Anna Norrby-Teglund group - Disease mechanisms in severe acute bacterial infections
Our overall research goal is to decipher mechanisms contributing to severe manifestations of acute bacterial infections and thereby identify targets for therapeutic intervention. The research is translational in nature and is based largely on clinical isolates, patient materials and human cell and tissue model systems that mimic the clinical setting.
Our research aims to:
- Link clinical presentation of severe sepsis/septic shock to microbiological aetiology and associated pathogen-specific disease mechanisms.
- Identify central mediators in severe sepsis/septic shock and deduce their mechanistic action and potential value as prognostic risk markers.
- Identify pathogenic mechanisms contributing to severity of necrotizing soft tissue infections.
- Utilize identified disease mechanisms to develop tailored therapy and implement personalized medicine in severe infectious diseases
Of particular interest are the two Gram-positive bacteria Streptococcus pyogenes and Staphylococcus aureus, both of which may cause highly aggressive invasive infections such as toxic shock, necrotizing pneumonia and necrotizing fasciitis that are associated with substantial morbidity and mortality. The research strives to decipher bacterial properties contributing to disease outcome and events underlying tissue injury. A specific theme is to evaluate immunotherapeutic strategies in these diseases.
Keywords
Streptococcus, Staphylococcus, Sepsis, Macrophages, Neutrophils, Inflammation, Soft Tissue Infections
Group leader
Anna Norrby-Teglund
Group Leader, ProfessorPostal address: Karolinska Institutet, Centrum för infektionsmedicin/ANA Futura, Alfred Nobels Allé 8, 141 52 Huddinge
BSc in biology (microbiology) at Umeå University (1989) PhD in clinical bacteriology at Umeå University (1994) Postdoctoral studies at Univ. of Tennessee, Memphis, US (1994-97) Associate Professor at KI (1999). Establishment of research group at KI (1997) Professor in medical microbial pathogenesis at KI (2008)
Group members
Magdalini Lourda
Senior research specialistLaura Palma Medina
Assistant professorAffiliated members and collaborators
Mattias Svensson
Principal researcherKristoffer Strålin
Affiliated to researchJonas Sunden-Cullberg
Adjunct lecturerCarl Johan Treutiger
Affiliated to researchOlav Rooijackers
ProfessorOpen positions
If you are interested in doing research in our group, as a degree project, PhD student or postdoc, please feel free to contact the group leader Anna Norrby-Teglund. We are always interested in discussing with talented potential co-workers.
Former members
Including the position at CIM.
- Nahla Ihendyane, PhD (PhD student)
- Pontus Thulin, MD, PhD (PhD student)
- Jessica Darenberg, PhD (PhD student)
- Axana Haggar, PhD (Postdoc)
- Linda Johansson, PhD (Postdoc, Assistant Professor)
- Erika Hertzén, PhD (PhD student)
- Srikanth Mairpady Shambat, PhD (PhD student)
- Bhavya Chakrakodi, MSc (Lab technician)
- Anna Linnér, MD, PhD (PhD student)
- Nikolai Siemens, PhD (Postdoc)
- Julia Uhlmann, PhD (PhD student, postdoc)
- Johanna Snäll, PhD (PhD student, postdoc)
- Muhammad Afzal, PhD (PhD student, postdoc)
Projects
Disease signatures in group A streptococcal necrotizing soft tissue infections
In this project, we explore the role of macrophages and neutrophils in the necrotizing soft tissue infections caused by group A streptococcus. Specifically we propose to utilize transcriptomic analyses and advanced microscopy to identify and explore disease signatures in tissue biopsies of NSTI patients. Results will be further dissected and validated by use of human organotypic skin tissue models allowing for mechanistic studies of infection in a human tissue-like milieu. The translational nature of the project utilizing a study design based on patient samples, clinical strains, as well as optimized human tissue model systems promotes clinically relevant results. Together this puts us in a unique position to obtain new insight into pathogenic mechanisms of NSTI required to achieve improved diagnostic and therapeutic approaches for these patients.
