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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

Viremia in RAG1-/- mice after SC (A) and FP (B) inoculation with wt CHIKV (3 log10 PFU).C57BL/6J mice did not develop viremia after SC inoculation but developed a 10 PFU/ml viremia on day 1 after footpad inoculation. None of the vaccine cohorts in RAG1-/- or C57BL/6J mice developed viremia (limit of detection, 10 PFU/ml). Error bars represent one standard deviation; in (A) n = 4 for days 1–14 and n = 2 for day 28; in (B) n = 7 or 8 for days 1–14 and n = 3 for days 28, 42 and 56.
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pntd.0003800.g002: Viremia in RAG1-/- mice after SC (A) and FP (B) inoculation with wt CHIKV (3 log10 PFU).C57BL/6J mice did not develop viremia after SC inoculation but developed a 10 PFU/ml viremia on day 1 after footpad inoculation. None of the vaccine cohorts in RAG1-/- or C57BL/6J mice developed viremia (limit of detection, 10 PFU/ml). Error bars represent one standard deviation; in (A) n = 4 for days 1–14 and n = 2 for day 28; in (B) n = 7 or 8 for days 1–14 and n = 3 for days 28, 42 and 56.

Mentions: Unlike C57BL/6J mice, RAG1-/- mice developed persistent infection when inoculated with wt CHIKV by either route (Fig 2). Viremia reached a peak titer of about 4 log10 PFU/ml on days 5–6 after SC infection, gradually decreasing to 2 log10 PFU/ml on days 14 and 28; no viremia was detected after day 28 post-infection (Fig 2A). These findings were in contrast to the vaccine candidate strains, which never produced detectable viremia.


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)

Viremia in RAG1-/- mice after SC (A) and FP (B) inoculation with wt CHIKV (3 log10 PFU).C57BL/6J mice did not develop viremia after SC inoculation but developed a 10 PFU/ml viremia on day 1 after footpad inoculation. None of the vaccine cohorts in RAG1-/- or C57BL/6J mice developed viremia (limit of detection, 10 PFU/ml). Error bars represent one standard deviation; in (A) n = 4 for days 1–14 and n = 2 for day 28; in (B) n = 7 or 8 for days 1–14 and n = 3 for days 28, 42 and 56.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003800.g002: Viremia in RAG1-/- mice after SC (A) and FP (B) inoculation with wt CHIKV (3 log10 PFU).C57BL/6J mice did not develop viremia after SC inoculation but developed a 10 PFU/ml viremia on day 1 after footpad inoculation. None of the vaccine cohorts in RAG1-/- or C57BL/6J mice developed viremia (limit of detection, 10 PFU/ml). Error bars represent one standard deviation; in (A) n = 4 for days 1–14 and n = 2 for day 28; in (B) n = 7 or 8 for days 1–14 and n = 3 for days 28, 42 and 56.
Mentions: Unlike C57BL/6J mice, RAG1-/- mice developed persistent infection when inoculated with wt CHIKV by either route (Fig 2). Viremia reached a peak titer of about 4 log10 PFU/ml on days 5–6 after SC infection, gradually decreasing to 2 log10 PFU/ml on days 14 and 28; no viremia was detected after day 28 post-infection (Fig 2A). These findings were in contrast to the vaccine candidate strains, which never produced detectable viremia.

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