Genetic and immune determinants ofE. coliliver abscess formation

Abstract

AbstractSystemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation ofE.colileads 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 characterizeE. coliliver 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 ofE. colireplication 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 barcodedE. colirevealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks ofE. coliliver 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. coliundergo 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 characterizeE. coliliver 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.