scholarly journals Role for Matrix Metalloproteinase 9 in Granuloma Formation during Pulmonary Mycobacterium tuberculosis Infection

2006 ◽  
Vol 74 (11) ◽  
pp. 6135-6144 ◽  
Author(s):  
Jennifer L. Taylor ◽  
Jessica M. Hattle ◽  
Steven A. Dreitz ◽  
JoLynn M. Troudt ◽  
Linda S. Izzo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Flow Cytometric Analysis ◽  
Mycobacterial Infection ◽  
Granuloma Formation ◽  
Mycobacterium Tuberculosis Infection ◽  
Resistant Mouse ◽  
Flow Cytometric ◽  
Aerosol Infection ◽  
Metalloproteinase 9

ABSTRACT Recent studies have shown that matrix metalloproteinases (MMPs) are induced by Mycobacterium tuberculosis during pulmonary infection. Here, expression of MMP-9 during pulmonary M. tuberculosis infection was characterized to determine whether its production correlated with disease resistance in vivo and to determine what role, if any, MMP-9 might have in granuloma formation. Following aerosol infection with M. tuberculosis, dissemination of bacilli occurred earlier in the C57BL/6 resistant mouse strain than in the susceptible CBA/J strain, as was evident from an increased number of bacteria in the blood, spleen, and liver at day 14 after infection. In addition, early dissemination of the bacilli was associated with early induction of protective immunity as assessed from gamma interferon levels. Nonspecific blocking of MMPs in C57BL/6 mice early during infection reduced hematogenous spread of the bacilli, suggesting that MMPs indeed play a role in facilitating dissemination, likely via extracellular matrix degradation. The concentration of active MMP-9, specifically, was greater in the lungs of C57BL/6 mice than in those of the CBA/J mice at day 28, thereby suggesting that MMP-9 is not one of the MMPs directly involved in promoting early dissemination of M. tuberculosis. Instead, however, histological lung sections and flow cytometric analysis of lung cells from MMP-9-knockout mice showed that MMP-9 is involved in macrophage recruitment and granuloma development. These combined data support the idea that early MMP activity is an essential component of resistance to pulmonary mycobacterial infection and that MMP-9, specifically, is required for recruitment of macrophages and tissue remodeling to allow for the formation of tight, well-organized granulomas.

scholarly journals The Purinergic P2X7 Receptor Is Not Required for Control of Pulmonary Mycobacterium tuberculosis Infection

2005 ◽  
Vol 73 (5) ◽  
pp. 3192-3195 ◽  
Author(s):  
Amy J. Myers ◽  
Brandon Eilertson ◽  
Scott A. Fulton ◽  
JoAnne L. Flynn ◽  
David H. Canaday
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
P2x7 Receptor ◽  
Low Dose ◽  
Wild Type ◽  
Mycobacterium Tuberculosis Infection ◽  
P2x7 Receptors ◽  
Purinergic P2x7 Receptor ◽  
Aerosol Infection

ABSTRACT The importance in vivo of P2X7 receptors in control of virulent Mycobacterium tuberculosis was examined in a low-dose aerosol infection mouse model. P2X7−/− mice controlled infection in lungs as well as wild-type mice, suggesting that the P2X7 receptor is not required for control of pulmonary M. tuberculosis infection.

scholarly journals Effects of Glutathione Diminishment on the Immune Responses against Mycobacterium tuberculosis Infection

2021 ◽  
Vol 11 (17) ◽  
pp. 8274
Author(s):  
Ruoqiong Cao ◽  
Afsal Kolloli ◽  
Ranjeet Kumar ◽  
James Owens ◽  
Kayvan Sasaninia ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Lung Parenchyma ◽  
Granuloma Formation ◽  
Therapeutic Approaches ◽  
Mycobacterium Tuberculosis Infection ◽  
Load Following ◽  
Tnf Α ◽  
Insight Into

Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), continues to be a global health burden. We have reported that patients with marked deficiency in the production of glutathione (GSH) had impaired granulomatous effector responses against M. tb infection, which were restored when supplementing patients with liposomal GSH (lGSH). However, the effects of GSH deficiency in the lung parenchyma in altering granuloma formation and effector responses against M. tb infection remain unexplored. We aim to elucidate the effects of diethyl maleate (DEM)-induced GSH deficiency during an active M. tb infection in an in vivo mouse model. We assessed for total and reduced GSH levels, malondialdehyde (MDA) levels, cytokine profiles, granuloma formation and M. tb burden. DEM administration significantly diminished total and reduced GSH levels in the lungs and plasma and increased MDA levels in infected mice compared to sham-treated controls. DEM treatment was also associated with an increase in IL-6, TNF-α and ill-formed granulomas in infected mice. Furthermore, M. tb survival was significantly increased along with a higher pulmonary and extrapulmonary bacterial load following DEM treatment. Overall, GSH deficiency led to increased oxidative stress, impaired granuloma response, and increased M. tb survival in infected mice. These findings can provide insight into how GSH deficiency can interfere with the control of M. tb infection and avenues for novel therapeutic approaches.

scholarly journals Three-dimensional in situ morphometrics of Mycobacterium tuberculosis infection within lesions by optical mesoscopy and novel acid-fast staining