Systems biology approach to understand necrotizing soft tissue infections; INFECT-project, 2013-2018
The INFECT-project included 14 partners from across Europe, Israel and the US, and was coordinated by Karolinska Institutet (Norrby-Teglund). The overall goal of the project was to advance our understanding of the pathophysiological mechanisms, prognosis, and diagnosis of the multifactorial highly lethal necrotizing soft tissue infections (NSTIs). NSTIs are rapidly spreading infections that may cause extensive soft tissue or limb loss, multiorgan failure and are associated with a considerable fatality rate. There is an urgent need for novel diagnostic and therapeutic strategies in order to improve outcome of NSTIs. To achieve this, a comprehensive and integrated knowledge of diagnostic features, causative microbial agent, treatment strategies, and pathogenic mechanisms (host and bacterial disease traits and their underlying interaction network) was sought. INFECT obtained such insights through an integrated systems biology approach in patients and different clinically relevant experimental models. A key achievement of INFECT was the enrollment of NSTI patients and the creation of the world’s largest patient cohort and associated biobank. Analyses of the comprehensive clinical registry generated an advanced understanding of these patients and underlying disease mechanisms.
Personalized medicine in infectious Diseases: PerAID and PerMIT projects
The INFECT clinical registry and biobank now offer a resource for recently started multinational projects, PerAID and PERMIT, building on the advances made through the systems medicine approach to achieve personalized medicine in infectious diseases. The two projects are ambitious covering both severe soft tissue infections and the large heterogeneous group of sepsis. Activities range from establishment of a Nordic platform for personalized medicine in infections, to translational research aimed to identify disease signatures and biomarkers that can be used for individualized therapy, to development of clinical decision support tools.
Key collaborators
- Steinar Skrede, University of Bergen, Norway
- Ole Hyldegaard, Rigshospitalet and University of Copenhagen, Denmark
- Per Arnell, Sahlgrenska Hospital, Sweden
- Michael Nekludov, Karolinska University Hospital, Sweden
- Edoardo Saccenti, Wageningen University and Research, the Netherlands
- Vitor Martin dos Santos, WUR and LifeGlimmer, Berlin, Germany
- Jan-Kristian Damås and Erik Solligård, St Olav’s Hospital and NTNU, Trondheim, Norway
- Annebeth de Vries, Red Cross, the Netherlands
- Malak Kotb and Suba Nookala, University of North Dakota, USA
- Annelies Zinkernagel, University of Zürich, Switzerland
- Nikolai Siemens. Greifswald University, Germany
- John McCormick, Western University, Canada
- Jim Musser, Hoston Medical Center, US
- Fredric Carlsson, Lund University, Sweden
Research support
- CIMED
- European Commission, FP7-Health
- ERA PerMed
- Medical research Council
- Karolinska University hospital (ALF-grants)
- Karolinska Institutet
- Nordforsk
- Torsten and Ragnar Söderbergs Foundation
- Vinnova
- Wallenberg
Selected publications
2021
Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity.
Kvedaraite E, Hertwig L, Sinha I, Ponzetta A, Hed Myrberg I, Lourda M, Dzidic M, Akber M, Klingström J, Folkesson E, Muvva JR, Chen P, Gredmark-Russ S, Brighenti S, Norrby-Teglund A, Eriksson LI, Rooyackers O, Aleman S, Strålin K, Ljunggren HG, Ginhoux F, Björkström NK, Henter JI, Svensson M,
Proc Natl Acad Sci U S A 2021 02;118(6):
Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study.
Bruun T, Rath E, Madsen MB, Oppegaard O, Nekludov M, Arnell P, Karlsson Y, Babbar A, Bergey F, Itzek A, Hyldegaard O, Norrby-Teglund A, Skrede S,
Clin Infect Dis 2021 Jan;72(2):293-300
Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections.
Palma Medina LM, Rath E, Jahagirdar S, Bruun T, Madsen MB, Strålin K, Unge C, Hansen MB, Arnell P, Nekludov M, Hyldegaard O, Lourda M, Santos VAMD, Saccenti E, Skrede S, Svensson M, Norrby-Teglund A
J Clin Invest 2021 07;131(14):
Adjunctive Rifampicin Increases Antibiotic Efficacy in Group A Streptococcal Tissue Infection Models.
Bergsten H, Palma Medina LM, Morgan M, Moll K, Skutlaberg DH, Skrede S, Wajima T, Svensson M, Norrby-Teglund A
Antimicrob Agents Chemother 2021 10;65(11):e0065821
High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19.
Lourda M, Dzidic M, Hertwig L, Bergsten H, Palma Medina LM, Sinha I, Kvedaraite E, Chen P, Muvva JR, Gorin JB, Cornillet M, Emgård J, Moll K, García M, Maleki KT, Klingström J, Michaëlsson J, Flodström-Tullberg M, Brighenti S, Buggert M, Mjösberg J, Malmberg KJ, Sandberg JK, Henter JI, Folkesson E, Gredmark-Russ S, Sönnerborg A, Eriksson LI, Rooyackers O, Aleman S, Strålin K, Ljunggren HG, Björkström NK, Svensson M, Ponzetta A, Norrby-Teglund A, Chambers BJ,
Proc Natl Acad Sci U S A 2021 10;118(40):
Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study.
