Pathogenicity of Yersinia pestis synthesis of 1-dephosphorylated lipid A.
Synthesis of Escherichia coli LpxL, which transfers a secondary laurate chain to the 2' position of lipid A, in Yersinia pestis produced bisphosphoryl hexa-acylated lipid A at 37°C, leading to significant attenuation of virulence. Our previous observations also indicated that strain χ10015(pCD1Ap) (ΔlpxP32::P(lpxL) lpxL) stimulated a strong inflammatory reaction but sickened mice before recovery and retained virulence via intranasal (i.n.) infection. The development of live, attenuated Y. pestis vaccines may be facilitated by detoxification of its lipopolysaccharide (LPS). Heterologous expression of the lipid A 1-phosphatase, LpxE, from Francisella tularensis in Y. pestis yields predominantly 1-dephosphorylated lipid A, as confirmed by mass spectrometry. Results indicated that expression of LpxE on top of LpxL provided no significant reduction in virulence of Y. pestis in mice when it was administered i.n. but actually reduced the 50% lethal dose (LD(50)) by 3 orders of magnitude when the strain was administered subcutaneously (s.c.). Additionally, LpxE synthesis in wild-type Y. pestis KIM6+(pCD1Ap) led to slight attenuation by s.c. inoculation but no virulence change by i.n. inoculation in mice. In contrast to Salmonella enterica, expression of LpxE does not attenuate the virulence of Y. pestis.
Center for Infectious Disease and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
Wei
W
Sun
David A
DA
Six
C Michael
CM
Reynolds
Hak Suk
HS
Chung
Christian R H
CR
Raetz
Roy
R
Curtiss
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007928:Lethal Dose 50; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010930:Plague / Q000382:microbiology / Q000401:mortality; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*; D015010:Yersinia pestis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*
D029968:Escherichia coli Proteins; D008050:Lipid A; D008565:Membrane Proteins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000217:Acyltransferases; C492237:LpxL protein, E coli; C494778:LpxE protein, Francisella tularensis; D010744:Phosphoric Monoester Hydrolases