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A Rodent Model of Chikungunya Virus Infection in RAG1 -/- Mice, with Features of Persistence, for Vaccine Safety Evaluation.

Seymour RL, Adams AP, Leal G, Alcorn MD, Weaver SC - PLoS Negl Trop Dis (2015)

Bottom Line: In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development.To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model.Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.

View Article: PubMed Central - PubMed

Affiliation: Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Chikungunya virus (CHIKV) is a positive sense, single stranded RNA virus in the genus Alphavirus, and the etiologic agent of epidemics of severe arthralgia in Africa, Asia, Europe and, most recently, the Americas. CHIKV causes chikungunya fever (CHIK), a syndrome characterized by rash, fever, and debilitating, often chronic arthritis. In recent outbreaks, CHIKV has been recognized to manifest more neurologic signs of illness in the elderly and those with co-morbidities. The syndrome caused by CHIKV is often self-limited; however, many patients develop persistent arthralgia that can last for months or years. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Despite its importance as a reemerging disease, there is no licensed vaccine or specific treatment to prevent CHIK. Many studies have begun to elucidate the pathogenesis of CHIKF and the mechanism of persistent arthralgia, including the role of the adaptive immune response, which is still poorly understood. In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development. To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model. Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.

No MeSH data available.


Related in: MedlinePlus

Hematoxylin and eosin staining of representative sections from RAG1-/- mice inoculated with wt CHIKV.(A) Brain Day 28, (B) Liver Day 42, (C) Lung Day 42; all images were taken at 20x; scale bar is 200μm. Arrows indicate areas of inflammation.
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pntd.0003800.g004: Hematoxylin and eosin staining of representative sections from RAG1-/- mice inoculated with wt CHIKV.(A) Brain Day 28, (B) Liver Day 42, (C) Lung Day 42; all images were taken at 20x; scale bar is 200μm. Arrows indicate areas of inflammation.

Mentions: To evaluate tissue damage following each inoculation route (SC or FP), the brain, heart, lung, kidney, spleen, stomach, intestines, liver, gonads and leg tissues (including joints) were collected on days 7, 14, 28, 42, 56 and 70 post-inoculation and evaluated histologically. Poorly formed granulomatous inflammation was identified in the brain, liver and lungs of RAG1-/- mice inoculated SC with wt CHIKV on days 28–56 (Fig 4). No inflammation was identified in the leg tissues of these animals. C57BL/6J animals showed poorly formed granulomatous inflammation only in the liver (Fig 4A). The areas of granulomatous-type inflammation were identified in small foci. The inflammation in the brain of the RAG1-/- mouse was small and confined to the cerebrum, with no evidence of meningitis (Fig 4B). The inflammation in the lung consisted of tiny foci (Fig 4C). Several small poorly formed granulomas were identified in the livers of RAG1-/- and C57BL/6J mice, with no evidence of hepatocyte necrosis (Fig 4A). Granulomatous inflammation in the RAG1-/- mice occurred only in those identified to have persistent CHIKV in either their serum or organs. Those RAG1-/- mice that were negative for persistent CHIKV were histologically normal. This was observed only in mice with persistent CHIKV infection and not in those without detectable CHIKV housed in the same cages. This finding suggests that the inflammation was caused by persistent CHIKV infection and not another pathogen infecting the colony or cages of immunodeficient mice. In similar fashion, some animals (both RAG1-/- and C57BL/6J) inoculated via the FP had very small granulomas in the liver only, similar to Fig 4B.


A Rodent Model of Chikungunya Virus Infection in RAG1 -/- Mice, with Features of Persistence, for Vaccine Safety Evaluation.

Seymour RL, Adams AP, Leal G, Alcorn MD, Weaver SC - PLoS Negl Trop Dis (2015)

Hematoxylin and eosin staining of representative sections from RAG1-/- mice inoculated with wt CHIKV.(A) Brain Day 28, (B) Liver Day 42, (C) Lung Day 42; all images were taken at 20x; scale bar is 200μm. Arrows indicate areas of inflammation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482609&req=5

pntd.0003800.g004: Hematoxylin and eosin staining of representative sections from RAG1-/- mice inoculated with wt CHIKV.(A) Brain Day 28, (B) Liver Day 42, (C) Lung Day 42; all images were taken at 20x; scale bar is 200μm. Arrows indicate areas of inflammation.
Mentions: To evaluate tissue damage following each inoculation route (SC or FP), the brain, heart, lung, kidney, spleen, stomach, intestines, liver, gonads and leg tissues (including joints) were collected on days 7, 14, 28, 42, 56 and 70 post-inoculation and evaluated histologically. Poorly formed granulomatous inflammation was identified in the brain, liver and lungs of RAG1-/- mice inoculated SC with wt CHIKV on days 28–56 (Fig 4). No inflammation was identified in the leg tissues of these animals. C57BL/6J animals showed poorly formed granulomatous inflammation only in the liver (Fig 4A). The areas of granulomatous-type inflammation were identified in small foci. The inflammation in the brain of the RAG1-/- mouse was small and confined to the cerebrum, with no evidence of meningitis (Fig 4B). The inflammation in the lung consisted of tiny foci (Fig 4C). Several small poorly formed granulomas were identified in the livers of RAG1-/- and C57BL/6J mice, with no evidence of hepatocyte necrosis (Fig 4A). Granulomatous inflammation in the RAG1-/- mice occurred only in those identified to have persistent CHIKV in either their serum or organs. Those RAG1-/- mice that were negative for persistent CHIKV were histologically normal. This was observed only in mice with persistent CHIKV infection and not in those without detectable CHIKV housed in the same cages. This finding suggests that the inflammation was caused by persistent CHIKV infection and not another pathogen infecting the colony or cages of immunodeficient mice. In similar fashion, some animals (both RAG1-/- and C57BL/6J) inoculated via the FP had very small granulomas in the liver only, similar to Fig 4B.

Bottom Line: In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development.To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model.Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.

View Article: PubMed Central - PubMed

Affiliation: Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Chikungunya virus (CHIKV) is a positive sense, single stranded RNA virus in the genus Alphavirus, and the etiologic agent of epidemics of severe arthralgia in Africa, Asia, Europe and, most recently, the Americas. CHIKV causes chikungunya fever (CHIK), a syndrome characterized by rash, fever, and debilitating, often chronic arthritis. In recent outbreaks, CHIKV has been recognized to manifest more neurologic signs of illness in the elderly and those with co-morbidities. The syndrome caused by CHIKV is often self-limited; however, many patients develop persistent arthralgia that can last for months or years. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Despite its importance as a reemerging disease, there is no licensed vaccine or specific treatment to prevent CHIK. Many studies have begun to elucidate the pathogenesis of CHIKF and the mechanism of persistent arthralgia, including the role of the adaptive immune response, which is still poorly understood. In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development. To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model. Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.

No MeSH data available.


Related in: MedlinePlus