Biology subjects

Dailey, K. G.

Publications and source records attributed to Dailey, K. G..

5 recordsLinked to original sources

bioRxiv2025

TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral Yersinia infection

Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a Gram-negative enteric pathogen, closely related to the plague agent Y. pestis, that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyers patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination, and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate, using Sequence Tag-based Analysis of Microbial Populations in R (STAMPR), that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, populations of Yersinia are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both tissue colonization and lymphatic dissemination of intestinal bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens. ImportanceBacterial escape from the intestine can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.

microbiology↗

bioRxiv2025

A connection between Vibrio cholerae motility and inter-animal transmission

Outbreaks of cholera are caused by the highly transmissive pathogen Vibrio cholerae. Here, a transposon screen revealed that inactivation of the V. cholerae motility-linked gene motV increases infant mouse intestinal colonization. Compared to wild-type V. cholerae, a {Delta}motV mutant, which exhibits heightened motility in the form of constitutive straight swimming, localizes to the crypts earlier in infection and over a larger area of the small intestine. Aberrant localization of the mutant was associated with an increased number of V. cholerae initiating infection, and elevated pathogen burden, diarrhea, and lethality. Moreover, the deletion of motV causes V. cholerae to transmit from infected suckling mice to naive littermates more efficiently. Even in the absence of cholera toxin, the {Delta}motV mutant continues to transmit between animals, although less than in the presence of toxin, indicating that phenotypes other than cholera toxin-driven diarrhea contribute to transmission. Collectively, this work provides experimental evidence linking intra-animal bottlenecks, colonization, and disease to inter-animal transmission.

microbiology↗

bioRxiv2024

Patterns of Klebsiella pneumoniae bacteremic dissemination from the lung

Bacteremia, a leading cause of death, generally arises after bacteria establish infection in a particular tissue and transit to secondary sites. Studying dissemination from primary sites by solely measuring bacterial burdens does not capture the movement of individual clones. Here, by barcoding Klebsiella pneumoniae, a leading cause of bacteremia, we tracked pathogen dissemination following pneumonia. Variability in organ bacterial burdens was attributable to two distinct dissemination patterns distinguished by the extent of clonal expansion in the lungs. In "metastatic" dissemination, bacterial clones underwent heterogeneous clonal expansion within the lung and the dominant clones spread to secondary organs. In "direct" dissemination, bacterial clones exited the lungs without clonal expansion, leading to lower burdens in systemic sites. We uncover bacterial and host factors that govern these two modes of dissemination. Our data reveal unexpected heterogeneity in the dynamics of Klebsiella bacteremia and define a new paradigm for understanding within-host bacterial dissemination.

microbiology↗

bioRxiv2023

Genetic and immune determinants of E. coli liver abscess formation

Systemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation of E. coli leads to bacterial replication within liver abscesses while other organs such as the spleen largely clear the pathogen. Abscesses are macroscopic necrotic regions that comprise the vast majority of the bacterial burden in the animal, yet little is known about the processes underlying their formation. Here, we characterize E. coli liver abscesses and identify host determinants of abscess susceptibility. Spatial transcriptomics revealed that liver abscesses are associated with heterogenous immune cell clusters comprised of macrophages, neutrophils, dendritic cells, innate lymphoid cells, and T-cells that surround necrotic regions of the liver. Susceptibility to liver abscesses is heightened in the C57BL/6 lineage, particularly in C57BL/6N females. Backcross analyses demonstrated that abscess susceptibility is a polygenic trait inherited in a sex-dependent manner without direct linkage to sex chromosomes. As early as one day post infection, the magnitude of E. coli replication in the liver distinguishes abscess-susceptible and abscess-resistant strains of mice, suggesting that the immune pathways that regulate abscess formation are induced within hours. We characterized the early hepatic response with single-cell RNA sequencing and found that mice with reduced activation of early inflammatory responses, such as those lacking the LPS receptor TLR4, are resistant to abscess formation. Experiments with barcoded E. coli revealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks of E. coli liver abscess formation and suggest that hyperactivation of the hepatic innate immune response drives liver abscess susceptibility. ImportanceAnimal models of disseminating bacterial infections are critical for developing therapeutic interventions. Following systemic dissemination in mice, E. coli undergo dramatic replication within abscesses in the liver but not in other organs. Although liver abscesses are the largest reservoir of bacteria within the animal, the processes that lead to abscess formation are not known. Here, we characterize E. coli liver abscess formation and identify several determinants of abscess susceptibility, including sex, mouse genotype, and innate immune factors. By combining spatial and single-cell transcriptomics with genetic and phenotypic analyses, we delineate critical host pathways that underlie abscess formation. Our findings define several avenues for future studies to unravel how abscess susceptibility determinants interact to modulate clearance of systemic infections and govern tissue-specific bacterial replication.

microbiology↗

bioRxiv2023

Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose

To cause infection, pathogens must overcome bottlenecks imposed by the host immune system. These bottlenecks restrict the inoculum and largely determine whether pathogen exposure results in disease. Infection bottlenecks therefore quantify the effectiveness of immune barriers. Here, using a model of Escherichia coli systemic infection, we identify bottlenecks that tighten or widen with higher inoculum sizes, revealing that the efficacy of innate immune responses can increase or decrease with pathogen dose. We term this concept "dose scaling". During E. coli systemic infection, dose scaling is tissue specific, dependent on the LPS receptor TLR4, and can be recapitulated by mimicking high doses with killed bacteria. Scaling is therefore due to sensing of pathogen molecules rather than interactions between the host and live bacteria. We propose that dose scaling quantitatively links innate immunity with infection bottlenecks and is a valuable framework for understanding how the inoculum size governs the outcome of pathogen exposure.

microbiology↗