期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：51
DOI：10.1073/pnas.2113951118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Some infections are exceedingly difficult to cure, even with adequate antimicrobial chemotherapy. How pathogens can survive exposure to antimicrobials in tissues remains poorly understood. Using three-dimensional whole-organ tomography, we show that
Salmonella colonization of the mouse spleen is uneven. Low
Salmonella density in the white pulp triggers only limited local infiltration by inflammatory cells that are crucial for supporting antimicrobial
Salmonella clearance. Inflammatory cell density declines further during treatment in response to receding
Salmonella loads, resulting in insufficient support for clearance and eradication failure. However, sustaining inflammation during antimicrobial chemotherapy enables effective clearance. Our findings identify heterogeneous host–pathogen interactions in compartmentalized tissues as a main mechanism underlying the antibiotic persistence of
Salmonella.
Antimicrobial chemotherapy can fail to eradicate the pathogen, even in the absence of antimicrobial resistance. Persisting pathogens can subsequently cause relapsing diseases. In vitro studies suggest various mechanisms of antibiotic persistence, but their in vivo relevance remains unclear because of the difficulty of studying scarce pathogen survivors in complex host tissues. Here, we localized and characterized rare surviving
Salmonella in mouse spleen using high-resolution whole-organ tomography. Chemotherapy cleared >99.5% of the
Salmonella but was inefficient against a small
Salmonella subset in the white pulp. Previous models could not explain these findings: drug exposure was adequate,
Salmonella continued to replicate, and host stresses induced only limited
Salmonella drug tolerance. Instead, antimicrobial clearance required support of
Salmonella-killing neutrophils and monocytes, and the density of such cells was lower in the white pulp than in other spleen compartments containing higher
Salmonella loads. Neutrophil densities declined further during treatment in response to receding
Salmonella loads, resulting in insufficient support for
Salmonella clearance from the white pulp and eradication failure. However, adjunctive therapies sustaining inflammatory support enabled effective clearance. These results identify uneven
Salmonella tissue colonization and spatiotemporal inflammation dynamics as main causes of
Salmonella persistence and establish a powerful approach to investigate scarce but impactful pathogen subsets in complex host environments.
关键词：bacterial infection; antimicrobial chemotherapy; treatment failure; 3D microscopy; salmonellosis
