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.