant in the acute infection, are modified or selected against during chronic infection. In particular, changes in P. aeruginosa PAMPs lead to escape host innate immune system and endorse pathogenesis. Our findings emphasize studies to define novel virulence determinants in adapted P. aeruginosa population and to identify novel targets which may lead to improved antimicrobial therapeutic strategies. We have taken two approaches of functional genomics, through trascriptomics and insertion mutagenesis, to obtain a genome scale picture of P. aeruginosa expression and identify novel functions involved in the lung pathogenesis that can be used for targeted interventions to reduce lung damaging infection and inflammation.
Evaluation of novel molecules for treating respiratory infection and inflammation. Remarkable progress has been made in understanding how aberrant CFTR function leads to development of CF disease. Today, much of the effort needs to be directed to in vivo studies and pre-clinical research. To cover this area of research, animal models and testing are needed. Over the years, we have accumulated expertise on mouse model for acute infection, established a mouse model for airway chronic infection and collected unique reagents such as a selection of highly virulent CF-related pathogens. Based on this expertise, we have established the Cystic Fibrosis Animal Core Facility (CFaCore) responding to an emerging need among Italian CF investigators. CFaCore supports investigators to conduct their animal experiments and to provide access to specialized expertise, tools and technologies. The objective is to support investigations on pathogenesis and on candidate therapeutic molecules to favor the translation of basic research projects into pre-clinical applications.
Research Program
Pseudomonas aeruginosa is the fourth most commonly isolated hospital pathogen, and one of the most recalcitrant, difficult-to-treat and potentially deadly causes of pneumonia. Individuals in intensive care units can develop ventilator-associated pneumonia and/or sepsis from this organism. P. aeruginosa is the cause of lung function deterioration leading to death in patients with Cystic Fibrosis (CF) who also suffer from infections caused by Staphylococcus aureus or Burkholderia cenocepacia. Our research program has been specifically designed to provide key answers to host-pathogen interaction and mobilize the relevant know-how to generate new antimicrobial drugs by bypassing current antimicrobial mechanisms of resistance in Gram-negative bacteria.
Cellular and molecular mechanisms involved in P. aeruginosa-host pathogen interactions. The ability of P. aeruginosa to cause a variety of serious acute and chronic infections can be traced to its great genetic adaptability to different and specific host conditions. Although P. aeruginosa is acquired from environmental sources the subsequent microevolution of the bacterial genome within the human body has been observed in chronically infected CF patients, but typically not in the acute process. In patients with CF, long term colonization of the respiratory tracts provides a selective environment for the emergence of pathoadaptive variants derived from the initially acquired strain. To pursue the understanding and dissection of the bacterial and host processes involved in the initiation of acute lung infections as well as the development and maintenance (persistence) of chronic infections (especially treatment-refractory biofilm infections), we have established a mouse model of chronic infection. Virulence of early and late clonally related CF isolates was assessed by monitoring acute mortality versus survival, and P. aeruginosa persistence versus clearance in mice of different genetic backgrounds, including CF. We found that chronic infection is established with P. aeruginosa pathogenic variants distinguished by initially acquired strains and attenuated in causing acute mortality. Of particular interest is the finding that P. aeruginosa virulence factors, relevant in the acute infection, are modified or selected against during chronic infection. In particular, changes in P. aeruginosa PAMPs lead to escape host innate immune system and endorse pathogenesis. Our findings emphasize studies to define novel virulence determinants in adapted P. aeruginosa population and to identify novel targets which may lead to improved antimicrobial therapeutic strategies. We have taken two approaches of functional genomics, through trascriptomics and insertion mutagenesis, to obtain a genome scale picture of P. aeruginosa expression and identify novel functions involved in the lung pathogenesis that can be used for targeted interventions to reduce lung damaging infection and inflammation.
Evaluation of novel molecules for treating respiratory infection and inflammation. Remarkable progress has been made in understanding how aberrant CFTR function leads to development of CF disease. Today, much of the effort needs to be directed to in vivo studies and pre-clinical research. To cover this area of research, animal models and testing are needed. Over the years, we have accumulated expertise on mouse model for acute infection, established a mouse model for airway chronic infection and collected unique reagents such as a selection of highly virulent CF-related pathogens. Based on this expertise, we have established the Cystic Fibrosis Animal Core Facility (CFaCore) responding to an emerging need among Italian CF investigators. CFaCore supports investigators to conduct their animal experiments and to provide access to specialized expertise, tools and technologies. The objective is to support investigations on pathogenesis and on candidate therapeutic molecules to favor the translation of basic research projects into pre-clinical applications.
