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Role of CD14 in Responses to Clinical Isolates of Escherichia coli: Effects of K1 Capsule Expression

Shalaka Metkar,^1, Shanjana Awasthi,^2,, Erick Denamur,³ Kwang Sik Kim,⁴ Sophie C. Gangloff,^2, Saul Teichberg,² Alain Haziot,^2,¶ Jack Silver,¹ and Sanna M. Goyert^1*

Department of Microbiology and Immunology, CUNY Medical School, and Sophie Davis School for Biomedical Sciences, City College of New York, New York, New York,¹ Center of Immunology and Inflammation, Laboratory of Innate Immunity, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health Systems, Manhasset, New York,² Ecologie et évolution des micro-organismes, INSERM U722, Faculté de Médecine Xavier Bichat, Paris, France,³ Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland⁴

Received 26 April 2007/ Returned for modification 8 June 2007/ Accepted 8 August 2007

Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14^–/– and CD14^+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14^–/– mice were resistant to the lethal effects of the K1-negative isolates. This resistance was accompanied by significantly lower levels of systemic tumor necrosis factor alpha (TNF-) and interleukin-6 (IL-6) in these mice than in CD14^+/+ mice, enhanced clearance of the bacteria, and significantly fewer additional gross symptoms. In contrast, CD14^–/– mice were as sensitive as CD14^+/+ mice to the lethal effects of the K1-positive isolates, even though they had significantly lower levels of TNF- and IL-6 than CD14^+/+ mice. These studies show that different bacterial isolates can use distinctly different mechanisms to cause disease and suggest that new, nonantibiotic therapeutics need to be directed against multiple targets.

Published ahead of print on 20 August 2007.

Editor: J. B. Bliska

S. Metkar and S. Awasthi contributed equally to this work.

Present address: Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, OK.

Present address: Laboratoire d'Immunologie et de Microbiologie, EA 3796-IFR53, UFR Pharmacie, 1 Av. M^al Juin, 51100 Reims, France.

^¶ Present address: Institut National de la Santé et de la Recherche Médicale Unité 396, Paris, France.