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Tuesday February 23 2010

News on Chikungunya

Chikungunya disease in nonhuman primates due to long-term viral persistence in macrophages. K. Labadie, T. Larcher, C. Joubert, A. Mannioui, B. Delache, P. Brochard, L. Guigand, L. Dubreil, P. Lebon, B. Verrier, X. de Lamballerie, A. Suhrbier, Y. Cherel, R. Le Grand, and P. Roques. Journal of Clinical Investigation, online, 2010.
James Gathany
A research team co-led by the CEA, Paris-Sud 11 University, the INRA and Nantes-Oniris National Veterinary College, with contributions the IRD, the CNRS, Méditerranée University and Paris Descartes University, have just cracked a number of the mechanisms of action of Chikungunya virus, using an animal model that most closely mimics what happens in humans. The science team has demonstrated, for the first time, that it macrophages hosts that conserve the virus within the body, thus strongly suggesting that these same macrophages play a role in the persistence of the symptoms observed even several months after the chronic phase of the infection. This work, which is published in the online version of the Journal of Clinical Investigation, opens up avenues for the development of both preventive and curative therapies for treating what has become a major public health risk.


Over the 2005 to 2006 period, close on 300,000 cases of Chikungunya virus [1] were recorded on Réunion, i.e. 38% of the island’s population. Around 2,200 patients had to be admitted to hospital, where 250 died. There is currently no vaccine or specific treatment for the infection in human patients. The recent emergence – or re-emergence – of the virus that causes Chikungunya in India and several Indian Ocean island has made it urgent to gain critical insights into the disease as the key to finding ways to counter its spread.

The task of understanding the chain of mechanisms employed by the disease (pathogenesis) is made particularly difficult in humans. This is largely because it is impossible to obtain relevant biological samples such as deep tissue (liver, spleen) in which the disease replicates, and the situation is further complicated by the sheer multiplicity of the patients’ medical backgrounds and other chronic illnesses. The most severe Chikungunya cases were more prevalent in elderly patients already weakened by pre-existing heart, kidney liver, etc. diseases. Against this backdrop, how do you go about pinpointing the virus in the body, characterizing how it interacts with host cells inside body tissue, understanding the body’s natural defence mechanisms, and discriminating between cell damage specific to the disease and pre-existing cell damage related to other background diseases? Rodent models of infection can provide some of the answers. These models use either neonate or adult animals genetically modified to knock out natural defence mechanisms, but they are only partially representative of human disease patterns. Moreover, they generally prove ill-suited to testing vaccines or treatments.

Looking to capitalize on their work on the pathogenesis of AIDS, the team developed a model of the disease in adult cynomolgus macaques, which share a very similar physiology and functional immune system to humans. They showed that these animals, when infected with the Chikungunya virus isolated from patients during the Réunion island epidemic, present the same clinical and viral features observed in human disease. They highlighted certain Chikungunya-specific features, such as hepatic disorders during the acute phase. More importantly still, the study revealed that the virus infects cells involved in the first steps of the body’s defence mechanisms, i.e. macrophages [2] and dendritic cells. These cells are can host the virus for several months at a time, and are also capable of infiltrating a range of tissues including joints, muscle, lymphoid tissue and liver, which could explain the long-lasting disease symptoms observed in human patients, such as debilitating muscular and joint pain. The infected macrophages identified through this study therefore make a potential target for the development of new therapies for treating the more chronic disease-related disorders.

This key insight into the disease’s mechanisms of action represents a major step in the process of pioneering new therapies. The CEA team now has the tools it needs to be able to lab-test new treatments, which is a crucial step forward, since the treatments currently available to doctors are purely symptomatic.

The outreach from this study almost certainly extends beyond Chikungunya. This viral persistence identified in macrophages and dendritic cells could be shared by several other viruses in the same arbovirus family of insect-borne viruses.

Notes:

[1] Chikungunya: tropical disease caused by an alphavirus (written ‘CHIKV’, for Chikungunya virus) transmitted to humans by virus-carrying Aedes mosquitoes.

[2] Macrophages: immune-system cells.

Research teams:

Immunovirology Department, Institute of Emerging Diseases and Innovative Therapy, UMR-E1, CEA Fontenay-aux-Rose/ Paris-Sud 11 University, Orsay

UMR 703 INRA/National College of Veterinary Science, Nutrition and Agrifoods at Nantes (ONIRIS)

Virology Department, Paris Descartes University/Hôpital Cochin–St Vincent-de-Paul, Paris

UMR 5086, Institute of Protein Chemistry and Biology, CNRS/ Claude Bernard Lyon 1 University, Lyon.

Emerging Viruses Unit, Méditerranée University (Aix-Marseille II)/Institute of Development Research, Marseille.

[These findings were covered in a press release dated 23 February 2010]