Susanna Brighenti group - Discovery of pathogenesis in human tuberculosis

Our research aims to study immunopathogenesis in tuberculosis (TB) infection and to explore therapeutic strategies that enhance the ability of the immune system to effectively eradicate Mycobacterium tuberculosis.

The Susanna Brighenti research group at CIM, MedH. Photo: Amalia Kewenter

About our research

We study specific immune responses including the induction and regulation of antimicrobial effector functions in macrophages and T cells, particularly at the local site of Mtb infection. Integration of patient materials with well-defined cell and tissue models in vitro are used to explore pathogenic mechanisms of human TB and associated comorbidities such as HIV and type 2 diabetes.

This translational approach aims to unravel specific cellular and molecular targets relevant for immune reconstitution in vivo. Here, compounds with immunomodulatory properties are used to discover novel host-directed therapies that could enhance immune cell function(s) and support conventional antibiotics in Mtb killing and/or growth control.

The overall purpose of our research is to promote the development of next-generation individualized treatment options for different groups of difficult-to-treat TB patients.

A human macrophage infected with Mtb (red rods in phagosome) is surrounded by T cells. Photo: N/A

Tuberculosis 

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and continues to be one of the world-leading killers among infectious diseases; every second a person in the world is infected with Mtb and every 25 second a person dies from TB. Inadequate use of chemotherapy has resulted in resistance of Mtb to most known antibiotics and increased rates of multidrug-resistant TB (MDR-TB) with low treatment success rates is a growing global threat.

Similar to other serious bacterial infections, effective development of resistance to antibacterial drugs rapidly diminishes the pipeline of drug candidates with efficacy towards Mtb. Host-directed therapies target multiple immune pathways to enhance cure, while reducing disease severity, side effects and problems with drug-resistance. The importance of the immune response in TB control is highlighted by the increased risk of TB in primary immunodeficiencies, HIV infection and upon treatment with TNF-α inhibitors.

Keywords

tuberculosis, infection, immune responses, antimicrobial mechanisms, drug resistance, host-directed therapy, global health

Group leader

Susanna Brighenti

Associate Professor, Group leader
H7 Department of Medicine, Huddinge

Susanna Brighenti is Group leader at CIM since 2008.

  • Susanna is Master of Science in Cell biology at Lund University (1997).
  • PhD in Immunology at Active Biotech Research and Lund University (2002).
  • Postdoc in Infection and Immunology at KI (2003-2008).
  • Assistant professor at Karolinska Institutet (2008-2014). 
  • Associate professor in Immunology at Karolinska Institutet (2014).
     

Group members

Mily Akhirunnesa

PhD, Postdoctoral fellow
H7 Department of Medicine, Huddinge

Mily Akhirunessa is postdoctoral fellow at CIM since March 2021.

  • Mily is Master of Science in Biochemistry and Molecular Biology at the International Centre for Diarrhoeal Disease Research (icddrb), Bangladesh (2005).
  • Senior Research Officer at icddrb (2006-2016).
  • PhD in infection and immunology at CIM. 

Marco Loreti

PhD student
H7 Department of Medicine, Huddinge
  • Marco Loreti is Master of Science in Biomedical Sciences at the University of Groningen, the Netherlands (2017).
  • Bachelor of Science in Medical Biotechnology, University of Milan “Statale” (2015).
  • PhD student at Karolinska Institutet from 2019, with his thesis work “Modulation of protective immunity in human tuberculosis”.

Sadaf Kalsum

PhD, Postdoctoral fellow
H7 Department of Medicine, Huddinge

Sadaf Kalsum is Postdoctoral fellow at CIM since March 2020.

  • Sadaf is Master of Science in Medical Biosciences at Linköping University (2009).
  • Research assistant at the Department of Clinical and Experimental Medicine, Linköping University (2011).
  • Laboratory Engineer at the Division of Microbiology, Infection and Inflammation, Linköping University (2013).
  • PhD in Mycobacterium tuberculosis and drug discovery at the Division of Microbiology, infection and Inflammation, Linköping University.

