Research Article: PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Aroon Supramaniam, Helle Bielefeldt-Ohmann, Penny A. Rudd, Julie Webster, Vito Ferro, Lara J. Herrero, Partha Mukhopadhyay.


Recently the anti-viral effects of prophylactic treatment with the low-molecular-weight heparan sulfate mimetic PG545 in Ross River virus (RRV) infected mice were reported. We further investigated the related, transient pathophysiology of PG545 drug treatment in RRV-infected and mock-infected PG545-treated mice. PG545 treatment resulted in mild lethargy and piloerection, on days after the drug administration. Mice were treated with two or three doses of PG545 within a ten-day period and were subsequently culled at peak disease or at disease resolution. The treatment responses of the spleen and liver were assessed through histology, flow cytometry, gene arrays and serum biochemistry. Microscopy showed an expanded red pulp in the spleen following either two or three treatments with PG545. The red pulp expansion was further demonstrated by the proliferation of megakaryocytes and erythrocyte precursors within the spleen. In addition, flow cytometry and gene array analyses revealed a reduction of lymphocytes within the spleens of PG545-treated mice. Previously unreported, RRV-induced elevations of aspartate aminotransferase (AST) and alanine transaminase (ALT) enzymes and creatinine were also noted in the RRV-infected mice. However, PG545 only reduced AST and ALT levels but not the creatinine levels in infected mice during treatment. Mice treated with three doses of PG545 also showed hepatosplenomegaly and anaemia, which were reversed upon discontinuation of the treatment. In summary, this study demonstrates that dose and frequency related haemopoietic pathophysiology such as hepatosplenomegaly and anaemia, occurred in C57BL/6 mice treated with PG545. However, this effect was reversible once drug administration is terminated.

Partial Text

Australia is home to more than 70 arthropod-borne viruses that are mostly enzootic. However, a few exceptions, such as the Ross River virus (RRV) and Barmah Forest virus (BFV), can also infect humans and cause diseases [1]. Increased precipitation often leads to dramatic events such as extreme rainfall and non-tidal flooding [2]. These weather events in turn, enhance vector breeding and can exacerbate viral transmission to animal and human hosts, causing frequent, sporadic disease outbreaks [2]. RRV is an arthritogenic alphavirus in the Togaviridae family. It is transmitted either by the Aedes or Culex species of mosquitoes and causes notifiable diseases in Australia [3]. Infected individuals may be mildly febrile and experience debilitating peripheral polyarthralgia and myalgia. The musculoskeletal pain experienced can be either acute, or progress to chronic or recurrent pain, leading to significant morbidity [3]. In 2015, the largest epidemic in Australia reported a spike of 9,544 cases compared to the conventional annual incidence of around 5,000 cases [4, 5]. Then, in 2017, another 6,925 cases were reported [6]. Furthermore, the 2017 outbreak, also reported significant incidences of RRV disease (RRVD) in temperate regions such as Melbourne compared to the previous non-incidence in these cooler climate [7].

In the current study, we explored the consequences of prolonged treatment of PG545 in RRV-infected mice alongside, the recently published standard PG545 treatment for RRVD in mice. This was done, to determine if an increase in the treatment frequency could impact the duration and further reduce the acute clinical disease observed in the RRV-infected mice. Additionally, the occurrence of compound-induced lymphoid organ changes, if any, were also critically evaluated, to determine compound efficacy and tolerability. During this study, it was first noted that, the PG545 treatment to both mock- and RRV-infected mice groups caused a reduction in weight gain across the treated groups. Other comparable murine studies of PG545 administration have also reported weight losses in treated animals [30].




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