Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during bubonic plague

doi:10.1073/pnas.0601182103

Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during bubonic plague

*Laboratory of Zoonotic Pathogens and
^¶Genomics Core Facility, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
^‡Institut National de la Santé et de la Recherche Médicale Unité 801 and Faculté de Médecine Henri Warembourg, Université de Lille II, Lille F-59045, France; and
^§Institut Pasteur, Lille F-59021, France

Edited by John J. Mekalanos, Harvard Medical School, Boston, MA, and approved June 13, 2006 (received for review February 11, 2006)

Abstract

Yersinia pestis causes bubonic plague, characterized by an enlarged, painful lymph node, termed a bubo, that develops after bacterial dissemination from a fleabite site. In susceptible animals, the bacteria rapidly escape containment in the lymph node, spread systemically through the blood, and produce fatal sepsis. The fulminant progression of disease has been largely ascribed to the ability of Y. pestis to avoid phagocytosis and exposure to antimicrobial effectors of innate immunity. In vivo microarray analysis of Y. pestis gene expression, however, revealed an adaptive response to nitric oxide (NO)-derived reactive nitrogen species and to iron limitation in the extracellular environment of the bubo. Polymorphonuclear neutrophils recruited to the infected lymph node expressed abundant inducible NO synthase, and several Y. pestis homologs of genes involved in the protective response to reactive nitrogen species were up-regulated in the bubo. Mutation of one of these genes, which encodes the Hmp flavohemoglobin that detoxifies NO, attenuated virulence. Thus, the ability of Y. pestis to destroy immune cells and remain extracellular in the bubo appears to limit exposure to some but not all innate immune effectors. High NO levels induced during plague may also influence the developing adaptive immune response and contribute to septic shock.

Footnotes

**To whom correspondence should be addressed. E-mail: jhinnebusch{at}niaid.nih.gov
↵ ^†Present address: Institut National de la Santé et de la Recherche Médicale Unité 801, Universite de Lille II, and Institut Pasteur, Lille F-59021, France.
↵ ^‖Present address: Sandia National Laboratories, Albuquerque, NM 87185.
Author contributions: F.S., N.L., R.R., and B.J.H. designed research; F.S., N.L., R.R., and B.J.H. performed research; K.V. and S.F.P. contributed new reagents/analytic tools; F.S., N.L., D.E.S., S.F.P., and B.J.H. analyzed data; and F.S. and B.J.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The MIAME (Minimum Information About a Microarray Experiment) data have been submitted to the Gene Expression Omnibus repository (accession no. GSE3793).
Abbreviations:

RNS,

reactive nitrogen species;

ROS,

reactive oxygen species;

iNOS,

inducible nitric oxide synthase;

TTSS,

Type III secretion system;

PMN,

polymorphonuclear neutrophil;

GSNO,

nitrosoglutathione.
Freely available online through the PNAS open access option.