Cigana C, Lorè NI, Bernardini ML, Bragonzi A. Dampening host sensing and avoiding recognition in Pseudomonas aeruginosa pneumonia. Review. Journal of Biomedicine and Biotechnology. In press
Moalli F, Paroni M, Véliz Rodriguez T, Polentarutti N, Bottazzi B, Valentino S, Mantero S, Nebuloni M, Mantovani A, Bragonzi A, Garlanda C. (2011) The therapeutic potential of the humoral pattern recognition molecule PTX3 in chronic lung infection caused by Pseudomonas aeruginosa. J Immunol. 186(9):5425-34
Bianconi I, Milani A, Cigana C, Paroni M, Levesque RC, Bertoni G, Bragonzi A. (2011) Positive signature-tagged mutagenesis in Pseudomonas aeruginosa: tracking patho-adaptive mutations promoting airways chronic infection. PLoS Pathog. 7(2):e1001270.
Bragonzi A. (2010) Murine models of acute and chronic lung infection with cystic fibrosis pathogens. (invited review) IJMM 300(8):584-93
Bragonzi A. (2010) Fighting back: Peptidomimetics as a new weapon in the battle against antibiotic resistance. Sci. Transl. Med. 2, 21ps9
Cigana C, Curcurù L, Leone MR, Ieranò T, Lorè NI, Bianconi I, Silipo A, Cozzolino F, Lanzetta R, Molinaro A, Bernardini ML, Bragonzi A. (2009) Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PLoS One. 23;4(12):e8439.
Bragonzi A, Paroni M, Nonis A, Cramer N, Montanari S, Rejman J, Di Serio C, Döring G and Tümmler B. (2009) Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. AJRCCM 180(2):138-45
Pirone L, Bragonzi A, Farcomeni A, Paroni M, Auriche C, Conese M, Chiarini L, Bevivino A and Ascensioni F. (2008) Burkholderia cenocepacia strains isolated from cystic fibrosis patients are apparently more invasive and more virulent than rhizosphere strains. Environmental Microbiology 10(10):2773-84.
Kukavica-Ibrulj I, Bragonzi A, Winstanley C, Sanschagrin F, O`Toole G, Levesque RC. (2007) In vivo growth and comparisons between Pseudomonas aeruginosa strains PAO1, PA14, PAK and the hypervirulent strain LESB58 in a rat model of chronic lung infection. J Bact. 190(8): 2804-13
Ulrich M, * Bastian M, Cramton SE, Ziegler K, Pragman AA, Bragonzi A, Memmi G, Wolz C, Schlievert PM, Cheung A and Döring G. (2007) The staphylococcal respiratory response regulator SrrAB induces ica gene transcription and PIA expression, protecting Staphylococcus aureus from neutrophil killing under anaerobic growth conditions. Molecular Microbiology 65: 1276-87.
Sousa SA, Ulrich M, Bragonzi A, Burke M, Worlitzsch D, Leitão JH, Meisner C, Eberl L, Sá-Correia I, Döring G. (2007) Virulence of Burkholderia cepacia complex strains in gp91phox-/- mice. Cellular Microbiology 9(12):2817-25.
Montanari S., Oliver A., Salerno P., Mena A., Bertoni G., Tümmler B., Cariani L., Conese M., Döring G., Bragonzi A. (2007) Biological cost of hypermutation in Pseudomonas aeruginosa strains from patients with cystic fibrosis. Microbiology. 153: 1445-1454.
Moalli F, Paroni M, Véliz Rodriguez T, Polentarutti N, Bottazzi B, Valentino S, Mantero S, Nebuloni M, Mantovani A, Bragonzi A, Garlanda C. (2011) The therapeutic potential of the humoral pattern recognition molecule PTX3 in chronic lung infection caused by Pseudomonas aeruginosa. J Immunol. 186(9):5425-34
Bianconi I, Milani A, Cigana C, Paroni M, Levesque RC, Bertoni G, Bragonzi A. (2011) Positive signature-tagged mutagenesis in Pseudomonas aeruginosa: tracking patho-adaptive mutations promoting airways chronic infection. PLoS Pathog. 7(2):e1001270.
Bragonzi A. (2010) Murine models of acute and chronic lung infection with cystic fibrosis pathogens. (invited review) IJMM 300(8):584-93
Bragonzi A. (2010) Fighting back: Peptidomimetics as a new weapon in the battle against antibiotic resistance. Sci. Transl. Med. 2, 21ps9
Cigana C, Curcurù L, Leone MR, Ieranò T, Lorè NI, Bianconi I, Silipo A, Cozzolino F, Lanzetta R, Molinaro A, Bernardini ML, Bragonzi A. (2009) Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PLoS One. 23;4(12):e8439.
Bragonzi A, Paroni M, Nonis A, Cramer N, Montanari S, Rejman J, Di Serio C, Döring G and Tümmler B. (2009) Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. AJRCCM 180(2):138-45
Pirone L, Bragonzi A, Farcomeni A, Paroni M, Auriche C, Conese M, Chiarini L, Bevivino A and Ascensioni F. (2008) Burkholderia cenocepacia strains isolated from cystic fibrosis patients are apparently more invasive and more virulent than rhizosphere strains. Environmental Microbiology 10(10):2773-84.
