Relative contribution of IL-1α, IL-1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG.
TNF and IL-1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL-1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL-1α, IL-1β, and TNF. Using gene-targeted mice we show that absence of both IL-1α and IL-1β recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNγ, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice. However, presence of either IL-1α or IL-1β in single-deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL-1 pathway, but not in the absence of TNF. Therefore, although both IL-1α and IL-1β are required for a full host response to virulent M. tuberculosis, the presence of either IL-1α or IL-1β allows some control of acute M. tuberculosis infection, and IL-1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti-inflammatory therapy with IL-1β neutralizing antibodies.
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Marie-Laure
ML
Bourigault
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Noria
N
Segueni
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Stéphanie
S
Rose
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Nathalie
N
Court
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Rachel
R
Vacher
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Virginie
V
Vasseur
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
François
F
Erard
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Marc
M
Le Bert
Department of Pathology and Immunology, University of Geneva Medical School Geneva, Switzerland.
Irene
I
Garcia
Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo Tokyo, Japan.
Yoichiro
Y
Iwakura
Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town Cape Town, South Africa ; National Health Laboratory Service Cape Town, South Africa.
Muazzam
M
Jacobs
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France ; Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town Cape Town, South Africa.
Bernhard
B
Ryffel
CNRS, UMR7355 Orleans, France ; University of Orleans, Experimental and Molecular Immunology and Neurogenetics Orleans, France.
Valerie F J
VF
Quesniaux
Host response; IL-1β/IL-1α; M. bovis infection; M. tuberculosis; TNF