Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron.

Byrd, Thomas F.; Horwitz, Marcus A.

doi:10.1172/jci114038

Cited by 299 publications

(265 citation statements)

References 48 publications

(36 reference statements)

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“…We demonstrated that, in vitro, activation by IL-4 elicits a host macrophage type that is less hostile to intracellular M. tuberculosis, due to several factors including transcriptional regulation of arginase 1/iNOS and TfR. IFN-c activation down-regulates TfR expression [81], resulting in decreased iron uptake by the host cell [82], and IL-4 antagonizes the inhibitory effect of IFN-c activation on TfR mRNA expression [47]. Here, we demonstrate that during M. tuberculosis infection alternatively activated macrophages strikingly differ from classically activated macrophages in their ability to down-regulate TfR expression and that iron availability to intracellular M. tuberculosis is increased by alternative activation, as shown by down-regulation of mycobactin synthesis and up-regulation of bacterioferritin transcripts.…”

Section: Discussionmentioning

confidence: 87%

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

et al. 2006

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A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4-and IFN-c-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis.

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Section: Discussionmentioning

confidence: 87%

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

et al. 2006

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“…Non-specific adherence of bacteria to tissue culture wells can lead to overgrowth of the bacteria in tissue culture media and spurious results. Progression of infection in MDM monolayers is dependent on M. abscessus spreading from initially infected macrophages to uninfected macrophages as occurs with intracellular bacterial pathogens such as Legionella pneumophila (Byrd & Horwitz, 1989). Although M. abscessus can multiply to a limited extent in tissue culture medium, extensive washing of monolayers after initial infection and at time points throughout the experiment minimizes extracellular growth as an artefact (Greendyke & Byrd, 2008).…”

Section: Methodsmentioning

confidence: 99%

Deletion of the mmpL4b gene in the Mycobacterium abscessus glycopeptidolipid biosynthetic pathway results in loss of surface colonization capability, but enhanced ability to replicate in human macrophages and stimulate their innate immune response

et al. 2011

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Mycobacterium abscessus is considered to be the most virulent of the rapidly growing mycobacteria. Generation of bacterial gene knockout mutants has been a useful tool for studying factors that contribute to virulence of pathogenic bacteria. Until recently, the optimal genetic approach to generation of M. abscessus gene knockout mutants was not clear. Based on the recent identification of genetic recombineering as the preferred approach, a M. abscessus mutant was generated in which the gene mmpL4b, critical to glycopeptidolipid synthesis, was deleted. Compared to the previously well-characterized parental strain 390S, the mmpL4B deletion mutant had lost sliding motility and the ability to form biofilm, but acquired the ability to replicate in human macrophages and stimulate macrophage Toll-like receptor 2. This study demonstrates that deletion of a gene associated with expression of a cell-wall lipid can result in acquisition of an immunostimulatory, invasive bacterial phenotype and has important implications for the study of M. abscessus pathogenesis at the cellular level.

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“…Human mononuclear cells were isolated from buffy coats purchased from United Blood Services and cultured as described by Byrd & Horwitz (1989). After 48 h, cells were harvested and monocytes isolated by adherence to Primaria flat-bottomed wells (24 multiwell Falcon plates, Becton Dickinson), in Iscoves medium containing 10 % normal human serum at concentrations of approximately 1610 5 monocytes per well (500 ml) for 90 min in 5 % CO 2 /95 % air at 37 uC.…”

Section: Methodsmentioning

confidence: 99%

Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis

Pang

Byrd³

et al. 2007

Microbiology

157

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Two-component systems are important constituents of bacterial regulatory networks. Results of this investigation into the role of the MprAB two-component system of Mycobacterium tuberculosis indicate that it is associated with the regulation of several stress-responsive regulons. Using a deletion mutant lacking portions of the response regulator, MprA, and the histidine kinase, MprB, it was demonstrated by real-time PCR, primer extension analyses and DNA microarrays that MprAB activates sigma factor genes sigE and sigB, under SDS stress and during exponential growth. SDS-inducible, MprA-dependent transcriptional start points were identified for mprA, sigE and sigB, and variations in distance between these points and MprA-binding sites suggest that MprA is involved in different mechanisms of promoter activation. Although most of the SigE regulon was downregulated in the deletion mutant, the cluster of genes Rv1129c, Rv1130 and Rv1131, which is associated with growth in monoctyes, was upregulated in the deletion mutant under SDS stress, and this upregulation was dependent upon atmospheric growth conditions. Multiple stress-associated genes of the DosR, SigD and IdeR regulons were also upregulated in the deletion mutant, during exponential growth and/or in the presence of SDS. Surprisingly, the deletion mutant had increased resistance to SDS compared to the parental strain, and enhanced growth in human peripheral blood monocytes, characteristics which may result from a loss of repression of stress-associated genes. INTRODUCTIONAs evidenced by its historical and current impact on human populations (Corbett & Raviglione, 2005;Zink et al., 2005), Mycobacterium tuberculosis is a highly successful pathogen. To withstand the challenges of aerosol transmission, growth within host macrophages, and prolonged encapsulation within lung granuloma, these organisms require the ability to respond to different types of stress. M. tuberculosis has 13 sigma factors (Cole et al., 1998), and DNA microarray analyses have shown the importance of several of these in regulating the changes in gene expression patterns associated with various stresses (Geiman et al., 2004;Manganelli et al., 2001Manganelli et al., , 2002. In addition to sigma factors, the response regulators of some two-component systems (TCSs) (Rison et al., 2005), such as DosR (Kendall et al., 2004;Park et al., 2003) and PhoP Perez et al., 2001;Walters et al., 2006), and other transcriptional regulators, such as IdeR (Dussurget et al., 1999;Manabe et al., 2005) and EmbR (Sharma et al., 2006), have been shown to modulate mycobacterial gene expression in response to particular stresses. However, in general, the mechanisms by which M. tuberculosis senses a particular stress, and activates the appropriate regulatory factor(s) while inhibiting others, are largely unknown. The GEO accession numbers for the array data associated with this paper are GSM155424-155447 (series record no. GSE6750).Four supplementary tables are available with the online version of this paper.Abbreviati...

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Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron.

Cited by 299 publications

References 48 publications

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

Deletion of the mmpL4b gene in the Mycobacterium abscessus glycopeptidolipid biosynthetic pathway results in loss of surface colonization capability, but enhanced ability to replicate in human macrophages and stimulate their innate immune response

Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis

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