Bruun T, Rath E, Madsen MB, Oppegaard O, Nekludov M, Arnell P, Karlsson Y, Babbar A, Bergey F, Itzek A, Hyldegaard O, Norrby-Teglund A, Skrede S,
Clin Infect Dis 2021 01;72(2):293-300
2020
Integrated Univariate, Multivariate, and Correlation-Based Network Analyses Reveal Metabolite-Specific Effects on Bacterial Growth and Biofilm Formation in Necrotizing Soft Tissue Infections.
Afzal M, Saccenti E, Madsen MB, Hansen MB, Hyldegaard O, Skrede S, Martins Dos Santos VAP, Norrby-Teglund A, Svensson M
J Proteome Res 2020 02;19(2):688-698
Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections.
Bergsten H, Madsen MB, Bergey F, Hyldegaard O, Skrede S, Arnell P, Oppegaard O, Itzek A, Perner A, Svensson M, Norrby-Teglund A,
Clin Infect Dis 2020 Oct;71(7):1772-1775
Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment.
Siemens N, Oehmcke-Hecht S, Hoßmann J, Skorka SB, Nijhuis RHT, Ruppen C, Skrede S, Rohde M, Schultz D, Lalk M, Itzek A, Pieper DH, van den Bout CJ, Claas ECJ, Kuijper EJ, Mauritz R, Sendi P, Wunderink HF, Norrby-Teglund A
J Innate Immun 2020 ;12(4):291-303
2019
Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model.
Tarnutzer A, Andreoni F, Keller N, Zürcher C, Norrby-Teglund A, Schüpbach RA, Zinkernagel AS
Clin Microbiol Infect 2019 Apr;25(4):512.e7-512.e13
Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells' Type 1 Interferon Response.
Keller N, Woytschak J, Heeb LEM, Marques Maggio E, Mairpady Shambat S, Snäll J, Hyldegaard O, Boyman O, Norrby-Teglund A, Zinkernagel AS
J Invest Dermatol 2019 06;139(6):1284-1293
Necrotizing Soft Tissue Infection Staphylococcus aureus but not S. pyogenes Isolates Display High Rates of Internalization and Cytotoxicity Toward Human Myoblasts.
Baude J, Bastien S, Gillet Y, Leblanc P, Itzek A, Tristan A, Bes M, Duguez S, Moreau K, Diep BA, Norrby-Teglund A, Henry T, Vandenesch F,
J Infect Dis 2019 07;220(4):710-719
Is it time to rethink the group A streptococcus rheumatogenic concept?
Norrby-Teglund A, N Siemens. Invited commentary, Clin Infect Dis. 2019. Jul 23. pii: ciz427. doi: 10.1093/cid/ciz427
Molecular profiling of tissue biopsies reveals unique signatures associated with streptococcal necrotizing soft tissue infections.
Thänert R, Itzek A, Hoßmann J, Hamisch D, Madsen MB, Hyldegaard O, Skrede S, Bruun T, Norrby-Teglund A, , Medina E, Pieper DH
Nat Commun 2019 08;10(1):3846
Patient's characteristics and outcomes in necrotising soft-tissue infections: results from a Scandinavian, multicentre, prospective cohort study.
Madsen MB, Skrede S, Perner A, Arnell P, Nekludov M, Bruun T, Karlsson Y, Hansen MB, Polzik P, Hedetoft M, Rosén A, Saccenti E, Bergey F, Martins Dos Santos VAP, , Norrby-Teglund A, Hyldegaard O
Intensive Care Med 2019 09;45(9):1241-1251
MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome.
Emgård J, Bergsten H, McCormick JK, Barrantes I, Skrede S, Sandberg JK, Norrby-Teglund A
Proc Natl Acad Sci U S A 2019 12;116(51):25923-25931
2018
Protein SIC Secreted from Streptococcus pyogenes Forms Complexes with Extracellular Histones That Boost Cytokine Production.
Westman J, Chakrakodi B, Snäll J, Mörgelin M, Bruun Madsen M, Hyldegaard O, Neumann A, Frick IM, Norrby-Teglund A, Björck L, Herwald H
Front Immunol 2018 ;9():236
Polyspecific Intravenous Immunoglobulin in Clindamycin-treated Patients With Streptococcal Toxic Shock Syndrome: A Systematic Review and Meta-analysis.
