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DOE OSTI2022

Structure of the glucosyltransferase domain of TcdA in complex with RhoA provides insights into substrate recognition

Clostridioides difficile is one of the most common causes of antibiotic-associated diarrhea in developed countries. As key virulence factors of C. difficile, toxin A (TcdA) and toxin B (TcdB) act by glucosylating and inactivating Rho and Ras family small GTPases in host cells, which leads to actin cytoskeleton disruption, cell rounding, and ultimately cell death. Here we present the co-crystal structure of the glucosyltransferase domain (GTD) of TcdA in complex with its substrate human RhoA at 2.60-angstrom resolution. This structure reveals that TcdA GTD grips RhoA mainly through its switch I and switch II regions, which is complemented by interactions involving RhoA’s pre-switch I region. Comprehensive structural comparisons between the TcdA GTD–RhoA complex and the structures of TcdB GTD in complex with Cdc42 and R-Ras reveal both the conserved and divergent features of these two toxins in terms of substrate recognition. Taken together, these findings establish the structural basis for TcdA recognition of small GTPases and advance our understanding of the substrates selectivity of large clostridial toxins.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRSDate not supplied

SPACEFLIGHT-INDUCED CHANGES IN MICROBIAL VIRULENCE AND THE IMPACT TO THE HOST IMMUNE RESPONSE

INTRODUCTION Over the past 50 years, microorganisms have displayed unexpected responses relevant to infectious disease when grown in microgravity and microgravity analogue environments, including changes in final cell concentration, biofilm production, stress resistance, antibiotic sensitivity, gene expression, and virulence. In parallel, astronaut studies have characterized a persistent spaceflight-induced dysregulation of the human immune system; consisting of altered leukocyte distribution, reductions in T and NK cell function, altered cytokine profiles, and reactivation of latent herpesviruses. Further, astronauts have some degree of clinical incidence, primarily infectious disease episodes and atopic dermatitis. The impact of the microgravity environment on host-pathogen interactions and potential for clinical disease remains understudied and poorly characterized. SPECIFIC AIMS In the Host-Microorganism, Microbial Response aspect of this study, the following Specific Aims are being investigated, using the microbial pathogens, Salmonella enterica Enteritidis, Pseudomonas aeruginosa, Burkholderia cepacia, Streptococcus pneumoniae, and enterohemorrhagic Escherichia coli. Aim 1: Characterize the effect of spaceflight analogue culture on microbial pathogenesis-related stress responses and in vitro host-pathogen interactions. Analysis will include microbial stress responses as well as colonization and viability following pathogen challenge of three-dimensional (3-D) tissue co-culture models containing immune cells. We specifically selected obligate and opportunistic pathogens that are medically important and have been or are likely to be found aboard spacecraft. Aim 2: Characterize the effect of spaceflight analogue culture on the virulence potential of pathogenic microorganisms. Changes in virulence will be assessed using a mouse model of infection. SIGNIFICANCE The goal of this study is to use spaceflight analogue conditions to gain insight into the breadth of medically-significant International Space Station microorganisms that have altered virulence and the impact of those changes on the immune response of the host, including astronaut immune cells. This information will provide critical understanding into the impact of microgravity on potential alterations in microbial virulence and associated infectious disease risk to crew health during spaceflight missions.

C. M. Ott↗

NASA NTRSDate not supplied

Spaceflight-induced Changes in Microbial Virulence and the Impact to the Host Immune Response

INTRODUCTION Over the past 50 years, many microorganisms have displayed unexpected responses relevant to infectious disease when grown in microgravity and microgravity analogue environments, including changes in stress resistance, biofilm production, antibiotic sensitivity, final cell concentration, gene expression, enhanced host-pathogen interaction, and virulence. In parallel, astronaut studies have characterized a persistent spaceflight-induced dysregulation of the human immune system; consisting of altered leukocyte distribution, reductions in T and NK cell function, altered cytokine profiles, and reactivation of latent herpesviruses. Further, astronauts have some degree of clinical incidence, primarily infectious disease episodes and atopic dermatitis. The impact of the microgravity environment on host-pathogen interactions and potential for clinical disease remains understudied and poorly characterized. SPECIFIC AIMS In this study, the following Specific Aims are being investigated, using the microbial pathogens, Salmonella enterica Enteritidis, Pseudomonas aeruginosa, Burkholderia cepacia, Streptococcus pneumoniae, and enterohemorrhagic Escherichia coli (EHEC). Aim 1: Characterize the effect of spaceflight analogue culture on microbial pathogenesis-related stress responses and in vitro host-pathogen interactions. Analyses include microbial stress responses as well as colonization and viability following pathogen challenge of three-dimensional (3-D) tissue co-culture models containing immune cells. We specifically selected obligate and opportunistic pathogens that are medically important and have been or are likely to be found aboard spacecraft. Aim 2: Characterize the effect of spaceflight analogue culture on the virulence potential of pathogenic microorganisms. Virulence will be assessed using a mouse model of infection. SIGNIFICANCE The goal of this study is to use spaceflight analogue conditions to gain insight into the breadth of medically-significant International Space Station microorganisms that have altered virulence and the impact of those changes on the immune response of the host. This information will provide critical understanding into the impact of microgravity on potential alterations in microbial virulence and associated infectious disease risk to crew health during spaceflight missions.

