Modeling Host-Pathogen Interactions in the Context of the Microenvironment: Three-Dimensional Cell Culture Comes of Age
Year: 2018
Type: review
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.
Source: Infection and Immunity
DOI: 10.1128/iai.00282-18
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: bronze
Awards: Enterovirus Infection of Polarized Intestinal Cells, WHILE UNIQUE RESPONSES IN MICROORGANISMS ARE WELL DOCUMENTED FOR SHORT DURATION CULTURE, THE IMPACT OF LONG DURATION, MULTIGENERATIONAL GROWTH OF MIC, A MAJOR CHALLENGE IN MITIGATING INFECTIOUS DISEASE RISKS DURING SPACEFLIGHT IS TO UNDERSTAND MODEL AND INTEGRATE THE COMBINED ACTION OF CELLULAR MOLECULAR AND BIOCHEMICAL NETWORKS IN THE HOST THAT POTENTIATE TRANSITION TO DISEASE IN RESPONSE TO INFECTION BY PATHOGENS CULTURED INMICROGRAVITY. THIS IS A CRITICAL ISSUE TO ADDRESS AS SPACEFLIGHT NEGATIVELY IMPACTS CREW IMMUNE FUNCTION ANDALTERS MICROBIAL VIRULENCE GENE EXPRESSION AND ANTIMICROBIAL RESISTANCE STRONGLY SUGGESTING AN INCREASED RISK FOR IN-FLIGHT INFECTIOUS DISEASE. HEREIN WE PROPOSE TO APPLY OUR 3-D INTESTINAL CO-CULTURE MODELS AS HUMAN SURROGATES TO CHARACTERIZE THEIR TRANSCRIPTOMIC (VIA RNA-SEQ) METABOLOMIC (VIA MASS SPECTROMETRY) AND INFLAMMATORY RESPONSES TO INFECTION WITH SPACEFLIGHT ANALOGUE AND CONTROLCULTURED SALMONELLA TYPHIMURIUM. TO FACILITATE A PRACTICAL INTEGRATION OF THESE SYSTEMS THE COMBINED ANALYSIS PROPOSED IN THIS STUDY WILL FOCUS ON THE METABOLOMIC SUBSET ASSOCIATED WITH HOST OXIDATIVE STRESS REDOX AND INFLAMMATORY RESPONSES. THESE FACTORS ARE OF KEYIMPORTANCE IN THE INFECTION PROCESS AND MAY CONTRIBUTE TO REPORTED ABNORMALITIES AND DYSFUNCTION IN THE CREWS' IMMUNE SYSTEM DURING FLIGHT. WE WILL USE SYSTEMS MODELING APPROACHES BASED ON BOTH QUANTITATIVE GENE TRANSCRIPT AND BIOCHEMICAL METABOLITE CORRELATION AND ALL OF THEIR KNOWN/INFERABLE RELATIONSHIPS BETWEEN GENES PROTEINS PATHWAYS AND BIOCHEMISTRY THAT WILL ALLOW US TO FORM NEW BRIDGES AND A GENERAL FRAMEWORK FOR MAKING THESE LINKAGES BETWEEN GENE EXPRESSION (RNA-SEQ) AND BIOCHEMICAL (METABOLOMIC) DATA. THIS APPROACH WILL ALLOW FOR NEW INSIGHTS INTO RELATIONSHIPS BETWEEN REDOX FUNCTIONS OXIDATIVE STRESS INFLAMMATION AND INFECTION THAT EITHERAPPROACH ALONE WOULD NOT BE ABLE TO ACHIEVE. BY EXPLORING INTERCONNECTIONS BETWEEN THESE SYSTEMS OVER DIFFERENT KINETIC TIMEPOINTS BEFORE AND AFTER INFECTION THIS SYSTEMATIC APPROACH WILL PROVIDE AN UNPARALLELED LEVEL OF SENSITIVITY AND RESOLUTION OF THE DYNAMICS OF THE HOST RESPONSE TO A MICROGRAVITY-ANALOGUE CULTURED PATHOGEN WHICH MAY LEAD TO IDENTIFLCATION OF NOVEL INFECTION MECHANISMS AND STRATEGIES FOR PREVENTION AND CONTROL., Graduate and Undergraduate Training in Biomedicine at ASU, Definition of the Microenvironment in Breast Cancer
OpenAlex ID: W2890360767