Anna Norrby-Teglund group

Our overall 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.

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)8-585 83297

Carl-Johan Treutiger, MD PhD

MD, KI 1993. PhD in experimental microbiology/parasitology at KI 1998. Specialist in infectious diseases, Karolinska University Hospital Huddinge 2005. Associate Professor, KI 2010. 

Phone: +46 (0)8-5858 0000

Jonas Sundén-Cullberg, MD PhD

MD, KI 1996, PhD in infectious diseases at KI 2008. Specialist in infectious diseases, Karolinska University Hospital Huddinge 2005. 

Phone: +46 (0)8-5858 0000

Srikanth Mairpady Shambat, PhD student

MSc in biomedical Genetics at Vellore Institute of Technology University, India. 

Phone: +46 (0)8-585 82276

Julia Uhlmann, PhD student

Diploma from Heinrich-Heine Universität in Düsseldorf, Germany. 

Phone: +46 (0)8-585 82276

Nikolai Siemens, PhD, Postdoc

PhD in Microbiology from University of Rostock, Germany.

Johanna Snäll, PhD student

Bhavya Chakrakodi, FoU intern

 MSc in Microbiology at Mysore University, India. 

Phone: +46 (0)8-585 82276

Helena Bergsten, PhD

Projects

Novel mediators/markers of sepsis

Recent studies have shown that the systemic inflammatory response involved in the pathophysiology of sepsis is more prolonged and heterogeneous in nature than previously thought, including also newly discovered mediators. Our research aims to decipher the mechanistic action of these mediators, in particular the neutrophil-derived mediators resistin and heparin-binding protein (HBP), which we have shown to be significantly associated with severity of infection (Crit Care Med, 2007; J Immunol. 2009; Cell 2004).

Another inflammatory mediator was found to have prognostic value when used in combination with APACHE II score. A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR was proposed (Giamarellos et al Crit Care 2012).

Collaborations

  • Herwald, Åkesson,
  • Linder: Lund University.

Immunomodulatory properties of S. pyogenes

S. pyogenes primarily cause severe infections by modulating and exploiting immune cells. This project focuses on the interaction between streptococci and phagocytic cells, in particular immune escape events. We identified intracellular persistence as a significant pathogenic mechanism contributing to bacterial eradication failure at the tissue site of infection (PLoS Med 2006). Further studies by Hertzén et al (J innate Immun. 2010) provided evidence that intracellular survival is linked to impaired phagolysosomal maturation. A differential gene expression is evident during the early compared to late stages of the bacterial intracellular cycle (PLoS One, 2012).

Collaborations

  • Holden
  • Imperial College, UK
  • Kotb, Univ Cincinatti, US
  • Nizet, Univ. California, San Diego, US

Both beneficial and detrimental effects of neutrophil responses have been emphasized in severe streptococcal infections. Our patient biopsy data (Infect Immun 2008, J Immunol. 2009) are in line with the detrimental effect of neutrophils, as neutrophil infiltration and degree of granule proteins correlate with bacterial load and severity of tissue disease. These findings will be further explored in primary human cell cultures and 3D-organotypic skin and lung tissue models.

Collaboration

  • Mattias Svensson, KI.

S. aureus: pathogenesis and identification of novel targets for intervention

Severe invasive S. aureus represent a significant health problem globally with certain clones giving rise to unusually severe pathological signs, such as necrotizing pneumonia and fasciitis. Several different putative virulence determinants have been described including the greatly debated PVL. A recent study by Löffler et al (PLoS Path 2010) showed striking differences in host susceptibility to PVL with human cells being highly susceptible. Here we aim to decipher the role of specific toxins and their potential synergistic effects in the pathogenesis of these infections, by use of human cell and 3D organotypic tissue cultures and well-characterized clinical isolates.

Collaborations

  • Mattias Svensson, KI
  • Arakere, Bangalore, India
  • Etienne, Lyon Univ, France

Necrotizing soft tissue infections: EU-project INFECT

In January 2013, the EU-funded project INFECT (www.fp7infect.eu) was launched and will be ongoing for five years. INFECT involves 14 partners in Sweden, Europe and the US. The project was initiated by Norrby-Teglund, who is also the coordinator of INFECT.

The focus of the project is to advance the understanding of necrotizing soft tissue infections (NSTI) that are associated with high mortality rates (>30%) and often require extensive surgery of the tissue, sometimes even amputation of the affected body parts. INFECT aims to identify risk factors and disease mechanisms that contribute to tissue damage and fatal processes. This is the first time an integrated systems biology approach is used in necrotizing deep tissue infections using patient samples and clinically relevant experimental models.

Collaborators

  • Mattias Svensson (project manager)
  • INFECT engages 14 partners from 10 countries: Sweden (with Karolinska Institutet as coordinator), Denmark, Norway, USA, Germany, France, the Netherlands, Israel, Austria and Great Britain

See website fp7infect.eu

Financial support

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

Selected publications

Siemens N, Chakrakodi B, Mairpady Shambat S, Morgan M,  Bergsten H, Hyldegaard O, Skrede S, Arnell P, Madsen M B, Johansson L, INFECT study group, Juarez J, L Bosnjak, Mörgelin M, Svensson M*, and Norrby-Teglund A*. 2016. Biofilm in group A streptococcal necrotizing soft tissue infections.  J Clin Invest INSIGHT. 1(10):e87882. Doi:11.1172/jci.insight.87882. * equal contribution

A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains.
Mairpady Shambat S, Siemens N, Monk I, Mohan D, Mukundan S, Krishnan K, et al
Sci Rep 2016 ;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 Jul;12(7):e1005732

[pubmed:26641861]

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 ;6():21288

Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections.
Siemens N, Kittang B, Chakrakodi B, Oppegaard O, Johansson L, Bruun T, et al
Sci Rep 2015 ;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 W, 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 V, Brahmadathan K, 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 D, 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 A, 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 N, 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 L, Olin A, 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 M, Mullins G, 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 D, Gan B, 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 K, 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 B, 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 M, 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.

Infectious Disease Medicine