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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 footpads from C57BL/6J or RAG1-/- mice inoculated with PBS or wt CHIKV.(A) PBS Day 7, (B) C57BL/6J wt CHIKV Day 7, (C) RAG1-/- wt CHIKV Day 7, (D) PBS Day 14, (E) C57BL/6J wt CHIKV Day 14, (F) RAG1-/- wt CHIKV Day 14, (G) PBS Day 28, (H) C57BL/6J wt CHIKV Day 28, (I) RAG1-/- wt CHIKV Day 28; all images were taken at 20x; scale bar is 200μm. Images of PBS controls were taken from RAG1-/- mice.
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pntd.0003800.g005: Hematoxylin and eosin staining of representative footpads from C57BL/6J or RAG1-/- mice inoculated with PBS or wt CHIKV.(A) PBS Day 7, (B) C57BL/6J wt CHIKV Day 7, (C) RAG1-/- wt CHIKV Day 7, (D) PBS Day 14, (E) C57BL/6J wt CHIKV Day 14, (F) RAG1-/- wt CHIKV Day 14, (G) PBS Day 28, (H) C57BL/6J wt CHIKV Day 28, (I) RAG1-/- wt CHIKV Day 28; all images were taken at 20x; scale bar is 200μm. Images of PBS controls were taken from RAG1-/- mice.

Mentions: These findings contrasted with those seen in the animals inoculated via the FP (Fig 5); following this route, C57BL/6J mice exhibited severe myositis in the inoculated leg on day 7 (Fig 5B). By day 14 post inoculation, inflammation was resolving and muscle regeneration had begun (Fig 5E); lymphocytes and neutrophils had left the lesions leaving only macrophages behind. Many of the cells present, which appeared large, were regenerating myocytes. By day 14 macrophages would be expected to be present to promote wound healing and muscle regeneration. By day 28, the lesions were healed (Fig 5H). The results in RAG1-/- mice inoculated via the FP were surprising because, as noted above, no footpad swelling was noted after day 2 in these mice following FP injection with wt CHIKV (Fig 3). Based on these results and previous studies, we did not expect to observe any inflammation or tissue damage in the RAG1-/- mice. At day 7 post-inoculation, no inflammation or tissue damage was noted in these animals (Fig 5C). However, at day 14 post inoculation, severe muscle damage was observed along with a mild inflammatory infiltrate. The muscle damage observed at day 14 (Fig 5F) in RAG1-/- mice was comparable to damage seen in wt mice at day 7 post inoculation (Fig 5B). By day 28 the lesions were healed (Fig 5I). Sham-infected animals had no evidence of histologic damage in the FP (Fig 5A, 5D and 5G). The PBS groups from RAG1-/- and C57BL/6J mice were identical.


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 footpads from C57BL/6J or RAG1-/- mice inoculated with PBS or wt CHIKV.(A) PBS Day 7, (B) C57BL/6J wt CHIKV Day 7, (C) RAG1-/- wt CHIKV Day 7, (D) PBS Day 14, (E) C57BL/6J wt CHIKV Day 14, (F) RAG1-/- wt CHIKV Day 14, (G) PBS Day 28, (H) C57BL/6J wt CHIKV Day 28, (I) RAG1-/- wt CHIKV Day 28; all images were taken at 20x; scale bar is 200μm. Images of PBS controls were taken from RAG1-/- mice.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003800.g005: Hematoxylin and eosin staining of representative footpads from C57BL/6J or RAG1-/- mice inoculated with PBS or wt CHIKV.(A) PBS Day 7, (B) C57BL/6J wt CHIKV Day 7, (C) RAG1-/- wt CHIKV Day 7, (D) PBS Day 14, (E) C57BL/6J wt CHIKV Day 14, (F) RAG1-/- wt CHIKV Day 14, (G) PBS Day 28, (H) C57BL/6J wt CHIKV Day 28, (I) RAG1-/- wt CHIKV Day 28; all images were taken at 20x; scale bar is 200μm. Images of PBS controls were taken from RAG1-/- mice.
Mentions: These findings contrasted with those seen in the animals inoculated via the FP (Fig 5); following this route, C57BL/6J mice exhibited severe myositis in the inoculated leg on day 7 (Fig 5B). By day 14 post inoculation, inflammation was resolving and muscle regeneration had begun (Fig 5E); lymphocytes and neutrophils had left the lesions leaving only macrophages behind. Many of the cells present, which appeared large, were regenerating myocytes. By day 14 macrophages would be expected to be present to promote wound healing and muscle regeneration. By day 28, the lesions were healed (Fig 5H). The results in RAG1-/- mice inoculated via the FP were surprising because, as noted above, no footpad swelling was noted after day 2 in these mice following FP injection with wt CHIKV (Fig 3). Based on these results and previous studies, we did not expect to observe any inflammation or tissue damage in the RAG1-/- mice. At day 7 post-inoculation, no inflammation or tissue damage was noted in these animals (Fig 5C). However, at day 14 post inoculation, severe muscle damage was observed along with a mild inflammatory infiltrate. The muscle damage observed at day 14 (Fig 5F) in RAG1-/- mice was comparable to damage seen in wt mice at day 7 post inoculation (Fig 5B). By day 28 the lesions were healed (Fig 5I). Sham-infected animals had no evidence of histologic damage in the FP (Fig 5A, 5D and 5G). The PBS groups from RAG1-/- and C57BL/6J mice were identical.

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