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Innate Immunogenetic Study of Invasive Aspergillosis in Hematopoietic Cells Transplant Recipients

English title Innate Immunogenetic Study of Invasive Aspergillosis in Hematopoietic Cells Transplant Recipients
Applicant Bochud Pierre-Yves
Number 127613
Funding scheme Project funding (Div. I-III)
Research institution Service des Maladies Infectieuses Département de Médecine Interne CHUV
Institution of higher education University of Lausanne - LA
Main discipline Clinical Immunology and Immunopathology
Start/End 01.11.2009 - 31.10.2012
Approved amount 350'387.00
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All Disciplines (2)

Discipline
Clinical Immunology and Immunopathology
Infectious Diseases

Keywords (7)

Innate Immunity; Hematopoietic Cell Transplantatoin; Genetics; Invasive Aspergillosis; Predictive Medicine; pattern recognition receptors; single nucleotide polymorphisms

Lay Summary (English)

Lead
Lay summary
Major improvements in our understanding of the innate immune system have resulted from the discovery of pattern recognitions receptors such as Toll-like receptors, C-type lectins, Nod-like receptors and RIG-I like receptors, all located on the surface or within the cytosol of immune cells such as macrophages, monocytes or dendritic cells. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and their signaling pathways have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming yeas.Infections are a major cause of morbidity and death in hematopoietic stem cell transplant recipients. Invasive aspergillosis is a one of the most important infection in this population, with an incidence rate of up to 12% and an associated mortality ranging from 50% to 80%. However, it remains unclear why certain patients develop IA while others undergoing identical transplant treatments with similar post transplant immunosuppression, do not.We hypothesize that the detection of single nucleotide polymorphisms in pattern recognition receptors in hematopoietic stem cells donors and recipients influence susceptibility to invasive aspergillosis. The identification of single nucleotide polymorphisms at risk will allow predictive/preventive strategies aimed at reducing mortality and morbidity in these patients. Overall, this proposal seeks to prove that genetic factors in the innate immune system are important in the biology of invasive aspergillosis after hematopoietic stem cell transplantation, and to provide the rationale for new prevention strategies.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Host genetics of invasive Aspergillus and Candida infections
Wojtowicz Agnieszka, Bochud Pierre-Yves (2015), Host genetics of invasive Aspergillus and Candida infections, in SEMINARS IN IMMUNOPATHOLOGY, 37(2), 173-186.
IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation
Wojtowicz Agnieszka, Gresnigt Mark S., Lecompte Thanh, Bibert Stephanie, Manuel Oriol, Joosten Leo A. B., Rueeger Sina, Berger Christoph, Boggian Katia, Cusini Alexia, Garzoni Christian, Hirsch Hans H., Weisser Maja, Mueller Nicolas J., Meylan Pascal R., Steiger Juerg, Kutalik Zoltan, Pascual Manuel, van Delden Christian, van de Veerdonk Frank L., Bochud Pierre-Yves (2015), IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation, in JOURNAL OF INFECTIOUS DISEASES, 211(10), 1646-1657.
PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant
