Martin Rottenberg and Hans Wigzell Group
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The intracellular Mycobacterium tuberculosis infect large number of individuals. However, only a small fraction of the infected individuals will develop Tuberculosis. TB will reactivate in a fraction of asymptomatically infected individuals. It is not completely understood why some individuals will develop a life threatening disease while others harbour a lifelong asymptomatic infection, but cytokines with rapid induction and high local concentration are of importance. To avoid host cell damage, cytokine responses must be controlled.
Suppressor of cytokine signalling-3 (SOCS3) inhibit STAT3 activation in response to different cytokines. We employed mice knocked down of SOCS3 expression in different immune populations. Interestingly, mice lacking SOSC3 in either macrophages and neutrophils (by targeting the LysM gene) or in T cells (by targeting the lck gene) were both found to be extremely susceptible to M. tuberculosis infection.
While SOCS3 in myeloid (macrophages and dendritic cells) promoted protection by allowing a fast and potent release of IL-12, allowing IFN-Gamma secretion by Th1 cells, SOCS3 expression in T cells regulated the levels of Gamma Delta+ T cells, and was associated to increased IL-17 secretion and neutrophil accumulation. SOCS3 thus regulates different biological responses in diverse immune cell populations that independently play a critical role in defense against the infection.
We have used humanized mice, in which human immune cells differentiate de novo from transplanted cord blood progenitor cells, to study the human immune responses to infection with Mycobacterium bovis BCG and M. tuberculosis.
Granulomas mainly composed of human macrophages surrounded by T cells resembling those of human Tuberculosis, were observed in organs from infected mice. The lesions from mice depleted of CD4+ T cells were scarcer, minimal and irregular compared to those from mice depleted of CD8+ cells or non-depleted controls.
Granulomas of BCG-infected humanized mice administered with a TNF-neutralizing TNF receptor fusion molecule preserved their structure, but contained higher levels of intracellular bacilli. Thus, humanized mice can be used as a model to study the formation and maintenance of human granuloma in TB and other infectious or non- infectious diseases.
The penetration of T cells and trypanosomes into the brain parenchyma is a major pathogenetic event in African trypanosomiasis, caused by infection of the protozoan parasite Trypanosoma brucei. The role of innate immune responses in the penetration of T cells and Trypanosoma brucei into the brain was studied in different knockout mice. Our data indicate that parasite stimulate innate immune TLR signals induce the expression of TNF-alpha and IFN-alpha/beta. These cytokines are required for invasion of T cells and trypanosomes into the brain. TLR signal also control T.b. brucei load in the brain by molecules distinct from TNF and IFN-alpha/beta.
STAT3 expression by myeloid cells is detrimental for the T- cell-mediated control of infection with Mycobacterium tuberculosis.
PLoS Pathog. 2018 Jan;14(1):e1006809
CISH controls bacterial burden early after infection with Mycobacterium tuberculosis in mice.
Tuberculosis (Edinb) 2017 Dec;107():175-180
Synergistic antibacterial effect of silver and ebselen against multidrug-resistant Gram-negative bacterial infections.
EMBO Mol Med 2017 Aug;9(8):1165-1178
Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3.
Cell Rep 2016 12;17(11):2827-2836
lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets.
J. Immunol. 2016 09;197(6):2261-8
Nitric Oxide Protects against Infection-Induced Neuroinflammation by Preserving the Stability of the Blood-Brain Barrier.
PLoS Pathog. 2016 Feb;12(2):e1005442
Suppressor of cytokine signaling-1 and chemokine (C-X-C Motif) receptor 3 expressions are associated with caseous necrosis in granulomas from patients with tuberculous lymphadenitis.
J Microbiol Immunol Infect 2016 Dec;49(6):984-987
Microinjection of Francisella tularensis and Listeria monocytogenes reveals the importance of bacterial and host factors for successful replication.
Infect. Immun. 2015 Aug;83(8):3233-42
SOCS3, a Major Regulator of Infection and Inflammation.
Front Immunol 2014 ;5():58
Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3.
Clin. Immunol. 2014 Apr;151(2):84-99
Differential Early Secreted Antigen Target (ESAT) 6 kDa-induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis.
J Infect Dev Ctries 2014 Jan;8(1):59-66
T cells modulate Epstein-Barr virus latency phenotypes during infection of humanized mice.
J. Virol. 2014 Mar;88(6):3235-45
Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.
J. Med. Chem. 2013 Dec;56(24):9861-73
Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.
J. Biol. Chem. 2013 Sep;288(38):27456-68
Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.
PLoS Pathog. 2013 ;9(7):e1003442
CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria.
Proc. Natl. Acad. Sci. U.S.A. 2013 Apr;110(16):6482-7
Expression of M. tuberculosis-induced suppressor of cytokine signaling (SOCS) 1, SOCS3, FoxP3 and secretion of IL-6 associates with differing clinical severity of tuberculosis.
BMC Infect. Dis. 2013 Jan;13():13
In vitro and in vivo activities of 2-aminopyrazines and 2-aminopyridines in experimental models of human African trypanosomiasis.
Antimicrob. Agents Chemother. 2013 Feb;57(2):1012-8
SOCS1 gene expression is increased in severe pulmonary tuberculosis.
Scand. J. Immunol. 2012 Oct;76(4):398-404
Tuberculosis and HIV co-infection.
PLoS Pathog. 2012 Feb;8(2):e1002464
Distinct Toll-like receptor signals regulate cerebral parasite load and interferon α/β and tumor necrosis factor α-dependent T-cell infiltration in the brains of Trypanosoma brucei-infected mice.
J. Infect. Dis. 2012 Jan;205(2):320-32
Mycobacterium tuberculosis Sonicate-Induced IFNγ, CXCL10 and IL10 can Differentiate Severity in Tuberculosis.
Scand. J. Immunol. 2012 Feb;75(2):220-6
Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner.
J. Biol. Chem. 2011 Jul;286(30):26873-87
Identification of stage biomarkers for human African trypanosomiasis.
Am. J. Trop. Med. Hyg. 2010 Jun;82(6):983-90
Alloreactivity but failure to reject human islet transplants by humanized Balb/c/Rag2gc mice.
Scand. J. Immunol. 2010 Feb;71(2):83-90
|Berit Annika Carow||Postdoc|
Former group members
Genetically controlled interactions between mycobacteria and host cells that are regulated by the host innate and adaptive immune responses dictate the outcome of mycobacterial infection.