Affiliated group members

H7 Department of Medicine, Huddinge
  • Sanait Ashenafi has a Medical Degree at Addis Ababa University (AAU), Ethiopia (1987).
  • Master of Science in Medical Biotechnology at Bergen University, Norway (1992).
  • Resident Physician in Pathology, "ST-läkare" at AAU, Ethiopia (1997).
  • PhD in Infection and Immunology at Karolinska Institutet (2013).
  • Postdoc in Infection and Immunology at Karolinska Institutet (2014-2015).
  • Assistant professor at Karolinska Institutet (2016-2019),
  • Associate professor at AAU, Ethiopia from 2019.
H7 Department of Medicine, Huddinge
  • Jagadees Rao Muvva has a Bachelor of Medicine and Bachelor of Surgery.
  • MBBS at Guntur Medical College, India (2004).
  • Resident Physician in Emergency & General practice, India & Botswana (2010).
  • Master of Science in Biomedicine at Örebro University, Sweden (2013).
  • Master Thesis & Research assistantship in immunology at Karolinska Institutet (2011-2012).
  • PhD in Infection and Immunology at Karolinska Institutet (2019).
  • Resident Physician in India from 2019.

Jan Andersson

Professor, Head of Research and Development, Stockholm County Council
H7 Department of Medicine, Huddinge
  • Jan Andersson has a Medical Degree at Karolinska Institutet (1978).
  • Resident Physician in Infectious Diseases, "ST-läkare" at Danderyd Hospital (1982).
  • PhD in Infection and Immunology at Karolinska Institutet and Danderyd Hospital (1985).
  • Postdoc in Infection and Immunology at the DNAX research Institute, CA, USA (1987) and North Western University Medical School, Chicago, USA (1988).
  • Associate professor in Infectious Diseases at KI (1996).
  • Professor in Infectious Diseases at KI (1998).
  • Vice President at KI (2010-2012), Head of Research and Development, Stockholm County Council from 2013.

Open positions

We always want to get in touch with talented potential co-workers. If you are interested in doing research within our group, as a degree project or as a researcher, please contact the group leader Susanna Brighenti.

Previous group members

Jagadees Rao Muvva, PhD student.Thesis work at KI: "Studies of effector functions in Mycobacterium tuberculosis-infected macrophages with implications for host-directed therapies" (2013-2019).

Nebiat Gebreselassie, postdoc (2012-2015)

Pablo Giusti, postdoc (2012-2014)

Jubayer Rahman, postdoc (2010-2012)

Anders Rehn, postdoc (2008-2010)

Senait Ashenafi, PhD student, postdoc and Assistant professor Thesis work at KI: "Studies of dysfunctional cellular immunity in human tuberculosis disease with implications for immune reconstitution" (2007-2013).

Sayma Rahman, PhD student. Thesis work at KI: "Local immune responses in tuberculosis: Cytolytic effector functions at the site of Mycobacterium tuberculosis infection" (2007-2013).

Arina Samarina, Licentiate student. Thesis work at KI: "Cell mediated immune responses in tissue from patients with pulmonary tuberculosis" (2003-2005).

Key collaborations

The IRETB (Immune Reconsitution in TB disease) project team in Addis Ababa, Ethiopia. From top left: Dr. Wondwossen Amogne, Dr. Amsalu Bekele, Prof. Getachew Aderaye, Dr. Senait Ashenafi and Dr. Endale Kassa (Dept. of Internal Medicine, Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia). From lower left: Dr. Nebiat Gebreselassie, Armauer Hansen Research Institute (AHRI, Addis Ababa, Ethiopia), Prof. Getachew Aseffa (Dept. of Radiology, Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia), Prof. Jan Andersson and Dr. Susanna Brighenti, MedH, KI.

Karolinska Institutet

Karolinska Institutet, Department of Laboratory Medicine (Labmed): 
Assoc. Prof. Peter Bergman and Prof. Birgitta Agerberth.

