A new coding mutation in the Tnf-α leader sequence in tuberculosis-sensitive I/St mice causes higher secretion levels of soluble TNF-α

Ak, Kähler; As, Persson; Sánchez, Fabio; Källström, Helena; Apt, Alexander S.; Schurr, Erwin; Lavebratt, Catharina

doi:10.1038/sj.gene.6364249

Cited by 12 publications

(5 citation statements)

References 48 publications

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“…The chromosome 17 QTL has been narrowed down to a smaller candidate region encompassing mouse MHC using a series of interval-specific congenic mice. Functional analysis demonstrated that the susceptible I/St-derived MHC allele was associated with higher bacterial loads, more pronounced inflammation, and lower Th1 cell response in the lungs after aerosol infection with virulent M.tb [ 121 – 123 ]. In yet another model of necrotic TB inflammation in DBA/2 mice, two QTLs have been mapped to chromosomes 8 and 19 also in a cross with C57BL/6.…”

Section: Mechanisms Of Necrotizing Responses As Studied In Mouse Modementioning

confidence: 99%

Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies

2015

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A key aspect of TB pathogenesis that maintains Mycobacterium tuberculosis in the human population is the ability to cause necrosis in pulmonary lesions. As co-evolution shaped M. tuberculosis (M.tb) and human responses, the complete TB disease profile and lesion manifestation are not fully reproduced by any animal model. However, animal models are absolutely critical to understand how infection with virulent M.tb generates outcomes necessary for the pathogen transmission and evolutionary success. In humans, a wide spectrum of TB outcomes has been recognized based on clinical and epidemiological data. In mice, there is clear genetic basis for susceptibility. Although the spectra of human and mouse TB do not completely overlap, comparison of human TB with mouse lesions across genetically diverse strains firmly establishes points of convergence. By embracing the genetic heterogeneity of the mouse population, we gain tremendous advantage in the quest for suitable in vivo models. Below, we review genetically defined mouse models that recapitulate a key element of M.tb pathogenesis—induction of necrotic TB lesions in the lungs—and discuss how these models may reflect TB stratification and pathogenesis in humans. The approach ensures that roles that mouse models play in basic and translational TB research will continue to increase allowing researchers to address fundamental questions of TB pathogenesis and bacterial physiology in vivo using this well-defined, reproducible, and cost-efficient system. Combination of the new generation mouse models with advanced imaging technologies will also allow rapid and inexpensive assessment of experimental vaccines and therapies prior to testing in larger animals and clinical trials.

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Section: Mechanisms Of Necrotizing Responses As Studied In Mouse Modementioning

confidence: 99%

Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies

2015

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“…Soluble and membrane‐bound TNF are both important in the response to mycobacterial infection. Knock‐in mice, in which endogenous TNF is replaced by a non‐cleavable form, appear to be protected from infection , whereas a coding mutation in the TNF leader sequence that causes higher secretion levels of soluble TNF is found in the I/St strain of mice, which are highly sensitive to tuberculosis, displaying an extremely rapid disease progression after intravenous challenge with a virulent human isolate of M. tuberculosis .…”

Section: The Effects Of Tnf On Bacterial Infectionsmentioning

confidence: 99%

Tumour necrosis factor in infectious disease

Waters

Pober

Bradley

2013

The Journal of Pathology

117

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TNF signals through two distinct receptors, designated TNFR1 and TNFR2, which initiate diverse cellular effects that include cell survival, activation, differentiation, and proliferation and cell death. These cellular responses can promote immunological and inflammatory responses that eradicate infectious agents, but can also lead to local tissue injury at sites of infection and harmful systemic effects. Defining the molecular mechanisms involved in TNF responses, the effects of natural and experimental genetic diversity in TNF signalling and the effects of therapeutic blockade of TNF has increased our understanding of the key role that TNF plays in infectious disease.

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“…23,24 The effect of Chr. 17 on host response to M. tuberculosis has recently been attributed to a functional polymorphism in the tumor necrosis factor-a gene, 25 suggesting a possible modifying effect of this pleitropic proinflammatory cytokine on Nramp1-mediated resistance.…”

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confidence: 99%

Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guérin) infection in wild-derived Mus spretus mice

et al. 2006

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Susceptibility to Mycobacterium bovis Bacille Calmette-Gué rin (BCG) is genetically controlled by Nramp1 (Slc11a1). Inbred mouse strains harbor either the resistance (Nramp1 G169 ) or the susceptibility (Nramp1 D169 ) allele at Nramp1. Mus spretus (Nramp1 G169; SPRET/EiJ) is shown to display an intermediate level of BCG replication in the spleen (log 10 colony-forming units (CFU)B5), compared to resistant A/J (log 10 CFUB4.0) and susceptible C57BL/6J (log 10 CFUB6.0) mice. The presence of genetic modifiers of Nramp1-dependent susceptibility to M. bovis (BCG) infection in Mus spretus was analyzed by wholegenome scanning in 175 mice of an informative (C57BL/6J Â SPRET/EiJ) Â C57BL/6J backcross. Nramp1 showed a major effect (D1Mcg4, Po1e À4 ), but additional single marker effects were identified on chromosomes 4 (D4Mit150) and Â (DXMit249) in male mice, and on chromosome 9 (D9Mit77) and 17 (D17Mit81) in female mice. A strong interaction between Nramp1 and the major histocompatibility locus was also noted in female mice. The mapped loci may act as modifiers of Nramp1 action, and constitute novel entry points for the parallel search of loci regulating susceptibility to mycobacterial infections in humans.

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A new coding mutation in the Tnf-α leader sequence in tuberculosis-sensitive I/St mice causes higher secretion levels of soluble TNF-α

Cited by 12 publications

References 48 publications

Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies

Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies

Tumour necrosis factor in infectious disease

Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guérin) infection in wild-derived Mus spretus mice

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