Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.
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.
Department of Comparative Medicine, University of Washington, Seattle, Washington, USA. hajjar@uw.edu
Adeline M
AM
Hajjar
Robert K
RK
Ernst
Edgardo S
ES
Fortuno
Alicia S
AS
Brasfield
Cathy S
CS
Yam
Lindsay A
LA
Newlon
Tobias R
TR
Kollmann
Samuel I
SI
Miller
Christopher B
CB
Wilson
D000215:Acylation; D000818:Animals; D002460:Cell Line; D022202:Chromosomes, Artificial, Bacterial; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology; D057809:HEK293 Cells; D006801:Humans; D008050:Lipid A / Q000737:chemistry / Q000276:immunology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010930:Plague / Q000276:immunology* / Q000382:microbiology; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology; D019779:Salmonella enterica / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D015398:Signal Transduction; D013696:Temperature; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D015010:Yersinia pestis / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*
D016207:Cytokines; D008050:Lipid A; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4