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Review
. 2018 Oct 25;86(11):e00282-18.
doi: 10.1128/IAI.00282-18. Print 2018 Nov.

Modeling Host-Pathogen Interactions in the Context of the Microenvironment: Three-Dimensional Cell Culture Comes of Age

Jennifer Barrila  1 , Aurélie Crabbé  2 , Jiseon Yang  1 , Karla Franco  1 , Seth D Nydam  1 , Rebecca J Forsyth  1 , Richard R Davis  1 , Sandhya Gangaraju  1 , C Mark Ott  3 , Carolyn B Coyne  4 , Mina J Bissell  5 , Cheryl A Nickerson  6   7
Affiliations
Review

Modeling Host-Pathogen Interactions in the Context of the Microenvironment: Three-Dimensional Cell Culture Comes of Age

Jennifer Barrila et al. Infect Immun. .

Abstract

Tissues and organs provide the structural and biochemical landscapes upon which microbial pathogens and commensals function to regulate health and disease. While flat two-dimensional (2-D) monolayers composed of a single cell type have provided important insight into understanding host-pathogen interactions and infectious disease mechanisms, these reductionist models lack many essential features present in the native host microenvironment that are known to regulate infection, including three-dimensional (3-D) architecture, multicellular complexity, commensal microbiota, gas exchange and nutrient gradients, and physiologically relevant biomechanical forces (e.g., fluid shear, stretch, compression). A major challenge in tissue engineering for infectious disease research is recreating this dynamic 3-D microenvironment (biological, chemical, and physical/mechanical) to more accurately model the initiation and progression of host-pathogen interactions in the laboratory. Here we review selected 3-D models of human intestinal mucosa, which represent a major portal of entry for infectious pathogens and an important niche for commensal microbiota. We highlight seminal studies that have used these models to interrogate host-pathogen interactions and infectious disease mechanisms, and we present this literature in the appropriate historical context. Models discussed include 3-D organotypic cultures engineered in the rotating wall vessel (RWV) bioreactor, extracellular matrix (ECM)-embedded/organoid models, and organ-on-a-chip (OAC) models. Collectively, these technologies provide a more physiologically relevant and predictive framework for investigating infectious disease mechanisms and antimicrobial therapies at the intersection of the host, microbe, and their local microenvironments.

Keywords: 3-D; 3D; RWV; gut-on-a-chip; host-microbe interaction; host-pathogen interactions; mechanotransduction; organ-on-a-chip; organoid; rotating wall vessel.

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Figures

FIG 1
FIG 1
Recreating the complex intestinal microenvironment to study host-pathogen interactions. (A) In vitro model advancement from 2-D to 3-D by incorporation of physiological factors to better mimic the in vivo environment. (Intestinal lumen, cell, intestine, and intestinal microbe images are republished from references to , respectively, with permission of the publisher.) (B) Three-dimensional approaches routinely used to develop advanced intestinal models: (a) RWV bioreactor, (b) (republished from reference with permission of the publisher), and (c) OAC (republished from reference with permission of the publisher). (d) Scanning electron micrograph (SEM) showing an RWV colon model. (Republished from PLoS One [152].) (e) Light micrograph of an enteroid model. (Republished from Physiological Reports [240].) (f) SEM of a gut-on-a-chip model (republished from reference with permission of the publisher). (g) Oxygen-dependent host cell colocalization of S. Typhimurium in an RWV 3-D coculture model of intestinal epithelium and macrophages. Following aerobic culture of bacteria, no macrophages were found, but following microaerobic culture, macrophages were present and either were empty (left inset) or contained internalized bacteria (right inset). Macrophages (CD45; yellow), Salmonella (green; white when overlaid with CD45), and nuclei (4′,6-diamidino-2-phenylindole [DAPI]; blue) are visible. Scale bar = 10 μm. (Republished from npj Microgravity [171].) (h) iHIOs injected with E. coli O157:H7. Nuclei (blue), neutrophils (CD11b; red), and E. coli (green) are visible. Scale bar = 100 μm. (Republished from PLoS One [260].) (i) CVB-infected gut-on-a-chip. CVB (green), F-actin (red), and nuclei (blue) are visible. (Republished from PLoS One [343].)
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