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Anna Norrby-Teglund group

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

Members

Anna Norrby-Teglund, Group Leader, Professor
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 Karolinska Institutet (KI)(1997). Professor in medical microbial pathogenesis at KI (2008).

Phone: +46 (0)8-524 82354

Muhammad Afzal, PhD, postdoc

Helena Bergsten, MD; PhD student

Majda Dzidic, PhD; postdoc (from August 2019)

Magdalena Lourda, PhD; Assistant professor

Laura Palma Medina, postdoc

Kirsten Moll, PhD, Lab manager (from August 2019)

Victoria Vassen, PhD; postdoc (from August 2019)

Affiliated members and collaborators

Mattias Svensson, PhD

Kristoffer Strålin, MD, PhD, Associate Professor. Specialist in Infectious Diseases, Karolinska University Hospital.

Jonas Sundén-Cullberg, MD, PhD. Specialist in Infectious Diseases, Karolinska University Hospital

Carl-Johan Treutiger, MD, PhD, Associate Professor. Specialist in Infectious Diseases, Karolinska University Hospital

Former members (position in the group)

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)

Recent and ongoing projects  

Disease signatures in group A streptococcal necrotizing soft tissue infections. 
Supported by research grant from the Swedish Research Council (VR)

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.

INFECT-project, 2013-2018.

INFECT-project, 2013-2018.
Supported by EU FP7 Health

Infect logotype

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). NSTI’s 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.

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

Financial support

  • European Commission, FP7-Health
  • Medical research Council
  • Wallenberg
  • Karolinska University hospital (ALF-grants)
  • Karolinska Institutet
  • Torsten and Ragnar Söderbergs Foundation

Selected publications

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 Oct;67(9):1434-1436

Siemens K and A Norrby-Teglund. 2017. Shocking superantigens promote establishment of bacterial superantigens. PNAS 114(38):10000-10002.

M B Hansen, L S Rasmussen, M Svensson, B Chakrakodi, T Bruun, M B Madsen, P Garred, INFECT Study Group, O Hyldegaard, A Norrby-Teglund. 2017. The association between cytokine response and LRINEC score in patients with necrotizing soft tissue infections: a multicenter, prospective, observational study. Scientific Reports. 7:42179. doi: 10.1038/srep42179

Madsen MB, PB Hjortrup, MB Hansen, T Lange, A Norrby-Teglund, O Hyldegaard, A Perner. 2017. Immunoglobulin G for patients with necrotizing soft tissue infection: a blinded, placebo-controlled randomized trial. Int Care Med. 2017 43(11):1585-1593. doi: 10.1007/s00134-017-4786-0

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, et al
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, et al
JCI Insight 2016 07;1(10):e87882

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, et al
Sci Rep 2016 08;6():31360

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, et al
PLoS Pathog. 2016 07;12(7):e1005732

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, et al
Sci Rep 2016 Feb;6():21288

Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections.
Siemens N, Kittang BR, Chakrakodi B, Oppegaard O, Johansson L, Bruun T, et al
Sci Rep 2015 Nov;5():16945

Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology.
Mairpady Shambat S, Chen P, Nguyen Hoang A, Bergsten H, Vandenesch F, Siemens N, et al
Dis Model Mech 2015 Nov;8(11):1413-25

Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study.
Linnér A, Darenberg J, Sjölin J, Henriques-Normark B, Norrby-Teglund A
Clin. Infect. Dis. 2014 Sep;59(6):851-7

Levels of alpha-toxin correlate with distinct phenotypic response profiles of blood mononuclear cells and with agr background of community-associated Staphylococcus aureus isolates.
Mairpady Shambat S, Haggar A, Vandenesch F, Lina G, van Wamel WJ, Arakere G, et al
PLoS ONE 2014 ;9(8):e106107

HMGB1 in severe soft tissue infections caused by Streptococcus pyogenes.
Johansson L, Snäll J, Sendi P, Linnér A, Thulin P, Linder A, et al
Front Cell Infect Microbiol 2014 ;4():4

Intracellular Streptococcus pyogenes in human macrophages display an altered gene expression profile.
Hertzén E, Johansson L, Kansal R, Hecht A, Dahesh S, Janos M, et al
PLoS ONE 2012 ;7(4):e35218

Clinical and microbiologic characteristics of invasive Streptococcus pyogenes infections in north and south India.
Haggar A, Nerlich A, Kumar R, Abraham VJ, Brahmadathan KN, Ray P, et al
J. Clin. Microbiol. 2012 May;50(5):1626-31

Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections.
Johansson L, Thulin P, Low DE, Norrby-Teglund A
Clin. Infect. Dis. 2010 Jul;51(1):58-65

M1 protein-dependent intracellular trafficking promotes persistence and replication of Streptococcus pyogenes in macrophages.
Hertzén E, Johansson L, Wallin R, Schmidt H, Kroll M, Rehn AP, et al
J Innate Immun 2010 ;2(6):534-45

Inducible cyclooxygenase released prostaglandin E2 modulates the severity of infection caused by Streptococcus pyogenes.
Goldmann O, Hertzén E, Hecht A, Schmidt H, Lehne S, Norrby-Teglund A, et al
J. Immunol. 2010 Aug;185(4):2372-81

Erysipelas caused by group A streptococcus activates the contact system and induces the release of heparin-binding protein.
Linder A, Johansson L, Thulin P, Hertzén E, Mörgelin M, Christensson B, et al
J. Invest. Dermatol. 2010 May;130(5):1365-72

Neutrophil-derived hyperresistinemia in severe acute streptococcal infections.
Johansson L, Linnér A, Sundén-Cullberg J, Haggar A, Herwald H, Loré K, et al
J. Immunol. 2009 Sep;183(6):4047-54

Bacterial phenotype variants in group B streptococcal toxic shock syndrome.
Sendi P, Johansson L, Dahesh S, Van-Sorge NM, Darenberg J, Norgren M, et al
Emerging Infect. Dis. 2009 Feb;15(2):223-32

Soluble M1 protein of Streptococcus pyogenes triggers potent T cell activation.
Påhlman LI, Olin AI, Darenberg J, Mörgelin M, Kotb M, Herwald H, et al
Cell. Microbiol. 2008 Feb;10(2):404-14

Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans.
Johansson L, Thulin P, Sendi P, Hertzén E, Linder A, Akesson P, et al
Infect. Immun. 2008 Aug;76(8):3399-404

Pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock.
Sundén-Cullberg J, Nyström T, Lee ML, Mullins GE, Tokics L, Andersson J, et al
Crit. Care Med. 2007 Jun;35(6):1536-42

Viable group A streptococci in macrophages during acute soft tissue infection.
Thulin P, Johansson L, Low DE, Gan BS, Kotb M, McGeer A, et al
PLoS Med. 2006 Mar;3(3):e53

Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock.
Sundén-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al
Crit. Care Med. 2005 Mar;33(3):564-73

M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage.
Herwald H, Cramer H, Mörgelin M, Russell W, Sollenberg U, Norrby-Teglund A, et al
Cell 2004 Feb;116(3):367-79

Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome.
Darenberg J, Söderquist B, Normark BH, Norrby-Teglund A
Clin. Infect. Dis. 2004 Mar;38(6):836-42

Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial.
Darenberg J, Ihendyane N, Sjölin J, Aufwerber E, Haidl S, Follin P, et al
Clin. Infect. Dis. 2003 Aug;37(3):333-40

An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.
Kotb M, Norrby-Teglund A, McGeer A, El-Sherbini H, Dorak MT, Khurshid A, et al
Nat. Med. 2002 Dec;8(12):1398-404

Open 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.