A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease The ´re ` se Couderc 1,2[ , Fabrice Chre ´ tien 3,4,5,6[ , Cle ´ mentine Schilte 7,8[ , Olivier Disson 1,2,9 , Madly Brigitte 4,5,6 , Florence Guivel-Benhassine 1,2 , Yasmina Touret 10 , Georges Barau 10 , Nade ` ge Cayet 11 , Isabelle Schuffenecker 12 , Philippe Despre `s 13 , Fernando Arenzana-Seisdedos 14,15 , Alain Michault 16 , Matthew L. Albert 7,8[ , Marc Lecuit 1,2,9,17[* 1 Groupe ‘‘Microorganismes et Barrie ` res de l’Ho ˆte’’, Institut Pasteur, Paris, France, 2 E ´ quipe Avenir INSERM U604 Paris, France, 3 Unite ´ ‘‘Cellules Souches et De ´ veloppement’’, CNRS URA 2578, Institut Pasteur, Paris, France, 4 INSERM, U841, Team 10, Cre ´teil, France, 5 AP-HP, Groupe Hospitalier Albert Chenevier-Henri Mondor, De ´ partement de Pathologie, Cre ´ teil, France, 6 Universite ´ Paris XII, Faculte ´ de Me ´decine, Cre ´ teil, France, 7 Groupe ‘‘Immunobiologie des Cellules Dendritiques’’, Institut Pasteur, Paris, France, 8 INSERM U818, Paris, France, 9 Unite ´ ‘‘Interactions Bacte ´ ries-Cellules’’, Institut Pasteur, Paris, France, 10 De ´partement de Gyne ´cologie et Obste ´trique, Groupe Hospitalier Sud-Re ´ union, Saint-Pierre, La Re ´union, France, 11 Plateforme de Microscopie Ultrastructurale, Institut Pasteur, Paris, France, 12 Centre National de Re ´fe ´rence des Arbovirus, Institut Pasteur Lyon, France, 13 Unite ´ ‘‘Interactions Mole ´ culaires Flavivirus-Ho ˆ tes’’, Institut Pasteur, Paris, France, 14 Laboratoire ‘‘Pathoge ´nie Virale Mole ´ culaire’’, Institut Pasteur, Paris, France, 15 CNRS URA 3015, Paris, France, 16 Laboratoire de Microbiologie, Groupe Hospitalier Sud-Re ´union, Saint-Pierre, Ile de la Re ´ union, France, 17 Centre d’Infectiologie Necker-Pasteur, Ho ˆ pital Necker-Enfants malades, Assistance Publique-Ho ˆ pitaux de Paris, Universite ´ Paris Descartes, Paris, France Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-a/bR þ/  ) or totally (IFN-a/bR /  ) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates. Citation: Couderc T, Chre ´tien F, Schilte C, Disson O, Brigitte M, et al. (2008) A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS Pathog 4(2): e29. doi:10.1371/journal.ppat.0040029 Introduction Chikungunya virus (CHIKV) was first isolated in Tanzania in 1953 [1], and has recently emerged in islands of the Indian Ocean in 2005, and engendered the largest Chikungunya fever epidemic on record [2]. The most affected region was the island of La Re ´ union, where CHIKV infected approx- imately a third of the island’s inhabitants (i.e., ;300,000) [3– 5]. The outbreak, which now also involves India with an estimated 1.3 million cases [6–8], has a significant potential to spread globally given the wide distribution of its arthropod vector [9,10]. CHIKV is a member of the genus Alphavirus in the family of Togaviridae. Alphaviruses are small, enveloped viruses with a message-sense RNA genome that encodes four non-structural proteins (nsP1–4) and three structural proteins (C, E1–2). This arbovirus is maintained in nature by uninterrupted cycles of transmission between mosquitoes and vertebrate hosts such as macaques [11–13]. Several alphaviruses cause disease in humans, primarily as a result of epizootic infections. These include the American encephalitic alphavi- ruses and several species in the Semliki Forest Virus group, principally the Afro-Asian CHIKV, the African O’Nyong- Nyong virus, as well as the Australasian Barmah Forest virus and Ross River virus [14]. CHIKV infection is characterized by fever, arthralgia, myalgia, rash and headache. During the La Re ´ union Island outbreak, previously unreported severe forms of Chikungunya infection were observed in adults, compli- Editor: Michael J. Buchmeier, The Scripps Research Institute, United States of America Received August 24, 2007; Accepted December 28, 2007; Published February 15, 2008 Copyright: Ó 2008 Couderc et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: BBB, blood-brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; D, day; DAB, diaminobenzidine; HRP, horseradish-peroxidase; ID, intra-dermal; IFN-a/bR, IFN-a/b receptor; LD50, lethal dose 50; MOI, multiplicity of infection; pi, post infection; TCID50, tissue cytopathic infectious dose 50 * To whom correspondence should be addressed. E-mail: mlecuit@pasteur.fr [ These authors contributed equally to this work. PLoS Pathogens | www.plospathogens.org February 2008 | Volume 4 | Issue 2 | e29 0001