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

Date Published: June 26, 2015

Publisher: Public Library of Science

Author(s): Robert L. Seymour, A. Paige Adams, Grace Leal, Maria D. H. Alcorn, Scott C. Weaver, David Joseph Diemert. http://doi.org/10.1371/journal.pntd.0003800

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.

Partial Text: Chikungunya virus (CHIKV) is a positive sense, single-stranded RNA virus in the genus Alphavirus, and the etiologic agent of many epidemics in Africa, Asia, Europe and most recently the Americas [1–6]. CHIKV causes chikungunya fever (CHIKF), a syndrome characterized by rash, fever, and debilitating arthralgia. In recent outbreaks, CHIKV has been recognized to manifest neurologic signs of illness in the young, elderly and in patients with co-morbidities [7]. The CHIKF syndrome is often self-limited; however many patients develop persistent arthralgia that can last months or years [8–10]. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Currently, there are no licensed vaccines or specific treatments to prevent or control CHIKF.

Our study had three key findings: 1) the adaptive immune system is not only critical for clearance of CHIKV, but it plays a role in the inflammatory response to infection; 2) tissue damage occurs in the absence of an adaptive immune response, and; 3) the newly developed CHIKV/IRES vaccine candidate and strain 181/25 do not persist in mice, even in the absence of T/B cells. The latter point is very important when considering vaccine safety, because many people in developing countries who are exposed to CHIKV are also immunocompromised due to various conditions (e.g., HIV, malnourishment, etc.).

Source:

http://doi.org/10.1371/journal.pntd.0003800

 

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