Wojtowicz Agnieszka, Lecompte T. Doco, Bibert Stephanie, Manuel Oriol, Rüeger Sina, Berger Christoph, Boggian Katia, Cusini Alexia, Garzoni Christian, Hirsch Hans, Khanna Nina, Mueller Nicolas J., Meylan Pascal R., Pascual Manuel, van Delden Christian, Bochud Pierre-Yves (2015), PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant, in CLINICAL INFECTIOUS DISEASES, 61(4), 619-622.
The Swiss Transplant Cohort Study: Lessons from the First 6 Years
Berger Christoph, Bochud Pierre-Yves, Boggian Katja, Cusini Alexia, Egli Adrian, Garzoni Christian, Hirsch Hans H., Hoffmann Matthias, Khanna Nina, Manuel Oriol, Meylan Pascal, Nadal David, van Delden Christian, Weisser Maja, Mueller Nicolas J. (2015), The Swiss Transplant Cohort Study: Lessons from the First 6 Years, in CURRENT INFECTIOUS DISEASE REPORTS, 17(6), 29.
IL-17RA and ADA2 Deficiency in Siblings with Recurrent Infections and Chronic Inflammation
Angelini F., Fellmann F., Wassenberg J., Perreau M., Ramirez N. Arenas, Simon G., Boyman O., Demaria O., Christen-Zaech S., Luder M. T., Hohl D., von Scheven-Gete A., Belfiore M., Gilliet M., Bochud P. Y., Perrin Y., Popovich M. Beck, Bart P. A., Martinet D., Hofer M. (2014), IL-17RA and ADA2 Deficiency in Siblings with Recurrent Infections and Chronic Inflammation, in JOURNAL OF CLINICAL IMMUNOLOGY, 34, Supplement 2, 145-145.
Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia
Kumar Vinod, Cheng Shih-Chin, Johnson Melissa D., Smeekens Sanne P., Wojtowicz Agnieszka, Giamarellos-Bourboulis Evangelos, Karjalainen Juha, Franke Lude, Withoff Sebo, Plantinga Theo S., de Veerdonk Frank L. van, van der Meer Jos W. M., Joosten Leo A. B., Sokol Harry, Bauer Hermann, Herrmann Bernhard G., Bochud Pierre-Yves, Marchetti Oscar, Perfect John R., Xavier Ramnik J., Kullberg Bart Jan, Wijmenga Cisca, Netea Mihai G. (2014), Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia, in NATURE COMMUNICATIONS, 5, 4675.
Polymorphisms in Tumor Necrosis Factor- a Increase Susceptibility to Intra- Abdominal Candida Infection in High-Risk Surgical ICU Patients*
Wojtowicz Agnieszka, Tissot Frederic, Lamoth Frederic, Orasch Christina, Eggimann Philippe, Siegemund Martin, Zimmerli Stephan, Flueckiger Ursula Maria, Bille Jacques, Calandra Thierry, Marchetti Oscar, Bochud Pierre-Yves (2014), Polymorphisms in Tumor Necrosis Factor- a Increase Susceptibility to Intra- Abdominal Candida Infection in High-Risk Surgical ICU Patients*, in CRITICAL CARE MEDICINE, 42(4), 304-308.
Host genetics and Aspergillus infections
Bochud P. Y. (2013), Host genetics and Aspergillus infections, in MYCOSES, 56, 28-28.
Species-specific recognition of Aspergillus fumigatus by Toll-like receptor 1 and Toll-like receptor 6
Rubino I., Coste A., Le Roy D., Roger T., Jaton K., Boeckh M., Monod M., Latgé J.-P., Calandra T., Bochud P.-Y. (2012), Species-specific recognition of Aspergillus fumigatus by Toll-like receptor 1 and Toll-like receptor 6, in Journal of Infectious Diseases, 205(6), 944-954.
Immunogenetics of invasive aspergillosis.
Lamoth Frédéric, Rubino Ivana, Bochud Pierre-Yves (2011), Immunogenetics of invasive aspergillosis., in Medical mycology : official publication of the International Society for Human and Animal Mycology, 49 Suppl 1, S125-S136.
Genetic polymorphisms and susceptibility to invasive aspergillosis
Lamoth F, Bochud PY, Boeckh M (2010), Genetic polymorphisms and susceptibility to invasive aspergillosis, in Journal of invasive fungal infections, 4(3), 104-114.
Reply to Cunha et al
Wojtowicz Agnieszka, Bochud Pierre-Yves, Reply to Cunha et al, in CLINICAL INFECTIOUS DISEASES.

