Understanding infectious disease risks during spaceflight is critical to provide safe passage for human space exploration and holds potential for innovations in infectious disease control for the general public. The key to this research is the novel way that cells adapt and respond to spaceflight, as they exhibit important biological characteristics that are directly relevant to human health and disease including changes in immune function, cellular stress responses, and infectious disease potential that are not observed using traditional experimental approaches. We discovered that spaceflight uniquely alters the virulence and gene expression of the bacterial pathogen Salmonella typhimurium, and that the conserved, small regulatory RNA-binding protein, Hfq, plays a central role in regulating the Salmonella spaceflight response. We have subsequently shown that spaceflight culture also alters the Hfq regulon in other bacterial pathogens. As Hfq regulation is often associated with ionic salt concentrations, we discovered that altering the concentration of certain ionic salts, like phosphates, in the growth media prevents the increased disease causing potential of Salmonella during spaceflight. Collectively, our results suggest that RNA binding regulatory proteins and their small RNA binding counterparts may be key to a conserved, common cellular spaceflight response mechanism in bacterial cells that can be manipulated by environmental salt/ion levels. The implications of our findings would affect NASA’s approach to infectious disease risk assessment, development of biological processing systems for exploration, and other mission-related functions. Knowledge gained from this work will broaden our knowledge of microbial cells for both spaceflight and Earth based applications and holds translational potential for the development of vaccines and therapeutics for the general public.