Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae

Abstract

Host genetic factors are important in determining the outcome of infections caused by intracellular pathogens, including mycobacteria and salmonellae, but until now have been poorly characterized. Recently, some individuals with severe infections due to otherwise weakly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis bacille Calmette-Guérin) or Salmonella species have been shown to be unable to produce or respond to interferon-gamma. This inability results from mutations in any of five genes encoding essential proteins of the type 1 cytokine cascade: interleukin-12p40, interleukin-12R beta 1, interferon-gamma R1, interferon-gamma R2 or STAT1. Ten syndromes have thus far been identified. Recent insights in genetically controlled host defense and susceptibility to mycobacterial disease are discussed.

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

“…2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virulence as this trace element is essential for microbial growth and proliferation [10,11].…”

“…In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9].…”

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

“…The release of proinflammatory cytokines such as IL-1b, TNF, IL-12 or IL-18 from monocytes and monocyte-derived macrophages induces the production of T-cell-derived cytokines, most importantly IFN-g, which in turn will activate macrophages for the killing and elimination of the microorganisms [5,6]. Patients with defects in receptors for IL-12 and IFN have an increased susceptibility to mycobacterial infections [7][8][9], while the association between low CD4 counts and TB is well-known in HIV-infected patients [2].While most of the research has focused on the mechanisms responsible for the IFN-g induction, relatively little is known about the mechanisms leading to the production and release of the first wave of cytokines that are needed for the activation of T cells. While TNF-a is known to be important for the integrity of the granuloma, two of the cytokines of the IL-1 family, IL-1b and IL-18, are considered to be crucial for the induction of IFN-g. IL-1-mediated signals have been recently demonstrated to be an essential component of the MyD88-dependent innate response to M. tuberculosis infection, while IL-18-dependent pathways seemed to be dispensable [10].…”

“…The release of proinflammatory cytokines such as IL-1b, TNF, IL-12 or IL-18 from monocytes and monocyte-derived macrophages induces the production of T-cell-derived cytokines, most importantly IFN-g, which in turn will activate macrophages for the killing and elimination of the microorganisms [5,6]. Patients with defects in receptors for IL-12 and IFN have an increased susceptibility to mycobacterial infections [7][8][9], while the association between low CD4 counts and TB is well-known in HIV-infected patients [2].…”

Salmonella septicemia in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Association with decreased interferon‐γ production and toll‐like receptor 4 expression

“…Recently, severe infections by Salmonella and Mycobacterium species have been described in patients with mutations that lead to defective receptors for IL-12 or IFN␥ (13), supporting a pivotal role of IFN␥ in the defense against these intracellular pathogens. This suggests that IFN␥ is crucial for host defense against Salmonella and Mycobacterium species only, whereas mechanisms of defense against other pathogens utilize redundant pathways.…”