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Pathogen clonal expansion underlies multiorgan dissemination and organ-specific outcomes during murine systemic infection.

ABSTRACT: The dissemination of pathogens through blood and their establishment within organs lead to severe clinical outcomes. However, the within-host dynamics that underlie pathogen spread to and clearance from systemic organs remain largely uncharacterized. In animal models of infection, the observed pathogen population results from the combined contributions of bacterial replication, persistence, death, and dissemination, each of which can vary across organs. Quantifying the contribution of each these processes is required to interpret and understand experimental phenotypes. Here, we leveraged STAMPR, a new barcoding framework, to investigate the population dynamics of extraintestinal pathogenic Escherichia coli, a common cause of bacteremia, during murine systemic infection. We show that while bacteria are largely cleared by most organs, organ-specific clearance failures are pervasive and result from dramatic expansions of clones representing less than 0.0001% of the inoculum. Clonal expansion underlies the variability in bacterial burden between animals, and stochastic dissemination of clones profoundly alters the pathogen population structure within organs. Despite variable pathogen expansion events, host bottlenecks are consistent yet highly sensitive to infection variables, including inoculum size and macrophage depletion. We adapted our barcoding methodology to facilitate multiplexed validation of bacterial fitness determinants identified with transposon mutagenesis and confirmed the importance of bacterial hexose metabolism and cell envelope homeostasis pathways for organ-specific pathogen survival. Collectively, our findings provide a comprehensive map of the population biology that underlies bacterial systemic infection and a framework for barcode-based high-resolution mapping of infection dynamics.

SUBMITTER: Hullahalli K

PROVIDER: S-EPMC8545400 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe number of Medicaid beneficiaries has increased under the Affordable Care Act, improving access to solid organ transplantation in this disadvantaged patient cohort. It is unclear what impact Medicaid expansion will have on transplantation outcomes. We performed a retrospective cohort analysis to measure the frequency and variation in Medicaid transplantation and post-transplantation survival in Medicaid patients.Study designAdult heart, lung, liver, and renal transplant recipients between 2002 and 2011 (n = 169,194) reported to the Scientific Registry of Transplant Recipients were identified. Transplant recipients were classified based on insurance status (private, Medicare or Medicaid). Outcomes measures included 5-year post-transplantation survival, summarized using Kaplan-Meier curves and compared with log-rank tests. Organ-specific Cox proportional hazards models were used to adjust for donor and recipient factors.ResultsMedicaid patients comprised 8.6% of all organ transplant recipients. Fewer transplantations were performed than expected among Medicaid beneficiaries for all organs except liver (liver: observed to expected ratio = 1.21; 95% CI, 0.68-1.90; heart: observed to expected ratio = 0.89; 95% CI, 0.44-1.49; lung: observed to expected ratio = 0.57; 95% CI, 0.22-1.06; renal: observed to expected ratio = 0.32; 95% CI, 0.08-0.72). Medicaid transplant recipients were listed with more severe organ failure and experienced shorter transplant wait times. Post-transplantation survival was lower in Medicaid patients compared with private insurance for all organs. Post-transplantation survival in Medicaid patients was similar to Medicare patients for heart, liver, and renal but lower in lung.ConclusionsMedicaid organ transplant beneficiaries had significantly lower survival compared with privately insured beneficiaries. The more severe organ failure among Medicaid beneficiaries at the time of listing, suggested a pattern of late referral, which might account for worse outcomes. Implementation of the Affordable Care Act gives the opportunity to develop the necessary infrastructure to ensure timely transplantation referrals and improve long-term outcomes in this vulnerable population.

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Pathogen clonal expansion underlies multiorgan dissemination and organ-specific outcomes during murine systemic infection.

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