The Therapeutic Potential for Steroid Treatment Strategies in the Treatment of Murine Venezuelan Equine Encephalitis Virus (VEEV) Infection

One highly consequential presentation of Venezuelan equine encephalitis virus (VEEV) infection is encephalitis. Here we considered anti-inflammatory interventions to limit the effects of this using a BALB/c subcutaneously challenged mouse model of disease. This disease model nearly ubiquitously presents with severe encephalitis, where viral neuroinvasion correlates with much of the outward clinical signs of disease. A selection of already licenced, commonly used anti-inflammatory drugs were tested in mice developing encephalitis (starting treatment at <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>24</mn><mo> </mo><mi mathvariant="normal">h</mi></mrow></semantics></math></inline-formula> post challenge). Drug regimens were used that had previously been shown to have pharmacodynamic effects in mice for unrelated conditions. None of the treatment regimens tested reduced brain inflammation. A single anti-inflammatory drug (dexamethasone) was further tested utilising ascending doses in an effort to provide an effective anti-inflammatory regimen. Higher doses of dexamethasone (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>20</mn></mrow></semantics></math></inline-formula> and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>50</mn><mo> </mo><mi mathvariant="normal">m</mi><mi mathvariant="normal">g</mi><mo>/</mo><mi mathvariant="normal">k</mi><mi mathvariant="normal">g</mi></mrow></semantics></math></inline-formula>) reduced inflammatory markers in the brain and lowered weight loss and clinical signs early on during infection. However, the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>50</mn><mo> </mo><mi mathvariant="normal">m</mi><mi mathvariant="normal">g</mi><mo>/</mo><mi mathvariant="normal">k</mi><mi mathvariant="normal">g</mi></mrow></semantics></math></inline-formula> regimen also caused the disease to become more severe at later time points when compared to controls. When combined with the antiviral drug molnupiravir, the negative effects of the dexamethasone treatment (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>20</mn></mrow></semantics></math></inline-formula> and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>50</mn><mo> </mo><mi mathvariant="normal">m</mi><mi mathvariant="normal">g</mi><mo>/</mo><mi mathvariant="normal">k</mi><mi mathvariant="normal">g</mi></mrow></semantics></math></inline-formula>) were absent, and the positive disease severity-reducing effects remained. When combined with a specific VEEV monoclonal antibody (1A3B7), dexamethasone significantly reduced the antibody’s protective effects. These data present currently unique insights into how anti-inflammatory approaches might benefit patients with VEEV disease and where caution might be advised.