Host response during unresolved urinary tract infection alters mammary tissue homeostasis through collagen deposition and TIMP1

Henry, Samantha, Lewis, Steven Macauley, Cyrill, Samantha Leeanne, Callaway, Mackenzie Kate, Chatterjee, Deeptiman, Hanasoge Somasundara, Amritha Varshini, Jones, Gina, He, Xue-Yan, Caligiuri, Giuseppina, Ciccone, Michael Francis, Diaz, Isabella Andrea, Biswas, Amelia, Hernandez, Evelyn, Ha, Taehoon, Wilkinson, John Erby, Egeblad, Mikala, Tuveson, David Arthur, Oresco dos Santos, Camila (February 2024) Host response during unresolved urinary tract infection alters mammary tissue homeostasis through collagen deposition and TIMP1. bioRxiv. (Public Dataset) (Submitted)

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Abstract

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explored how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell RNA sequencing and flow cytometry, we identified that mammary tissue from UTI-bearing mice display collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells were absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue were mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolved the infection and restored mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlated with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix (ECM) remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, or broad-spectrum antibiotic, prevented mammary collagen deposition, thus providing evidence for an unexpected link between the systemic host response during UTI and mammary alterations.

Item Type:	Paper
Subjects:	diseases & disorders > Bacterial Infections diseases & disorders
CSHL Authors:	Henry, Samantha Cyrill, Samantha L Caligiuri, Giuseppina Ciccone, Michael F Ha, Taehoon Egeblad, Mikala Tuveson, David A. Lewis, Steven M. Callaway, Mackenzie K. Chatterjee, Deeptiman Dos Santos, Camila O. Hanasoge Somasundara, Amritha Varshini Diaz, Isabella Hernandez-Veliz, Evelyn
Communities:	CSHL labs > Dos Santos lab CSHL labs > Egeblad lab CSHL labs > Kinney lab CSHL labs > Tuveson lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	6 February 2024
Date Deposited:	20 Mar 2024 13:16
Last Modified:	20 Mar 2024 13:16
Related URLs:	Publisher
Dataset ID:	BioProject: SUB11741283 BioProject: SUB8429356 https://github.com/dosSantosLabCSHL/scRNA-NP-P-UTI-SC-2022
URI:	https://repository.cshl.edu/id/eprint/41470

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