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Cutting Edge: Natural DNA Repetitive Extragenic Sequences from Gram-Negative Pathogens Strongly Stimulate TLR9¹

Mattias Magnusson^2,*, Raquel Tobes^2,, Jaime Sancho and Eduardo Pareja^3,

^* Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden; Era7 Information Technologies Societal Limitada, Business Innovation Center, Granada Centro Europeo de Empresas e Innovación, Parque Tecnológico de Ciencias de la Salud-Armilla Granada, Armilla, Spain; and Instituto de Parasitologia y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Armilla, Spain

Bacterial DNA exerts immunostimulatory effects on mammalian cells via the intracellular TLR9. Although broad analysis of TLR9-mediated immunostimulatory potential of synthetic oligonucleotides has been developed, which kinds of natural bacterial DNA sequences are responsible for immunostimulation are not known. This work provides evidence that the natural DNA sequences named repetitive extragenic palindromic (REPs) sequences present in Gram-negative bacteria are able to produce innate immune system stimulation via TLR9. A strong induction of IFN- production by REPs from Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, and Neisseria meningitidis was detected in splenocytes from 129 mice. In addition, the involvement of TLR9 in immune stimulation by REPs was confirmed using B6.129P2-Tlr9^tm1Aki knockout mice. Considering the involvement of TLRs in Gram-negative septic shock, it is conceivable that REPs play a role in its pathogenesis. This study highlights REPs as a potential novel target in septic shock treatment.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Ministerio de Educación y Ciencia (Grant SAF2005-06056-C02-01) and by the Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía (Grant P05-CVI-00908) to J.S.

² M.M. and R.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Eduardo Pareja, Immunology Unit, Era7 Information Technologies Societal Limitada, Business Innovation Center, Granada Centro Europeo de Empresas e Innovación, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada 18100, Spain. E-mail address: epareja{at}era7.com

⁴ Abbreviations used in this paper: ODN, oligodeoxynucleotide; REP, repetitive extragenic palindromic.

⁵ The online version of this article has supplemental material.