Genetic regulation of resistance to intracellular pathogens

Skamene, Emil; Gros, Philippe; Forget, A; Kongshavn, Patricia A. L.; Charles, Carole St; Taylor, Benjamin A.

doi:10.1038/297506a0

Cited by 350 publications

(177 citation statements)

References 8 publications

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“…This study shows, in agreement with the findings of others [1][2][3][4], that mice that possess the dominant resistance allele of the Bcg gene (Bcg r ) are more capable than those that possess the recessive susceptible allele (Bcg s ) of restricting the growth of BCG in their spleens during the first 20 days or so of infection initiated by inoculating the organism intravenously. Also in agreement with the findings of others [1] is the result showing that this resistance advantage was not maintained after the onset of specific immunity, in that after 20 days of progressive BCG growth, Bcg s mice were just as capable as Bcg r mice of resolving infection in their spleens.…”

Section: Discussionsupporting

confidence: 93%

“…It has been shown in mice [1][2][3][4] that innate resistance, as opposed to acquired specific immunity, to infection with the attenuated strain of Mycobacterium bovis, bacille Calmette-Guérin (BCG), is under the influence of a single, dominant autosomal gene designated Bcg, which is present in two allelic forms in inbred strains of mice, Bcg r (dominant resistance) and Bcg s (recessive susceptible). The Bcg locus also influences innate resistance of mice to other intracellular pathogens [4][5][6], and is believed to be phenotypically expressed by macrophages [7] and to provide these cells with a superior capacity to kill or restrict the growth of the pathogens intracellularly [8].…”

Section: Introductionmentioning

confidence: 99%

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Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

Medina

North

1996

Clinical and Experimental Immunology

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SUMMARYIn mice, natural resistance to infection with BCG is under the influence of an autosomal gene designated Bcg. It is shown here in agreement with others that mice that possess the dominant resistant allele of the gene (Bcg r ) are more capable than mice that possess the susceptible recessive allele (Bcg s ) at restricting the growth of BCG in their lungs, as well as in their spleens, during the first 20 days of infection. It is shown, in addition, that in the absence of specific immunity the resistance difference between Bcg r and Bcg s mice became much more pronounced as infection progressed beyond day 20. Whereas T celldepleted Bcg r mice developed a capacity after day 20 to cause infection in their lungs and spleens to stabilize and plateau for a least 40 days, T cell-depleted Bcg s mice were unable to prevent infection from progressing in these organs. On the other hand, both types of T cell-depleted mice were capable of causing infection to plateau in their livers and kidneys. Moreover, this T cell-independent mechanism of resistance was essentially abolished in all organs in which it was expressed by treating the mice with hydrocortisone. In the lungs of immunocompetent Bcg s mice, failure to stabilize infection was associated with heavily infected macrophages and failure to contain BCG at original sites of infection.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

Medina

North

1996

Clinical and Experimental Immunology

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“…41,42 These two loci were also located on mouse chromosome 1 to the same genomic subregion as Ity. 43,44 At that time, it was not clear if Bcg, Ity and Lsh were either the same or very closely related genes. The identification of a unique gene underlying Ity/ Bcg/Lsh came almost 20 years after its first description.…”

Section: Nramp1mentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. The outcome of an encounter between Salmonella and its host is dependent upon multiple factors including the host genetic background. To facilitate the study of the genetic factors involved in resistance to this pathogen, mouse models of Salmonella infection have been developed and studied for years, allowing identification of several genes and pathways that may influence the disease outcome. In this review, we will cover some of the genes involved in mouse resistance to Salmonella that were identified through the study of congenic mouse strains, cloning of spontaneous mouse mutations, use of site-directed mutagenesis or quantitative trait loci analysis. In parallel, the relevant information pertaining to genes involved in resistance to Salmonella in humans will be discussed.

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“…This model has been used successfully to identify a number of genetic determinants of the host and the pathogen governing host-pathogen interactions. 2,3 Salmonella Typhimurium is a natural pathogen of the mice that is also transmitted by the fecal-oral route. The bacteria invade the host by promoting its phagocytosis by M cells of the intestine, and subsequently colonize the Peyer's patches and mesenteric lymph nodes before disseminating through the host, establishing major sites of replication in the spleen and the liver.…”

Section: Introductionmentioning

confidence: 99%

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

et al. 2011

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In humans, Salmonella infection causes two major clinical diseases, typhoid fever and a self-limiting gastro-enteritidis. Salmonella transmission occurs by the fecal-oral route and the interactions between the bacteria and the digestive tract epithelium are central to the outcome of the infection. Using a mouse model of typhoid fever, we previously identified a mutation in USP18 affecting type I interferon (IFN) signaling resulting in increased susceptibility to systemic Salmonella infection. In this study, we demonstrate the effects of this mutation during the early response to Salmonella using a model of typhlitis. Mutant Usp18 mice showed a minimal inflammatory response early after Salmonella Typhimurium infection that was associated with low pathologic scores and low IFN-g production. This resulted in an increased interaction of Salmonella with the cecal epithelium and earlier systemic dissemination of the bacteria. The global transcriptional signature in the cecum of mouse during Salmonella infection showed normal expression of tissue specific genes and upregulation of type I IFN pathway in mutant mice. In control mice, there was a significant over-representation of genes involved in cellular recruitment and antibacterial activity paralleling the histopathological features. These results show the impact of USP18 in the development of Salmonella-induced typhlitis.

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Genetic regulation of resistance to intracellular pathogens

Cited by 350 publications

References 8 publications

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

Genetic regulation of host responses to Salmonella infection in mice

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

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