Parks T, Wilson C, Curtis N, Norrby-Teglund A, Sriskandan S
Clin Infect Dis 2018 10;67(9):1434-1436
High HMGB1 levels in sputum are related to pneumococcal bacteraemia but not to disease severity in community-acquired pneumonia.
Alpkvist H, Athlin S, Mölling P, Norrby-Teglund A, Strålin K
Sci Rep 2018 09;8(1):13428
2017
Fever in the emergency department predicts survival of critically ill patients with severe sepsis or septic shock.
Sundén-Cullberg J,R Rylance, J Svefors, A Norrby-Teglund,J Björk, M Inghammar. 2017. Crit Care Med. 45(4):591-599. doi: 10.1097/CCM.0000000000002249.
Neutrophils acquire the capacity for antigen presentation to memory CD4+ T cells in vitro and ex vivo.
Vono M, Lin A, Norrby-Teglund A, Koup RA, Liang F, Loré K
Blood 2017 04;129(14):1991-2001
Association between cytokine response, the LRINEC score and outcome in patients with necrotising soft tissue infection: a multicentre, prospective study.
Hansen MB, Rasmussen LS, Svensson M, Chakrakodi B, Bruun T, Madsen MB, Perner A, Garred P, Hyldegaard O, Norrby-Teglund A,
Sci Rep 2017 02;7():42179
Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial.
Madsen MB, Hjortrup PB, Hansen MB, Lange T, Norrby-Teglund A, Hyldegaard O, Perner A
Intensive Care Med 2017 Nov;43(11):1585-1593
Bacterial deception of MAIT cells in a cloud of superantigen and cytokines.
Sandberg JK, Norrby-Teglund A, Leeansyah E
PLoS Biol 2017 Jul;15(7):e2003167
Shocking superantigens promote establishment of bacterial infection.
Siemens N, Norrby-Teglund A
Proc Natl Acad Sci U S A 2017 09;114(38):10000-10002
Immunoregulation of Neutrophil Extracellular Trap Formation by Endothelial-Derived p33 (gC1q Receptor).
Neumann A, Papareddy P, Westman J, Hyldegaard O, Snäll J, Norrby-Teglund A, Herwald H
J Innate Immun 2018 ;10(1):30-43
Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.
Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, Rovina N, Tsangaris I, Gkavogianni T, Botsa E, Chassiou E, Kotanidou A, Kontouli C, Chaloulis P, Velissaris D, Savva A, Cullberg JS, Akinosoglou K, Gogos C, Armaganidis A, Giamarellos-Bourboulis EJ,
BMC Med 2017 09;15(1):172
2016
A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains.
Mairpady Shambat S, Siemens N, Monk IR, Mohan DB, Mukundan S, Krishnan KC, Prabhakara S, Snäll J, Kearns A, Vandenesch F, Svensson M, Kotb M, Gopal B, Arakere G, Norrby-Teglund A
Sci Rep 2016 08;6():31360
Differential neutrophil responses to bacterial stimuli: Streptococcal strains are potent inducers of heparin-binding protein and resistin-release.
Snäll J, Linnér A, Uhlmann J, Siemens N, Ibold H, Janos M, Linder A, Kreikemeyer B, Herwald H, Johansson L, Norrby-Teglund A
Sci Rep 2016 Feb;6():21288
LL-37 Triggers Formation of Streptococcus pyogenes Extracellular Vesicle-Like Structures with Immune Stimulatory Properties.
Uhlmann J, Rohde M, Siemens N, Kreikemeyer B, Bergman P, Johansson L, Norrby-Teglund A
J Innate Immun 2016 ;8(3):243-57
Phosphoglycerate Kinase-A Novel Streptococcal Factor Involved in Neutrophil Activation and Degranulation.
Uhlmann J, Siemens N, Kai-Larsen Y, Fiedler T, Bergman P, Johansson L, Norrby-Teglund A
J Infect Dis 2016 Dec;214(12):1876-1883
Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse.
Chella Krishnan K, Mukundan S, Alagarsamy J, Hur J, Nookala S, Siemens N, Svensson M, Hyldegaard O, Norrby-Teglund A, Kotb M
PLoS Pathog 2016 07;12(7):e1005732
Biofilm in group A streptococcal necrotizing soft tissue infections.
Siemens N, Chakrakodi B, Shambat SM, Morgan M, Bergsten H, Hyldegaard O, Skrede S, Arnell P, Madsen MB, Johansson L, , Juarez J, Bosnjak L, Mörgelin M, Svensson M, Norrby-Teglund A
JCI Insight 2016 07;1(10):e87882