Outpacing infectious disease: Mimicking the host-pathogen microenvironment in three-dimensions

In the past decade, a paradigm shift has occurred from the use of conventional two-dimensional (2-D) monolayer cultures to organotypic three-dimensional (3-D) cell culture models for infectious disease research. Central to this effort has been the NASA-designed rotating wall vessel (RWV) bioreactor, which has enabled the generation of organotypic 3-D cell culture models derived from a variety of human tissues, including the small intestine, colon, lung, vaginal, bladder, and liver tissues. RWV-derived 3-D tissue culture models mimic key aspects of the differentiated structure and function of their respective in vivo parental tissues, including 3-D cytoarchitecture, barrier function, apical-basolateral polarity, apical secretion of mucins, and multicellular complexity. As a result, these 3-D cell culture models are attractive platforms to help bridge the gap between cell-based discoveries at the bench, and clinical translation. This chapter provides an overview of RWV-derived 3-D organotypic models of human tissues, with an emphasis on mucosal models, that have been applied for infectious disease research. The characteristics of parental tissues that the 3-D models mimic are discussed, as well as new insights gained into both host and pathogen responses during their interactions. Highlighted models include: (a) 3-D monotypic and immunocompetent co-culture intestinal models for studying the enteric pathogen Salmonella enterica serovar Typhimurium, (b) 3-D monotypic and immunocompetent lung models to investigate host responses to the opportunistic pathogen Pseudomonas aeruginosa and its toxins, and (c) a 3-D vaginal model used to parallel host cytotoxic responses to an anti-HIV spermicide. Additional 3-D models derived from other human cell types and subsequently applied to study the host-pathogen interaction with bacterial, viral, and protozoan pathogens are also discussed. The establishment, characterization, and validation of 3-D tissues generated using RWV bioreactor technology has offered researchers biologically meaningful human surrogates for expanding their knowledge regarding the in vivo infectious disease process in ways that are not possible with traditional flat 2-D monolayer cultures. Using in vitro models that mimic key in vivo features and host-pathogen responses will accelerate the development of therapeutic modalities to prevent and combat infectious disease.