Heme oxygenase-1 promotes granuloma development and protects against dissemination of mycobacteria (original) (raw)
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Mycobacterium avium Infection and Modulation of Human Macrophage Gene Expression
The Journal of Immunology, 2002
Mycobacterium avium is a facultative intracellular pathogen cleared rapidly via intact host defense mechanisms. In the absence of adequate T cell function, as occurs in HIV-1-induced immunodeficiency, M. avium becomes an opportunistic infection with uncontrolled replication and reinfection of macrophage hosts. How M. avium infects, survives, and replicates in macrophages without signaling an effective microbicidal counterattack is unresolved. To address whether M. avium signals the expression of molecules, which influence mycobacterial survival or clearance, human monocyte-derived macrophage cultures were exposed to M. avium. Within minutes, M. avium, or its cell wall lipoarabinomannan, binds to the adherent macrophages and induces a spectrum of gene expression. In this innate response, the most abundant genes detected within 2 h by cDNA expression array involved proinflammatory chemokines, cytokines including TNF-␣ and IL-1, and adhesion molecules. Associated with this rapid initial up-regulation of recruitment and amplification molecules was enhanced expression of transcription factors and signaling molecules. By 24 h, this proinflammatory response subsided, and after 4 days, when some bacteria were being degraded, others escaped destruction to replicate within intracellular vacuoles. Under these conditions, inducible NO synthase was not up-regulated and increased transferrin receptors may facilitate iron-dependent mycobacterial growth. Sustained adhesion molecule and chemokine expression along with the formation of multinucleated giant cells appeared consistent with in vivo events. Thus, in the absence of T lymphocyte mediators, macrophages are insufficiently microbicidal and provide a nonhostile environment in which mycobacteria not only survive and replicate, but continue to promote recruitment of new macrophages to perpetuate the infection.
The Journal of Infectious Diseases, 2008
Background. The acute phase of mycobacterial lung infection is characterized by a nearly exponential outgrowth of mycobacteria in the alveolar airspace and lung parenchymal tissue, suggesting insufficient early protective immunity against mycobacterial challenge. In the current study, we tested the hypothesis that a CC chemokine ligand 2 (CCL2)-dependent increased mononuclear phagocyte subset accumulation in distal airspaces would improve the lungs' protective immunity to infection with Mycobacterium bovis bacille Calmette-Guérin (hereafter, "M. bovis BCG"). Methods. Wild-type mice and CCL2-overexpressing mice that exhibited increased pools of alveolar and lung mononuclear phagocytes-due to the lung-specific overexpression of human CCL2 in type-II alveolar epithelial cells-were infected intratracheally with M. bovis BCG and the developing lung inflammatory response was analyzed. Results. CCL2-overexpressing mice demonstrated significantly decreased mycobacterial loads in the bronchoalveolar space, lung parenchymal tissue, and spleen compared with wild-type mice, when both groups of mice were infected with M. bovis BCG. Moreover, in M. bovis BCG-infected mice, later-developing, accelerated resolution of lung granuloma formation was noted, particularly in CCL2-overexpressing mice as compared with wild-type mice. In addition, CCL2-overexpressing mice demonstrated an increased trafficking of mycobacteria-loaded dendritic cells towards lung-draining lymph nodes that was found to coincide with increased mycobacterial loads in this compartment. Conclusions. The data of the current study suggest that CCL2-dependent amplification of endogenous hostdefense programs in the lung may improve the lungs' protective immunity against mycobacterial infections.
Mycobacterium aviumReduces Expression of Costimulatory/Adhesion Molecules by Human Monocytes
Cellular Immunology, 1997
understanding of the mechanisms which this mycobacterium uses to ensure its survival within Mf may lead Organisms of the Mycobacterium avium complex surto development of improved therapy. A number of invive the hostile environment of their host cells, the tracellular pathogens such as Leishmania donovani macrophages, and evade immune response, in part, by perturb the costimulatory activity of Mf (2). It is coninterfering with processing and presentation of antigen. We studied the effect of infection with M. avium ceivable that MAC exerts similar effects on Mf. To on the expression of the costimulatory/adhesion mole-determine the influence of this organism on the cocules (referred to herein as accessory molecules) bestimulatory activity of its host cells, we analyzed hucause generating an efficient T cell response requires man peripheral blood monocytes infected in vitro with both the recognition of processed antigen and the par-MAC for: (i) the expression of accessory (AC) molecules, ticipation of accessory molecules. Human peripheral and (ii) the support of antigen (Ag)-independent prolifblood monocytes displayed reduced levels of CD54, eration of autologous CD4 / T cells. CD58, and CD86 molecules 1 day after in vitro infec-MAC, an intracellular facultative bacillus, resides tion. The reduction in the expression of accessory moland multiplies primarily in membrane-bound phagoecules was not mediated by endogenous IL-10 or prossomes within Mf (3). Like other member of its species, taglandin because monocytes infected in the presence MAC ensures its intramacrophage survival by limiting of either anti-IL-10 neutralizing antibody or indomeththe fusion of bacilli-containing vacuoles with the endoacin did not express normal levels of surface CD54, somal system of Mf (4-6). Particles phagocytosed by CD58, and CD86 molecules. Consistent with these phe-Mf are normally delivered into an acidic lysosomal notypic changes, M. avium-infected monocytes were compartment for degradation. Although bacilli-laden less effective in supporting Ag-independent proliferaphagosomes are not completely isolated from the endotion of autologous CD4 / T cells. ᭧ 1997 Academic Press somal network (5-8), by regulating the maturation of their vacuoles MAC impedes Mf processing and presentation of Ag. Immunity to mycobacteria is cell-medi-1 This work was supported, in part, by grants from the National ent Ag. Institute of Health (AI25769 and AI35190) and the Adelaid and Ed-Optimal activation of naive T cells requires both ocward Williams Research Funds.
