Substitution of the bordetella pertussis lipid a phosphate groups with glucosamine is required for robust nf-κb activation and release of proinflammatory cytokines in cells expressing human but not murine toll-like receptor 4-MD-2-CD14

Nico Marr, Adeline M. Hajjar, Nita R. Shah, Alexey Novikov, Cathy S. Yam, Martine Caroff, Rachel C. Fernandez

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Bordetella pertussis endotoxin is a key modulator of the host immune response, mainly due to the role of its lipid A moiety in Toll-like receptor 4 (TLR4)-mediated signaling. We have previously demonstrated that the lipid A phosphate groups of B. pertussis BP338 can be substituted with glucosamine in a BvgAS-regulated manner. Here we examined the effect of this lipid A modification on the biological activity of B. pertussis endotoxin. We compared purified endotoxin and heat-killed B. pertussis BP338 whole cells that have modified lipid A phosphate groups to an isogenic mutant lacking this modification with respect to their capacities to induce the release of inflammatory cytokines by human and murine macrophages and to participate in the TLR4-mediated activation of NF-κB in transfected HEK-293 cells. We found inactivated B. pertussis cells to be stronger inducers of proinflammatory cytokines in THP-1-derived macrophages when lipid A was modified. Most notably, lack of lipid A modification abolished the ability of purified B. pertussis endotoxin to induce the release of inflammatory cytokines by human THP-1-derived macrophages but led to only slightly reduced inflammatory cytokine levels when stimulating murine (RAW 264.7) macrophages. Accordingly, upon stimulation of HEK-293 cells with inactivated bacteria and purified endotoxin, lack of lipid A modification led to impaired NF-κB activation only when human, and not when murine, TLR4-MD-2-CD14 was expressed. We speculate that in B. pertussis, lipid A modification has evolved to benefit the bacteria during human infection by modulating immune defenses rather than to evade innate immune recognition.

Original languageEnglish
Pages (from-to)2060-2069
Number of pages10
JournalInfection and Immunity
Volume78
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Fingerprint

Bordetella pertussis
Lipid A
Toll-Like Receptor 4
Glucosamine
Phosphates
Cytokines
Lipids
Macrophages
Bordetella
HEK293 Cells
Endotoxins
Bacteria
Hot Temperature
Infection

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Substitution of the bordetella pertussis lipid a phosphate groups with glucosamine is required for robust nf-κb activation and release of proinflammatory cytokines in cells expressing human but not murine toll-like receptor 4-MD-2-CD14. / Marr, Nico; Hajjar, Adeline M.; Shah, Nita R.; Novikov, Alexey; Yam, Cathy S.; Caroff, Martine; Fernandez, Rachel C.

In: Infection and Immunity, Vol. 78, No. 5, 05.2010, p. 2060-2069.

Research output: Contribution to journalArticle

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