Sweden

Linköping University, Department of Clinical and Experimental Medicine:
Prof. Maria Lerm and Assoc. prof. Thomas Schön

Public Health Agency of Sweden (PHAS):
Dr. Ramona Groenheit and Dr. Melles Haile

International

Addis Ababa University (AAU) and Black Lion University Hospital, Ethiopia:
Dr. Amsalu Bekele, Dr. Wondwossen Amogne, Dr. Endale Kassa and Prof. Getachew Aderaye

Armauer Hansen Research Institute (AHRI), Ethiopia:
Assoc. prof. Abdissa Alemseged (Scientific Director of AHRI) and Prof. Abraham Aseffa

International Centre for Diarrhoeal Disease Research (icddrb), Bangladesh:
PhD Rubhana Raqib

University College London (UCL), UK:
Dr. Gabriele Pollara

Research support

  • The Swedish Heart- and Lung Foundation (HLF)
  • The Foundation to Prevent Antibiotic Resistance (Resist)
  • The Swedish Research Council (VR), (Medicine-Health and Development Research)
  • The Swedish International Development Cooperation Agency (SIDA)
  • The Swedish Civil Contingencies Agency (MSB)
  • The Swedish Society for Medical Research (SSMF)
  • Stiftelsen Clas Groschinskys Minnesfond
  • KI funding for doctoral education (KID)
  • KI funds

Selected publications

2018-2021

Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity.
Rao Muvva J, Ahmed S, Rekha RS, Kalsum S, Groenheit R, Schön T, Agerberth B, Bergman P, Brighenti S
J Infect Dis 2021 Jul;224(2):332-344

Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity.
Rao Muvva J, Ahmed S, Rekha RS, Kalsum S, Groenheit R, Schön T, Agerberth B, Bergman P, Brighenti S.
J Infect Dis. 2021 Jul 15;224(2):332-344.

Slow radiological improvement and persistent low-grade inflammation after chemotherapy in tuberculosis patients with type 2 diabetes.
Mily A, Sarker P, Taznin I, Hossain D, Haq MA, Kamal SMM, et al
BMC Infect Dis 2020 Dec;20(1):933

Polarization of M1 and M2 Human Monocyte-Derived Cells and Analysis with Flow Cytometry upon Mycobacterium tuberculosis Infection.
Mily A, Kalsum S, Loreti MG, Rekha RS, Muvva JR, Lourda M, et al
J Vis Exp 2020 09;(163):

Host and Pathogen Communication in the Respiratory Tract: Mechanisms and Models of a Complex Signaling Microenvironment.
Berry SB, Haack AJ, Theberge AB, Brighenti S, Svensson M
Front Med (Lausanne) 2020 ;7():537

Targeted Nutrition in Chronic Disease.
Bergman P, Brighenti S
Nutrients 2020 Jun;12(6):

Polarization of Human Monocyte-Derived Cells With Vitamin D Promotes Control of Mycobacterium tuberculosis Infection.
Rao Muvva J, Parasa VR, Lerm M, Svensson M, Brighenti S
Front Immunol 2019 ;10():3157

Vitamin D and Phenylbutyrate Supplementation Does Not Modulate Gut Derived Immune Activation in HIV-1.
Missailidis C, Sørensen N, Ashenafi S, Amogne W, Kassa E, Bekele A, et al
Nutrients 2019 Jul;11(7):

Daily Nutritional Supplementation with Vitamin D₃ and Phenylbutyrate to Treatment-Naïve HIV Patients Tested in a Randomized Placebo-Controlled Trial.
Ashenafi S, Amogne W, Kassa E, Gebreselassie N, Bekele A, Aseffa G, et al
Nutrients 2019 Jan;11(1):

Vitamin D₃ Status and the Association with Human Cathelicidin Expression in Patients with Different Clinical Forms of Active Tuberculosis.
Ashenafi S, Mazurek J, Rehn A, Lemma B, Aderaye G, Bekele A, et al
Nutrients 2018 Jun;10(6):

Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis.
Lange C, Alghamdi WA, Al-Shaer MH, Brighenti S, Diacon AH, DiNardo AR, et al
J. Intern. Med. 2018 May;():

Vitamin D and tuberculosis: where next?
Brighenti S, Bergman P, Martineau AR
J. Intern. Med. 2018 May;():

Friends and foes of tuberculosis: modulation of protective immunity.
Brighenti S, Joosten SA
J. Intern. Med. 2018 May;():

Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: a randomized controlled trial in Ethiopia.
Bekele A, Gebreselassie N, Ashenafi S, Kassa E, Aseffa G, Amogne W, et al
J. Intern. Med. 2018 Sep;284(3):292-306