Vaccine, 2009
In this study, we have compared the immunological responses associated with early pulmonary mycobacterial infection in two mouse strains, BALB/c and C57BL/6 known to exhibit distinct differences in susceptibility to infection with several pathogens. We infected mice via the intranasal route. We have demonstrated that BALB/c was less able to control mycobacterial growth in the lungs during the early phase of pulmonary infection. Our results showed that during the early phase (day 3 to week 1), BALB/c mice exhibited a delay in the production of TNF and IFN-gamma in the lungs compared to C57BL/6 mice. Levels of IL-12 and soluble TNF receptors (sTNFR) were comparable between the mouse strains. The cellular subset distribution in these mice before and after infection showed a higher increase in CD11b+ cells in the lungs of C57BL/6, compared to BALB/c as early as day 3 postinfection. At early time points, higher levels of monocyte chemoattractant protein (MCP)-1 and macrophage inflammator...
Cellular Microbiology, 2007
Little is known about the activation programme induced in alveolar macrophages upon phagocytosis of mycobacteria and the concomitant mononuclear phagocyte migratory responses that shape the acute phase of mycobacterial infection. Using high-speed cell sorting in conjunction with real-time RT-PCR analysis, we show that sorted alveolar macrophages of transgenic CX3CR1 +/GFP mice infected with red fluorescent-labelled Mycobacterium bovis BCG exhibited weak transcriptional changes of lysosomal cathepsins B, L, D, K and S, whereas antimicrobial cathepsin G was strongly induced upon infection. Moreover, mRNA levels of pattern recognition receptors TLR2, TLR4 and NOD2 were downregulated as were neutrophil chemoattractants KC, MIP-2 and IP-10, whereas highly upregulated mRNA levels of the monocyte chemoattractant CCL2 were observed. M. bovis BCG infection of the mice elicited the alveolar accumulation of highly CX 3CR1-positive alveolar dendritic cells but not neutrophils within the alveolar compartment, whereas no increased accumulation of CX3CR1 high lung parenchymal dendritic cells (lung DC) or CX3CR1 neg lung macrophages compared with controls was noted. In contrast, CX3CR1 +/GFP mice previously immunized with M. bovis BCG rapidly responded with increased accumulations of both CX 3CR1 high alveolar and lung parenchymal DC and CX3CR1 neg lung macrophages upon intratracheal M. bovis BCG challenge. Moreover, alveolar and lung macrophages and lung DC were found to contribute to early uptake of M. bovis BCG. Together, acute mycobacterial infection triggers both rapid changes in gene expression profiles in infected alveolar macrophages and a compartment-specific accumulation of mononuclear phagocyte subsets contributing to M. bovis BCG uptake in vivo.
Infection and Immunity, 2015
The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis , using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain of Mycobacterium avium . In this work, a mouse strain deleted of the hypoxia inducible factor 1α (HIF-1α) under the Cre-lox system regulated by the lysozyme M gene promoter was...
Infection and Immunity, 2015
The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology ofMycobacterium tuberculosis, using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain ofMycobacterium avium. In this work, a mouse strain deleted of the hypoxia inducible factor 1α (HIF-1α) under the Cre-lox system regulated by the lysozyme M gene promoter was use...
Infection and immunity, 2015
Mycobacterium avium subsp. hominissuis" is an opportunistic environmental pathogen that causes respiratory illness in immunocompromised patients, such as those with cystic fibrosis as well as other chronic respiratory diseases. Currently, there is no efficient approach to prevent or treat M. avium subsp. hominissuis infection in the lungs. During initial colonization of the airways, M. avium subsp. hominissuis forms microaggregates composed of 3 to 20 bacteria on human respiratory epithelial cells, which provides an environment for phenotypic changes leading to efficient mucosal invasion in vitro and in vivo. DNA microarray analysis was employed to identify genes associated with the microaggregate phenotype. The gene encoding microaggregatebinding protein 1 (MBP-1) (MAV_3013) is highly expressed during microaggregate formation. When expressed in noninvasive Mycobacterium smegmatis, MBP-1 increased the ability of the bacteria to bind to HEp-2 epithelial cells. Using anti-MBP-1 immune serum, microaggregate binding to HEp-2 cells was significantly reduced. By far-Western blotting, and verified by coimmunoprecipitation, we observed that MBP-1 interacts with the host cytoskeletal protein vimentin. As visualized by confocal microscopy, microaggregates, as well as MBP-1, induced vimentin polymerization at the site of bacterium-host cell contact. Binding of microaggregates to HEp-2 cells was inhibited by treatment with an antivimentin antibody, suggesting that MBP-1 expression is important for M. avium subsp. hominissuis adherence to the host cell. MBP-1 immune serum significantly inhibited M. avium subsp. hominissuis infection throughout the respiratory tracts of mice. This study characterizes a pathogenic mechanism utilized by M. avium subsp. hominissuis to bind and invade the host respiratory epithelium, suggesting new potential targets for the development of antivirulence therapy. " M ycobacterium avium subsp. hominissuis" is an environmen
A new model of chronic Mycobacterium abscessus lung infection in immunocompetent mice
2020
Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of MA pulmonary infection. To overcome this challenge we refined the method of agar beads to establish MA chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after MA infection. In this model, MA was able to establish a persistent lung infection up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of neutrophils, lymphocytes and aggregates of vacuolated foamy cell...