Humanized TLR4/MD-2 Mice Reveal LPS Recognition Differentially Impacts Susceptibility to Yersinia pestis and Salmonella enterica

PLoS Pathogens

Cathy S. Yam¹  Alicia S. Brasfield¹  Adeline M. Hajjar¹  Christopher B. Wilson²  Lindsay A. Newlon²  Robert K. Ernst³  Samuel I. Miller⁴  Edgardo S. Fortuno III⁵  Tobias R. Kollmann⁵ 

[1] Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America;Department of Immunology, University of Washington, Seattle, Washington, United States of America;Department of Microbial Pathogenesis, University of Maryland, Baltimore, Maryland, United States of America;Departments of Medicine, Genome Sciences, and Microbiology, University of Washington, Seattle, Washington, United States of America;Division of Infectious and Immunological Diseases, University of British Columbia, Vancouver, British Columbia, Canada

关键词: Yersinia pestis;    Mouse models;    Toll-like receptors;    Lipids;    Lipid structure;    Bacterial pathogens;    Gram negative bacteria;    Spleen;   

DOI  :  10.1371/journal.ppat.1002963

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Although lipopolysaccharide (LPS) stimulation through the Toll-like receptor (TLR)-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for “humanized” TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with “humanized” TLR4/MD-2 transgenic mice.

【 授权许可】

CC BY