Collaboration

Group / person Country
Types of collaboration
Hôpital Necker-Enfants malades; Pr. Lortholary France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
the Swiss Transplant Cohort Study (STCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
CHRU Lille France; Pr. B. Sendid France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
European Organization for Research and Treatment on Cancer (EORTC, TR65091) Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
ALLFUN FP7 Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Radboud University Medical Center, Nijmegen Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss HIV Cohort Study (SHCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Fungal Network of Switzerland (Funginos) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Pr. Jean-Paul Latgé Institut Pasteur France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
IDSA - ID Week, San Diego 2015 Individual talk Host susceptibility to fungal infections 07.10.2015 San Diego, United States of America Bochud Pierre-Yves;
13th National Congress of the Italian Society of Infectious Diseases (SIMIT) 2014 Individual talk Immunogenetics of Infectious Diseases 26.10.2014 Genova, Italy Bochud Pierre-Yves;
The Interscience Conference on Antimicrobial Agents And Chemotherapy (ICAAC), 2014 Poster PTX3 Polymorphisms are a Major Risk Factor for Invasive Mold Infection in Solid Organ Transplantant Recipients 05.09.2014 Washington DC, United States of America Bochud Pierre-Yves;
ALLFUN MEETING, Borgo Riccio 2014 Talk given at a conference IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid Organ Transplantation 13.04.2014 Borgo Riccio, Torchiara, Italy Bochud Pierre-Yves;
6th Trends in Medical Mycology (TIMM-6) Individual talk Immunogenetics of fungal infections 11.10.2013 Copenhague, Denmark Bochud Pierre-Yves;
Trends in the diagnostic of aspergillosis, 2013 Individual talk Host genetics and aspergillus infection 28.06.2013 Paris, France Bochud Pierre-Yves;
6ème Journée de Formation en Infectiologie & Hématologie – JFIH 2013 Individual talk Immunogenetics of fungal infections 28.06.2013 Paris, France Bochud Pierre-Yves;
3rd Annual Meeting of the Irish Fungal Society 2013 Individual talk Immunogenetic approach to fungal infections in humans 01.06.2013 Dublin, Ireland Bochud Pierre-Yves;
American Transplant Congress (ATC), 2013 Talk given at a conference IL-1β Polymorphism Increase Susceptibility to Invasive Mold Infection After Solid Organ Transplantation 18.05.2013 Seattle, United States of America Bochud Pierre-Yves;
Société Française d’Histocompatibilité et d’Immunogénétique (SFHI), 2013 Individual talk Immunogénétique des infections fongiques 23.01.2013 Paris, France Bochud Pierre-Yves;
ALLFUN MEETING, Siena 2012 Talk given at a conference Polymorphism in CARD9 and TNF-α influence Candida infection in ICU surgical patients 30.09.2012 Siena, Italy Bochud Pierre-Yves;
Immunogenetics of fungal infections. International Society for Human and Animal Mycology (ISHAM) 2012 Individual talk Genetic risk for invasive aspergillosis in hematopoietic stem cell transplantation 06.06.2012 Berlin, Germany Bochud Pierre-Yves;
Antimicrobial Therapy in Critically Ill Patients (ATCIP) 2012 Individual talk Immunogenetics of fungal infections in cancer patients 25.05.2012 Lugano, Switzerland Bochud Pierre-Yves;
Immunogenetics of fungal infections. Congress of the German Society of Infectious Disease (KIT) 2012 Individual talk Genetics of invasive fungal infections 25.04.2012 Köln, Germany Bochud Pierre-Yves;
European Congress for Clinical Microbiology and Infectious Diseases (ECCMID) 2012 Individual talk Genetics of invasive fungal infections: overview of polymorphsims 01.04.2012 London, Great Britain and Northern Ireland Bochud Pierre-Yves;
Genomics in Hematology, Perugia Individual talk Genetic susceptibility to fungal diseases: Pattern recognition receptors 29.01.2012 Perugia, Italy Bochud Pierre-Yves;
13th International Symposium on Current Topics in Infectious Diseases 2012 Individual talk Genetic predisposition and infections 24.01.2012 Grindelwald, Switzerland Bochud Pierre-Yves;
Trends in Medical Mycology (TIMM), Valencia 2011 Individual talk Host genomics of Aspergillus infection 02.10.2011 Valencia, Spain, Spain Bochud Pierre-Yves;
European Group for Blood and Marrow Transplantation (EBMT), Paris 2011 Individual talk Genetic predisposition to infection 03.04.2011 Paris, France Bochud Pierre-Yves;
Infectious Disease Society of America (IDSA) meeting, Vancouver 2010 Individual talk Polymorphisms in TLR4 and susceptibility to Aspergillosis. 22.10.2010 Vancouver, Canada, Canada Bochud Pierre-Yves;
Infectious Diseases Society of America (IDSA), Vancouver 2010 Talk given at a conference TLR1 and TLR6 Are Involved in the innate immune response to A. fumigatus in Mice 22.10.2010 Vancouver, Canada Bochud Pierre-Yves;
MSD forum on Invasive Fungal Infections, Rome 2010 Individual talk Polymorphisms in TLRs and susceptibility to aspergillosis 27.05.2010 Rome, Italy Bochud Pierre-Yves;
European Group for Blood and Marrow Transplantation (EBMT), Vienna 2010 Individual talk Enhancing our knowledge of the invisible killer in high risk hematological patients 15.03.2010 Vienna, Austria Bochud Pierre-Yves;
4th Advances Against Aspergillosis (AAA), Rome 2010 Individual talk Polymorphisms in TLRs and susceptibility to aspergillosis 01.02.2010 Rome, Italy Bochud Pierre-Yves;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media EHA Roadmap for Research of Blood Disorders in Europe Haematologica International 2015

Awards

Title Year
Prix Leenaards 2013 2012
SCIEX FELLOWSHIP, scientific project 09.088. 2010
Special citation award, Infectious Disease Society of America Meeting (IDSA), Vancouver 2010

