Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model

Tezera, Liku B.; Bielecka, Magdalena K; Chancellor, Andrew; Reichmann, Michaela T; Shammari, Basim R. Al; Brace, Patience; Batty, Alex; Tocheva, Annie; Jogai, Sanjay; Marshall, Ben G.; Tebruegge, Marc; Jayasinghe, Suwan N.; Mansour, Salah; Elkington, Paul

doi:10.7554/elife.21283

Cited by 67 publications

(73 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They then demonstrated that proteolytic collagen destruction of the lung ECM is the initial pathological event that reduces the survival of Mycobacterium tuberculosis ‐infected cells, resulting in caseous necrosis and cavitation, and so diverting the immune response in favour of the pathogen. Conversely, intact collagen fibrils increase survival of infected cells . In line with this, Parasa et al .…”

Section: The Ecm: An Integral Part Of the Innate Immune Response To Imentioning

confidence: 62%

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

2018

View full text Add to dashboard Cite

The role of the host extracellular matrix (ECM) in infection tends to be neglected. However, the complex interactions between invading pathogens, host tissues and immune cells occur in the context of the ECM. On the pathogen side, a variety of surface and secreted molecules, including microbial surface components recognizing adhesive matrix molecules and tissue-degrading enzymes, are employed that interact with different ECM proteins to effectively establish an infection at specific sites. Microbial pathogens can also hijack or misuse host proteolytic systems to modify the ECM, evade immune responses or process biologically active molecules such as cell surface receptors and cytokines that direct cell behaviour and immune defence. On the host side, the ECM composition and three-dimensional ultrastructure undergo significant modifications, which have a profound impact on the specific signals that the ECM conveys to immune cells at the forefront of infection. Unexpectedly, activated immune cells participate in the remodelling of the local ECM by synthesizing ECM glycoproteins, proteoglycans and collagen molecules. The close interplay between the ECM and the innate immune response to microbial pathogens ultimately affects the outcome of infection. This review explores and discusses recent data that implicate an active role for the ECM in the immune response to infection, encompassing antimicrobial activities, microbial recognition, macrophage activation, phagocytosis, leucocyte population balance, and transcriptional and post-transcriptional regulation of inflammatory networks, and may foster novel antimicrobial approaches.

show abstract

Section: The Ecm: An Integral Part Of the Innate Immune Response To Imentioning

confidence: 62%

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

2018

View full text Add to dashboard Cite

show abstract

“…To validate the successful establishment of a microscale in vitro granuloma model within our platform, we used three separate previously reported readouts: 1) aggregate formation, 2) encapsulation of the mycobacterium within host immune cells, and 3) soluble factor analysis. (Birkness et al 2007; Kapoor et al 2013; Crouser et al 2017; Tezera et al 2017) After initiating infection by mixing MDMs and BCG into the ECM (collagen I) and seeding it into the wells, we consistently observed aggregate formation in the granuloma layer containing BCG when wells were fixed and imaged on Day 4 post infection (p.i.) (Figure 2).…”

Section: Resultsmentioning

confidence: 87%

“…(Peyron et al 2008) However, many of these in vitro models consist of granulomas grown inside of well plates(Peyron et al 2008; Birkness et al 2007; Kapoor et al 2013; Puissegur et al 2004; Crouser et al 2017), limiting the ability of the researchers to easily manipulate the microenvironment of the granulomas and increase the complexity of their granuloma models through multiculture and introduction of key components of the microenvironment on demand. Recently, more complex, biomimetic models have been developed that have successfully recapitulated important biological phenomena(Venkata Ramanarao Parasa et al 2014; Venkata R. Parasa et al 2017) and examined novel therapeutic approaches to combat TB infection (Tezera et al 2017; Bielecka et al 2017), while simultaneously demonstrating innovative and tractable platforms. However, these models face limitations in studies where users wish to subject granulomas to various microenvironmental cues over time, or in enabling the addition of tissue components after the model is established.…”

Section: Introductionmentioning

confidence: 99%

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

Berry

Gower

et al. 2020

Preprint

View full text Add to dashboard Cite

Tuberculosis (TB) is one of the most potent infectious diseases in the world, causing more deaths than any other single infectious agent. TB infection is caused by inhalation of Mycobacterium tuberculosis (Mtb) and subsequent phagocytosis and migration into the lung tissue by innate immune cells (e.g., alveolar macrophages, neutrophils, dendritic cells), resulting in the formation of a fused mass of immune cells known as the granuloma. Considered the pathological hallmark of TB, the granuloma is a complex microenvironment that is crucial for pathogen containment as well as pathogen survival. Disruption of the delicate granuloma microenvironment via numerous stimuli, such as variations in cytokine secretions, nutrient availability, and the makeup of immune cell population, can lead to an active infection. Herein, we present a novel in vitro model to examine the soluble factor signaling between a mycobacterial infection and its surrounding environment. Adapting a newly developed suspended microfluidic platform, known as Stacks, we established a modular microscale infection model containing human immune cells and a model mycobacterial strain that can easily integrate with different microenvironmental cues through simple spatial and temporal “stacking” of each module of the platform. We validate the establishment of suspended microscale (4 μL) infection cultures that secrete increased levels of proinflammatory factors IL-6, VEGF, and TNFα upon infection and form 3D aggregates (granuloma model) encapsulating the mycobacteria. As a proof of concept to demonstrate the capability of our platform to examine soluble factor signaling, we cocultured an in vitro angiogenesis model with the granuloma model and quantified morphology changes in endothelial structures as a result of culture conditions (P < 0.05 when comparing infected vs. uninfected coculture systems). We envision our modular in vitro granuloma model can be further expanded and adapted for studies focusing on the complex interplay between granulomatous structures and their surrounding microenvironment, as well as a complementary tool to augment in vivo signaling and mechanistic studies.

show abstract

“…Towards this end, a number of factors may have to be considered in ensuring clinical relevance (BOX 2). In this context, it is worth noting the parallel development and application to Mtb infection studies of increasingly sophisticated systems for three-dimensional cell culture (135,136) since these might offer a useful intermediate in bridging the in vitro / in vivo divide.…”

Section: Introductionmentioning

confidence: 99%

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

et al. 2018

View full text Add to dashboard Cite

Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 70(9):926-937, 2018.

show abstract

Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model

Cited by 67 publications

References 73 publications

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

Contact Info

Product

Resources

About