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

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.

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

“…Recreation of the 3D microenvironment is crucial to model the initiation and progression of host–pathogen interactions in vitro . PHH in the MPCC model is permissive to infection by Plasmodium falciparum , the most virulent parasite responsible for most malaria‐related deaths.…”

Organoids – New Models for Host–Helminth Interactions

“…Part of this revolution has been in their use for a better understanding of host-pathogen interactions. Organoid models have been used to investigate viral, bacterial, and protozoan parasite infections [1,[3][4][5][6].…”

“…Currently, organoids are used as models of different pathologies, including infectious diseases caused by viruses, bacteria, and protozoans [3][4][5]. Viral infection studies with organoid systems have included: norovirus, rotavirus, enteric adenovirus, and coronavirus invasion of intestinal organoids [3][4][5][6]; herpes simplex virus 1 [23] and cytomegalovirus [24] infection of cerebral organoids; Zika virus infection of cerebral [4,5] and human testicular organoids [25]; human airway organoids to model pathology and assess infectivity of emerging influenza [26], parainfluenza [27] and respiratory syncytial viruses [28]; BK virus infection in human kidney tubuloids [29]; and human liver organoids to study infection with hepatitis B and its related tumorigenesis [30].…”

“…Organoid models of bacterial pathogenesis include enterohaemorrhagic, enteroaggregative, and enteropathogenic Escherichia coli, Vibrio cholerae, Salmonella, Clostridium difficile, and Shigella infecting intestinal organoids of mouse, bovine, porcine, and human origin [3][4][5][6]31], as well as Helicobacter pylori colonizing gastric (stomach) organoids [4][5][6]. In addition, the involvement of bacteria in adenocarcinoma formation in gallbladders has been studied using murine gallbladder organoids infected with Salmonella [4,5].…”

“…Tuft cells: chemosensory cells with blunt apical microvilli, found in the thymus and hollow organs or tubes lined by an epithelium such as the urinary tract, the digestive and respiratory systems. experiments using organoids are currently subject to variability due to inherent heterogeneity in size, shape, structural organization and functional capacity, and batch variability of both the ECM and growth factors used in culture [3,16,53].…”