Microarray analysis of the in vitro granulomatous response to Mycobacterium tuberculosis H37Ra

Reyes, Niradiz; Bettin, Alfonso; Reyes, Ismael; Geliebter, Jan

doi:10.25100/cm.v46i1.1570

Cited by 14 publications

(10 citation statements)

References 44 publications

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“…In this way, researchers hope to characterize the immunopathological changes consistent with productive infection leading to latency. in vitro granuloma models have been developed to study M. tuberculosis [29,[68][69][70][71][72][73][74][75][76], M. leprae [77], M. bovis [78], M. massiliense [79], and Map [44]. Unique iterations of the M. tuberculosis model were used to investigate resuscitation from latency [69,76], consequences of macrophage polarization [71], and effects of cytokine suppression on granuloma development [74].…”

Section: Discussionmentioning

confidence: 99%

Modelling Bovine Granuloma Formation In Vitro upon Infection with Mycobacterium Avium Subspecies Paratuberculosis

Rice

McDaniel

Holland

et al. 2019

Veterinary Sciences

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Mycobacterium avium subspecies paratuberculosis (Map) causes chronic granulomatous disease in cattle and ruminant livestock, causing substantial economic losses. Current vaccines delay clinical signs but cannot train the immune system to fully eradicate latent Map. During latency, Map uses host defenses, cage-like macrophage clusters called granuloma, as incubators for months or years. We used an in vitro model to investigate the early coordination of macrophages into granuloma upon Map infection over ten days. We found that at multiplicities of infection (MOI; Map:macrophages) of 1:2 and below, the macrophages readily form clusters and evolve pro-inflammatory cytokines in keeping with a cell-mediated immune response. At higher MOIs, viability of host macrophages is negatively impacted. At 1:4 MOI, we quantified viable Map in our model and confirmed that intracellular Map reproduced over the first five days of infection. Host cells expressed Type 1-specific cytokines, and Map-infected macrophages displayed reduced motility compared to Map-exposed, uninfected macrophages, suggesting an important role for uninfected macrophages in the early aggregative response. Reported is the first in vitro JD granuloma model capturing Map and macrophage viability, size distribution of resulting clusters, motility of monocyte-derived macrophages, and cytokine response during clustering, allowing quantitative analysis of multiple parameters of the Map-specific granulomatous response.

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Section: Discussionmentioning

confidence: 99%

Modelling Bovine Granuloma Formation In Vitro upon Infection with Mycobacterium Avium Subspecies Paratuberculosis

Rice

McDaniel

Holland

et al. 2019

Veterinary Sciences

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“…It is estimated that one third of the human population is infected with Mtb, predominantly in latent state. Only 10% of those infected with Mtb develop active TB disease over their lifetime, while 90% of otherwise healthy humans remain in a latent state following infection [ 4 , 5 ]; however the percentage of those with latent infection that develop active disease increases if they are immunocompromised, e.g., HIV or diabetes [ 1 ]. Inhaled bacteria that enter the lung airway and are ingested by alveolar macrophages which are highly regulated in their immune responses, and their ability to destroy digested bacteria is limited.…”

Section: Introductionmentioning

confidence: 99%

Modeling Granulomas in Response to Infection in the Lung

2016

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Alveolar macrophages play a large role in the innate immune response of the lung. However, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, which includes activated macrophages and lymphocytes, particularly T cells, is called upon to control the pathogens. This collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like Mycobacterium tuberculosis (Mtb). In the present work we develop a mathematical model of the dynamics of a granuloma by a system of partial differential equations. The ‘strength’ of the adaptive immune response to infection in the lung is represented by a parameter α, the flux rate by which T cells and M1 macrophages that immigrated from the lymph nodes enter into the granuloma through its boundary. The parameter α is negatively correlated with the ‘switching time’, namely, the time it takes for the number of M1 type macrophages to surpass the number of infected, M2 type alveolar macrophages. Simulations of the model show that as α increases the radius of the granuloma and bacterial load in the granuloma both decrease. The model is used to determine the efficacy of potential host-directed therapies in terms of the parameter α, suggesting that, with fixed dosing level, an infected individual with a stronger immune response will receive greater benefits in terms of reducing the bacterial load.

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“…It has been shown that lymphocytes in human PBMCs aggregates around infected bacteria to form assembly of micro-granulomas [34]. Furthermore, micro-granulomas are formed specifically in response to Mtb , whereas other microbes such as E.coli and S. aureus did not form these structures when incubated with human PBMCs [37].…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis WhiB3 maintains redox homeostasis and survival in response to reactive oxygen and nitrogen species

Mehta

Singh

2019

Free Radical Biology and Medicine

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Mycobacterium tuberculosis ( Mtb ) survives under oxidatively and nitosatively hostile niches inside host phagocytes. In other bacteria, adaptation to these stresses is dependent upon the redox sensitive two component systems ( e.g ., ArcAB) and transcription factors ( e.g ., FNR/SoxR). However, these factors are absent in Mtb . Therefore, it is not completely understood how Mtb maintains survival and redox balance in response to reactive oxygen species (ROS) and reactive nitrogen species (RNS). Here, we present evidences that a 4Fe-4S-cofactor containing redox-sensitive transcription factor (WhiB3) is exploited by Mtb to adapt under ROS and RNS stress. We show that Mtb Δ whiB3 is acutely sensitive to oxidants and to nitrosative agents. Using a genetic biosensor of cytoplasmic redox state (Mrx1-roGFP2) of Mtb , we show that WhiB3 facilitates recovery from ROS (cumene hydroperoxide and hydrogen peroxide) and RNS (acidified nitrite and peroxynitrite). Also, Mtb Δ whiB3 displayed reduced survival inside RAW 264.7 macrophages. Consistent with the role of WhiB3 in modulating host-pathogen interaction, we discovered that WhiB3 coordinates the formation of early human granulomas during interaction of Mtb with human peripheral blood mononuclear cells (PBMCs). Altogether, our study provides empirical proof that WhiB3 is required to mitigate redox stress induced by ROS and RNS, which may be important to activate host/bacterial pathways required for the granuloma development and maintenance.

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Microarray analysis of the in vitro granulomatous response to Mycobacterium tuberculosis H37Ra

Cited by 14 publications

References 44 publications

Modelling Bovine Granuloma Formation In Vitro upon Infection with Mycobacterium Avium Subspecies Paratuberculosis

Modelling Bovine Granuloma Formation In Vitro upon Infection with Mycobacterium Avium Subspecies Paratuberculosis

Modeling Granulomas in Response to Infection in the Lung

Mycobacterium tuberculosis WhiB3 maintains redox homeostasis and survival in response to reactive oxygen and nitrogen species

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