C M Ott↗

DOE OSTI2021

Price equation captures the role of drug interactions and collateral effects in the evolution of multidrug resistance

Bacterial adaptation to antibiotic combinations depends on the joint inhibitory effects of the two drugs (drug interaction [DI]) and how resistance to one drug impacts resistance to the other (collateral effects [CE]). Here we model these evolutionary dynamics on two-dimensional phenotype spaces that leverage scaling relations between the drug-response surfaces of drug-sensitive (ancestral) and drug-resistant (mutant) populations. We show that evolved resistance to the component drugs – and in turn, the adaptation of growth rate – is governed by a Price equation whose covariance terms encode geometric features of both the two-drug-response surface (DI) in ancestral cells and the correlations between resistance levels to those drugs (CE). Within this framework, mean evolutionary trajectories reduce to a type of weighted gradient dynamics, with the drug interaction dictating the shape of the underlying landscape and the collateral effects constraining the motion on those landscapes. We also demonstrate how constraints on available mutational pathways can be incorporated into the framework, adding a third key driver of evolution. Our results clarify the complex relationship between drug interactions and collateral effects in multidrug environments and illustrate how specific dosage combinations can shift the weighting of these two effects, leading to different and temporally explicit selective outcomes.

Gjini, Erida↗

NASA NTRSDate not supplied

Spaceflight Autonomous Multigenerational Microbial Sequencer in Support of Plant-Growth Systems

The CubeSat platform has proven successful in obtaining meaningful life science information when biological payloads are incorporated. Examples include: 1) the first-ever CubeSat with a biological payload, GeneSat-1, which demonstrated decreased growth rates for flight samples of Escherichia coli in low Earth orbit (Parra et al. 2008); 2) PharmaSat, demonstrated that Saccharomyces cerevisiae in the microgravity environment exhibits a significant level of metabolic activity even at high doses of applied antifungal (Ricco et al. 2011); 3) O/OREOS, which used Bacillus subtilis(bacteria) to demonstrate for the first time that microorganisms can be loaded in a dried, dormant form and then rehydrated and grown in orbit months after launch (Nicholson et al. 2011; Ehrenfreund et al. 2014; 4) the SporeSat payload, which investigated Ceratopteris richardii(fern spores) using lab-on-a-chip devices (BioCDs) and minicentrifuges to produce artificial gravitational forces in ground studies (Park et al. 2017), with demonstration of the BioCD and minicentrifuge in space; 5) EcAMSat, the first CubeSat to be directly deployed from the ISS for an experiment assessing antibiotic resistance of E. coli in the microgravity environment (Padgen et al. 2020); 6) BioSentinel, exposed a culture of yeast to galactic cosmic radiation (GCR) and solar particle events while in heliocentric orbit to measure the rate of double-strand-break repair using DNA-repair-deficient mutants. This effort measures the metabolic parameters of yeast in a deep-space environment compared to Earth ambient conditions using a 3-color LED detection system (Ricco et al. 2020; Padgen et al. 2021). We aim to expand this list to include a Spaceflight Autonomous Multigenerational Microbial Sequencer (SAMMS). SAMMS will allow for the genome level understanding of changes in growth and metabolic activity for any organism. While microbes are suitable for early studies in our proposed platform because of their small size, small and relatively less-complicated genomes, fast generation times, and relevance to life support systems; multicellular organisms can similarly be evaluated for their genetic response to the spaceflight environment. The Spaceflight Autonomous Multigenerational Microbial Sequencer (SAMMS) will enable autonomous sequencing of biological samples in plant production units, cislunar orbit and on the lunar surface to examine spaceflight effects (ie. radiation, altered gravity, reduced pressures) on plant and microbial genomes.On this team a Kennedy Space Center (KSC) space crop production and water systems microbiologist/molecular biologist works with a Johnson Space Center (JSC) International Space Station (ISS) microbial sequencing expert and an Ames Research Center (ARC) CubeSat Engineering team to convert an automated Oxford Nanopore librarypreparation and sequencing method to a fluidic CubeSat payload system. The Oxford Nanopore MinION sequencing platform has proven successful in the spaceflight environment onboard the ISS (Stahl-Rommel et al. 2021). Further long-duration spaceflight and exposure to high levels of radiation will cause genotypic effects in biological organisms that may affect their function. Monitoring the adaption of a population to the spaceflight environment and any subsequent beneficial mutations will allow for the harnessing of organisms best suited for use in life support systems. This will ensure that the selected life support-essential microorganisms maintain their intended specified function over generations of culturing in the relevant spaceflight environment without becoming hazardous to crew or spacecraft systems.

Aubrie E Orourke↗