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Robert J. Francis ◽  
Gillian Robb ◽  
Lee McCann ◽  
Bhagwati Khatri ◽  
James Keeble ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Three Dimensional ◽  
Large Field ◽  
Staining Procedure ◽  
3D Analysis ◽  
Mycobacterium Tuberculosis Infection ◽  
In Vivo Models ◽  
Novel Approach

AbstractTuberculosis (TB) preclinical testing relies on in vivo models including the mouse aerosol challenge model. The only method of determining colony morphometrics of TB infection in a tissue in situ is two-dimensional (2D) histopathology. 2D measurements consider heterogeneity within a single observable section but not above and below, which could contain critical information. Here we describe a novel approach, using optical clearing and a novel staining procedure with confocal microscopy and mesoscopy, for three-dimensional (3D) measurement of TB infection within lesions at sub-cellular resolution over a large field of view. We show TB morphometrics can be determined within lesion pathology, and differences in infection with different strains of Mycobacterium tuberculosis. Mesoscopy combined with the novel CUBIC Acid-Fast (CAF) staining procedure enables a quantitative approach to measure TB infection and allows 3D analysis of infection, providing a framework which could be used in the analysis of TB infection in situ.

scholarly journals Individual Mycobacterium tuberculosis Resuscitation-Promoting Factor Homologues Are Dispensable for Growth In Vitro and In Vivo

2004 ◽  
Vol 72 (1) ◽  
pp. 515-526 ◽  
Author(s):  
JoAnn M. Tufariello ◽  
William R. Jacobs, ◽  
John Chan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Stationary Phase ◽  
Essential Gene ◽  
Micrococcus Luteus ◽  
Expression Patterns ◽  
Active Growth ◽  
Prolonged Incubation ◽  
Aerosol Infection

ABSTRACT Mycobacterium tuberculosis possesses five genes with significant homology to the resuscitation-promoting factor (Rpf) of Micrococcus luteus. The M. luteus Rpf is a secreted ∼16-kDa protein which restores active growth to cultures of M. luteus rendered dormant by prolonged incubation in stationary phase. More recently, the Rpf-like proteins of M. tuberculosis have been shown to stimulate the growth of extended-stationary-phase cultures of Mycobacterium bovis BCG. These data suggest that the Rpf proteins can influence the growth of mycobacteria; however, the studies do not demonstrate specific functions for the various members of this protein family, nor do they assess the function of M. tuberculosis Rpf homologues in vivo. To address these questions, we have disrupted each of the five rpf-like genes in M. tuberculosis Erdman, and analyzed the mutants for their growth in vitro and in vivo. In contrast to M. luteus, for which rpf is an essential gene, we find that all of the M. tuberculosis rpf deletion mutant strains are viable; in addition, all show growth kinetics similar to Erdman wild type both in vitro and in mouse organs following aerosol infection. Analysis of rpf expression in M. tuberculosis cultures from early log phase through late stationary phase indicates that expression of the rpf-like genes is growth phase-dependent, and that the expression patterns of the five M. tuberculosis rpf genes, while overlapping to various degrees, are not uniform. We also provide evidence that mycobacterial rpf genes are expressed in vivo in the lungs of mice acutely infected with virulent M. tuberculosis.

scholarly journals Accuracy of the QuantiFERON-TB Gold in Tube for diagnosing tuberculosis in a young pediatric population previously vaccinated with Bacille Calmette-Guerin

2014 ◽  
Vol 32 (1) ◽  
pp. 04-10 ◽  
Author(s):  
Marcelo Genofre Vallada ◽  
Thelma Suely Okay ◽  
Gilda Maria B. Del Negro ◽  
Claudio Amaral Antonio ◽  
Lidia Yamamoto ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Roc Curve ◽  
Pediatric Population ◽  
Area Under The Curve ◽  
Mycobacterial Infection ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Assay Sensitivity ◽  
Negative Results ◽  
Release Assay

Objective: To evaluate the accuracy of an interferongamma release assay (QuantiFERON-TB Gold in Tube) for diagnosing Mycobacterium tuberculosis infection in a young pediatric population. Methods: 195 children previously vaccinated with BCG were evaluated, being 184 healthy individuals with no clinical or epidemiological evidence of mycobacterial infection, and 11 with Mycobacterium tuberculosis infection, according to clinical, radiological, and laboratory parameters. A blood sample was obtained from each child and processed according to the manufacturer's instructions. The assay performance was evaluated by a Receiver Operating Characteristic (ROC) curve. Results: In the group of 184 non-infected children, 130 (70.6%) were under the age of four years (mean age of 35 months). In this group, 177 children (96.2%) had negative test results, six (3.2%) had indeterminate results, and one (0.5%) had a positive result. In the group of 11 infected children, the mean age was 58.5 months, and two of them (18%) had negative results. The ROC curve had an area under the curve of 0.88 (95%CI 0.82-0.92; p<0.001), disclosing a predictive positive value of 81.8% for the test (95%CI 46.3-97.4). The assay sensitivity was 81.8% (95%CI 48.2-97.2) and the specificity was 98.8% (95%CI 96-99.8). Conclusions: In the present study, the QuantiFERON-TB Gold in Tube performance for diagnosing M. tuberculosis infection was appropriate in a young pediatric population.

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