Associated projects

Number Title Start Funding scheme
179636 Using Genetic Risk Factors to Stratify Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia 01.06.2018 Investigator Initiated Clinical Trials (IICT)
144054 Immunogenetics of Viral Infections - Extending the Scope beyond IL28B SNPs and Hepatitis C 01.10.2012 Project funding (special)
65462 Innate Immune Response of Macrophages to M. Leprae: the Role of Tolllike Receptor 2 Polymorphisms. 01.09.2001 Fellowships for prospective researchers
165954 Immunogenetics of Viral Infections - Focus on human herpesviruses (HHVs) 01.06.2016 Project funding (special)
145014 Acquisition of a QuantStudio 12K Flex Real-Time PCR System from Applied Biosystems for the Infectious Diseases Genotyping Platform 01.06.2013 R'EQUIP

Abstract

Innate immunity and immunogeneticsMajor improvements in our understanding of the innate immune system have resulted from the discovery of pattern recognitions receptors (PRRs) such as Toll-like receptors (TLRs), C-type lectins, Nod-like receptors (NLRs) and RIG-I like receptors (RLRs), all located on the surface or within the cytosol of immune cells such as macrophages, monocytes or dendritic cells. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, PRRs are at the molecular interface of hosts and pathogens. Polymorphisms in PRRs and their signaling pathways have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming yeas.Invasive aspergillosis (IA) in hematopoietic stem cells transplantation (HSCT)Infections are a major cause of morbidity and death in HSCT recipients. Invasive aspergillosis (IA) is a one of the most important infection in this population, with an incidence rate of up to 12% and an associated mortality ranging from 50% to 80%. However, it remains unclear why certain patients develop IA while others undergoing identical transplant treatments with similar post transplant immunosuppression, do not.Recent studies using in vitro or ex vivo experiments showed that the innate immune detection of Aspergillus fumigatus, the most frequent cause of invasive aspergillosis, is mediated through several PRR; including TLR4, TLR2 (a PRR that cooperates either with TLR1 or TLR6) and Dectin-1. In a recent study, we found that donor polymorphisms in TLR4 influence susceptibility to IA in the recipient.HypothesisWe hypothesize that the detection of single nucleotide polymorphisms (SNPs) in PRRs other than TLR4 such as TLR1, TLR6 or Dectin-1 in HSCT donors and recipients influence susceptibility to IA. The identification of SNPs at risk will allow predictive/preventive strategies aimed at reducing mortality and morbidity in these patients.This project will be divided in 3 specific aims.Aim 1. To determine whether polymorphisms in TLR1, TLR6 and Dectin-1 are associated with susceptibility to IA, using SNP genotyping in HSCT patients and donors. We will use existing discovery and validation studies of HSCT donor and recipientsAim 2. To determine whether TLR1 or TLR6 are involved in the innate immune responses to A. fumigatus1. To compare survival, inflammation and A. fumigatus invasion in a mice model of invasive aspergillosis, using wild-type mice and mice deficient in TLR1, TLR2, TLR4, TLR6 and MyD88 (a protein required for TLR signaling).2. To compare innate immune activation (e.g. cytokine production) of bone marrow derived macrophages from TLR1, TLR2, TLR4, TLR6 and MyD88 KO and wild-type mice after stimulation with A. fumigatus and A. fumigatus extracts3. To compare innate immune activation (e.g. NF-kB activation) either in cells complemented with TLR expressing plasmids (transfection), or cells with inhibited expression of TLRs (sh RNA), after stimulation with A. fumigatus and A. fumigatus extracts.Aim 3. To functionally assess the role of polymorphisms in human TLR4 and TLR1 (and TLR6 and Dectin-1 if appropriate) in innate immune responses to A. fumigatus1. To compare innate immune activation (e.g. cytokines production) after fungal stimulation of whole blood or blood cells from individuals carrying relevant polymorphisms. 2. To compare innate immune activation (e.g. NF-?B activation) in cells complemented with human wild-type and polymorphic plasmids expressing TLR1 and TLR6 (and if relevant, Dectin-1).Preliminary dataPreliminary data suggest that donor and recipients SNPs in TLR1 influence risk of invasive aspergillosis (IA) independently of TLR4 polymorphisms. Preliminary in vitro and ex vivo experiments suggest that these SNPs influence innate immune responses to A. fumigatus.RelevanceOverall, this proposal seeks to prove that genetic factors in the innate immune system are important in the biology of IA after HSCT, and to provide the rationale for new prevention strategies.
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