| Description |
Sepsis is a life-threatening systemic inflammatory condition that is characterized by a high degree of patient heterogeneity, making it notoriously difficult to diagnose and treat. Among the most common and lethal causes of sepsis are strains of Extraintestinal Pathogenic Escherichia coli (ExPEC). These genetically diverse pathogens are becoming increasingly problematic due to the rise of multidrug resistant strains. During sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation, while the host background is considered the primary variable affecting disease progression and outcome. My doctoral research challenges this assumption and establishes a novel zebrafish embryo infection model to study the effects of ExPEC strain differences on the maladaptive immune responses that are induced during sepsis. Zebrafish embryos infected with ExPEC isolates display many of the key pathophysiological features seen in human septic patients, including dysregulated inflammatory responses (cytokine storms), tachycardia, and endothelial leakage. Mirroring what is seen in human patients, antibiotic therapy reduces bacterial titers in infected embryos and improves host survival rates, but is only effective within limited time frames, and surviving animals often develop lasting edema and other defects. Intriguingly, genetically distant ExPEC isolates stimulate markedly different host responses, including disparate levels of inflammatory (e.g., IL-1 β, TNF-α) and immunomodulatory (e.g., IL-10) mediators. These variances are attributable to differential activation of TLR5 by these strains, which vary in the levels and the serotypes of flagellin that they express. To examine the specific effects of IL-10 on disease progression, I created and begun to characterize engineered gene knockout and inducible transgenic zebrafish lines for this cytokine. Altogether, my graduate research establishes zebrafish as a relevant model for studying sepsis and highlights the ability of genetically distinct ExPEC isolates to induce divergent host responses independent of baseline host attributes and implicates bacterial flagellin as a key mediator of inflammation during sepsis. |