Prostaglandin E2 suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: implications for treatment of Mycobacterium tuberculosis infection.
Wan M, Tang X, Rekha RS, Muvva SSVJR, Brighenti S, Agerberth B, et al
FASEB J. 2018 05;32(5):2827-2840

Enhanced CD8+ cytolytic T cell responses in the peripheral circulation of patients with sarcoidosis and non-Löfgren's disease.
Parasa VR, Forsslund H, Enger T, Lorenz D, Kullberg S, Eklund A, et al
Respir Med 2018 05;138S():S38-S44

2015-2017

Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model.
Parasa VR, Muvva JR, Rose JF, Braian C, Brighenti S, Lerm M
Front Microbiol 2017 ;8():2370

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.
Norrby M, Vesikari T, Lindqvist L, Maeurer M, Ahmed R, Mahdavifar S, et al
Vaccine 2017 03;35(12):1652-1661

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.
Norrby M, Vesikari T, Lindqvist L, Maeurer M, Ahmed R, Mahdavifar S, et al
Vaccine 2017 03;35(12):1652-1661

IL-7δ5 protein is expressed in human tissues and induces expression of the oxidized low density lipoprotein receptor 1 (OLR1) in CD14+ monocytes.
Rane L, Rahman S, Magalhaes I, Ambati A, Andersson J, Zumla A, et al
Int. J. Infect. Dis. 2017 Jun;59():29-36

Regulation of Immunity to Tuberculosis.
Brighenti S, Ordway DJ
Microbiol Spectr 2016 12;4(6):

A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection.
Braian C, Svensson M, Brighenti S, Lerm M, Parasa VR
J Vis Exp 2015 Oct;(104):

B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis.
Rao M, Valentini D, Poiret T, Dodoo E, Parida S, Zumla A, et al
Clin. Infect. Dis. 2015 Oct;61Suppl 3():S225-34

Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial.
Mily A, Rekha RS, Kamal SM, Arifuzzaman AS, Rahim Z, Khan L, et al
PLoS ONE 2015 ;10(9):e0138340

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages.
Rekha RS, Rao Muvva SS, Wan M, Raqib R, Bergman P, Brighenti S, et al
Autophagy 2015 ;11(9):1688-99

Pulmonary tuberculosis patients with a vitamin D deficiency demonstrate low local expression of the antimicrobial peptide LL-37 but enhanced FoxP3+ regulatory T cells and IgG-secreting cells.
Rahman S, Rehn A, Rahman J, Andersson J, Svensson M, Brighenti S
Clin. Immunol. 2015 Feb;156(2):85-97

2010-2014

Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3.
Ashenafi S, Aderaye G, Bekele A, Zewdie M, Aseffa G, Hoang AT, et al
Clin. Immunol. 2014 Apr;151(2):84-99

Modeling Mycobacterium tuberculosis early granuloma formation in experimental human lung tissue.
Parasa VR, Rahman MJ, Ngyuen Hoang AT, Svensson M, Brighenti S, Lerm M
Dis Model Mech 2014 Feb;7(2):281-8

BCG-specific IgG-secreting peripheral plasmablasts as a potential biomarker of active tuberculosis in HIV negative and HIV positive patients.
Ashenafi S, Aderaye G, Zewdie M, Raqib R, Bekele A, Magalhaes I, et al
Thorax 2013 Mar;68(3):269-76

Prime-boost vaccination with rBCG/rAd35 enhances CD8⁺ cytolytic T-cell responses in lesions from Mycobacterium tuberculosis-infected primates.
Rahman S, Magalhaes I, Rahman J, Ahmed RK, Sizemore DR, Scanga CA, et al
Mol. Med. 2012 May;18():647-58

Plasmacytoid dendritic cells infiltrate the skin in positive tuberculin skin test indurations.
Bond E, Liang F, Sandgren KJ, Smed-Sörensen A, Bergman P, Brighenti S, et al
J. Invest. Dermatol. 2012 Jan;132(1):114-23

A new potential biomarker for childhood tuberculosis.
Thomas T, Brighenti S, Andersson J, Sack D, Raqib R
Thorax 2011 Aug;66(8):727-9

Induction and regulation of CD8+ cytolytic T cells in human tuberculosis and HIV infection.
Brighenti S, Andersson J
Biochem. Biophys. Res. Commun. 2010 May;396(1):50-7