Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages
Karine Labadie, … , Roger Le Grand, Pierre Roques
Karine Labadie, … , Roger Le Grand, Pierre Roques
Published February 22, 2010
Citation Information: J Clin Invest. 2010;120(3):894-906. https://doi.org/10.1172/JCI40104.
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Research Article

Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, muscles, lymphoid organs, and liver, which could explain the long-lasting CHIKV disease symptoms observed in humans. In addition, the study identified macrophages as the main cellular reservoirs during the late stages of CHIKV infection in vivo. This model of CHIKV physiopathology should allow the development of new therapeutic and/or prophylactic strategies.

Authors

Karine Labadie, Thibaut Larcher, Christophe Joubert, Abdelkrim Mannioui, Benoit Delache, Patricia Brochard, Lydie Guigand, Laurence Dubreil, Pierre Lebon, Bernard Verrier, Xavier de Lamballerie, Andreas Suhrbier, Yan Cherel, Roger Le Grand, Pierre Roques

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Figure 2

Lesions observed in tissues collected from 12 macaques inoculated with intermediate doses of CHIKV.

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Lesions observed in tissues collected from 12 macaques inoculated with i...
Histology of tissues from CHIKV-infected macaques. (A) Spleen, 6 dpi. Density of mononuclear cells was diffusely increased in the red pulp. These mononuclear cells corresponded mostly to macrophages with abundant cytoplasm and large nucleolated nucleus (inset). Some mononuclear cells were undergoing mitosis (arrows). (B) Spleen, 32 dpi. Macrophages were still numerous in the red pulp; a few mitotic cells were visible (arrow). (C) Normal spleen. Red pulp contained numerous red blood cells. (D) Lymph node, 6 dpi. The cortex was distended by numerous macrophages (some denoted by arrowheads). (E) Lymph node, 44 dpi. Severe follicular enlargement (asterisks) was associated with macrophage infiltration. Postcapillary venules of the T-dependent area (arrows) and medulla (M) are indicated. (F and G) Normal lymph node. Lymphoid follicles (asterisks) and medulla are indicated. (H) Liver, 6 dpi. The number of apoptotic hepatocytes with nuclei (arrows), detected by TUNEL assay, increased. (I) Liver, 90 dpi. Multifocal interstitial mononuclear cell infiltration (arrowheads) was observed in the liver parenchyma. (J) Normal liver. (K and L) Skeletal muscle, 55 dpi. Mild multifocal necrosis of muscle fibers (asterisk) was associated with infiltration by mononuclear cells, including macrophages (arrowheads). (M) Normal muscle. (A–G and I–M) Hematoxylin eosin safran stain. (H) In situ detection of cell death using TUNEL staining. Scale bars: 100 μm (A–D, F, and H–M); 10 μm (insets); 1 mm (E and G).