Kukavica-Ibrulj I, Bragonzi A, Winstanley C, Sanschagrin F, O`Toole G, Levesque RC. (2007) In vivo growth and comparisons between Pseudomonas aeruginosa strains PAO1, PA14, PAK and the hypervirulent strain LESB58 in a rat model of chronic lung infection. J Bact. 190(8): 2804-13
Ulrich M, * Bastian M, Cramton SE, Ziegler K, Pragman AA, Bragonzi A, Memmi G, Wolz C, Schlievert PM, Cheung A and Döring G. (2007) The staphylococcal respiratory response regulator SrrAB induces ica gene transcription and PIA expression, protecting Staphylococcus aureus from neutrophil killing under anaerobic growth conditions. Molecular Microbiology 65: 1276-87.
Sousa SA, Ulrich M, Bragonzi A, Burke M, Worlitzsch D, Leitão JH, Meisner C, Eberl L, Sá-Correia I, Döring G. (2007) Virulence of Burkholderia cepacia complex strains in gp91phox-/- mice. Cellular Microbiology 9(12):2817-25.
Montanari S., Oliver A., Salerno P., Mena A., Bertoni G., Tümmler B., Cariani L., Conese M., Döring G., Bragonzi A. (2007) Biological cost of hypermutation in Pseudomonas aeruginosa strains from patients with cystic fibrosis. Microbiology. 153: 1445-1454.
Project Title:
Functional and genetic dissection of Pseudomonas aeruginosa and host response to respiratory infection
Pseudomonas aeruginosa is the fourth most commonly isolated hospital pathogen, and one of the most recalcitrant, difficult to-treat and potentially deadly causes of pneumonia. Individuals in intensive care units can develop ventilator-associated pneumonia and/or sepsis while cystic fibrosis (CF) develop chronic lung infections and death. After causing an initial acute disease state, which is kept in check by an adaptive immune response, P. aeruginosa establishes persistent infection by changing its pathogen-associated molecular patterns and colonizes the host by evading immune surveillance.
This research project has been designed to find novel microbial virulence traits involved in the adaptation to host and host genetic factors involved in susceptibility to opportunistic P. aeruginosa infections.
Step1: identification of novel microbial virulence traits by functional genomics. We have generated an annotated P. aeruginosa database of novel genes involved in the initiation of acute lung infections as well as in the development and maintenance of chronic infections. Biological and chemical characterization of these novel virulence functions will be carried out in this project.
Step2: validation of novel microbial virulence traits in clinical strains. To address the clinical need, we will exploit the essential conservation of the genomic sequences of P. aeruginosa strains from different origins and use this information to select for virulence traits adequate to cover a spectrum of phenotypically and genotypically different P. aeruginosa strains encountered in medical practice.
Step3: host response to novel microbial virulence traits. The balance between systemic infection and mortality or chronic persistence and morbidity depends on complex relationships in which the bacterial biodiversity but also the immunological status and genetic potential of the host are determinant factors. The impact of the genetic makeup of the host on the variation in the immune responses to acute and chronic infection by variants of P. aeruginosa strains will be evaluated. Classical inbred strains of mice will be tested for resistance or susceptibility to infection with various P. aeruginosa clinical strains to identify mouse strains presenting deviant clinical and immunological phenotypes amenable for genetic analyses.
This research project has been designed to find novel microbial virulence traits involved in the adaptation to host and host genetic factors involved in susceptibility to opportunistic P. aeruginosa infections.
Step1: identification of novel microbial virulence traits by functional genomics. We have generated an annotated P. aeruginosa database of novel genes involved in the initiation of acute lung infections as well as in the development and maintenance of chronic infections. Biological and chemical characterization of these novel virulence functions will be carried out in this project.
Step2: validation of novel microbial virulence traits in clinical strains. To address the clinical need, we will exploit the essential conservation of the genomic sequences of P. aeruginosa strains from different origins and use this information to select for virulence traits adequate to cover a spectrum of phenotypically and genotypically different P. aeruginosa strains encountered in medical practice.
Step3: host response to novel microbial virulence traits. The balance between systemic infection and mortality or chronic persistence and morbidity depends on complex relationships in which the bacterial biodiversity but also the immunological status and genetic potential of the host are determinant factors. The impact of the genetic makeup of the host on the variation in the immune responses to acute and chronic infection by variants of P. aeruginosa strains will be evaluated. Classical inbred strains of mice will be tested for resistance or susceptibility to infection with various P. aeruginosa clinical strains to identify mouse strains presenting deviant clinical and immunological phenotypes amenable for genetic analyses.