In Vitro Granuloma Models of Tuberculosis: Potential and Challenges

Abstract

Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.

TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

“…Despite IL-17A being actively released upon in-vitro granuloma formation, the presence of SEK did not trigger Mtb resuscitation within granulomas, supporting independently a previous report [35]. As reviewed recently [67], PBMC-based, in-vitro granuloma models usually lack neutrophils, non-hematopoieticderived cells, vascularization, plasticity, and continuous influx of freshly recruited immune cells, which constitute important limitations. Since not all cellular targets of IL-17A (e.g.…”

Topologically correct synthetic reconstruction of pathogen social behavior found in deep tissue sites

“…These pathogen-immune cell aggregates are intricate structures in which the pathogen interfaces with host cells, but also result in significant self and social interactions, making it difficult to reproduce in culture the entire set of events present in tissue. Although there is considerable research on infectious lesions caused by these pathogens, there are few informative culture models that reconstruct the pathogen-immune cell architecture occurring in tissues that preserve inter-microbial interactions (Elkington et al, 2019; Fitzgerald et al, 2014; Fonseca et al, 2017; Guggenberger et al, 2012; Guirado et al, 2015).…”

Multinucleated Giant Cell Formation as a Portal to Chronic Bacterial Infections

“…With the complex nature of Bpm pathogenesis culminating in cell fusion events and granuloma-like lesion formation in chronic cases, it would be very useful to adapt some of the advanced cell culture techniques to study MNGCs and granuloma formation in systems that more closely resemble the organs where the events take place. The tuberculosis field has made significant progress in this area and many novel in vitro techniques have been used to define the role of these cell structures in the pathology of M. tuberculosis [ 49 ]. Because of the similarities between melioidosis and tuberculosis, the adoption of these methods to study melioidosis is attractive but limited in scope because the primary focus is the lung.…”