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

Samantha Henry, Steven Macauley Lewis, Samantha Leeanne Cyrill, Mackenzie Kate Callaway, Deeptiman Chatterjee, Amritha Varshini Hanasoge Somasundara, Gina Jones, Xue-Yan He, Giuseppina Caligiuri, Michael Francis Ciccone, Isabella Andrea Diaz, Amelia Aumalika Biswas, Evelyn Hernandez, Taehoon Ha, John Erby Wilkinson, Mikala Egeblad, David Arthur Tuveson and Camila Oresco dos Santos ()
Additional contact information
Samantha Henry: Cold Spring Harbor Laboratory
Steven Macauley Lewis: Cold Spring Harbor Laboratory
Samantha Leeanne Cyrill: Cold Spring Harbor Laboratory
Mackenzie Kate Callaway: Cold Spring Harbor Laboratory
Deeptiman Chatterjee: Cold Spring Harbor Laboratory
Amritha Varshini Hanasoge Somasundara: Cold Spring Harbor Laboratory
Gina Jones: Cold Spring Harbor Laboratory
Xue-Yan He: Department of Cell Biology and Physiology. School of Medicine in St. Louis. Washington University
Giuseppina Caligiuri: Cold Spring Harbor Laboratory
Michael Francis Ciccone: Cold Spring Harbor Laboratory
Isabella Andrea Diaz: Cold Spring Harbor Laboratory
Amelia Aumalika Biswas: Cold Spring Harbor Laboratory
Evelyn Hernandez: Cold Spring Harbor Laboratory
Taehoon Ha: Cold Spring Harbor Laboratory
John Erby Wilkinson: University of Washington
Mikala Egeblad: Department of Cell Biology, Department of Oncology, School of Medicine, Johns Hopkins University
David Arthur Tuveson: Cold Spring Harbor Laboratory
Camila Oresco dos Santos: Cold Spring Harbor Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore 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 transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.

Date: 2024
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DOI: 10.1038/s41467-024-47462-7

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