Antimicrobial Peptides as Dual Therapeutic Strategies to Treat Venezuelan Equine Encephalitis Virus Infections and the Associated Inflammatory Response



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Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses, causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, which can progress to encephalitis and cause permanent neurological sequelae and death in a small number of cases. VEEV is classified as a category B select agent due to ease of aerosolization and high retention of infectivity in the aerosol form. Currently, there are no FDA-approved vaccines or therapeutics available to combat VEEV infections. VEEV infection in vivo is characterized by extensive systemic and neurological inflammation that can exacerbate infection by potentially increasing the susceptibility of off-site cells to infection and dissemination of the virus, and in encephalitic cases by leading to disruption of blood-brain barrier (BBB) function. Hence, a therapeutic targeting both the infection and associated inflammation represents an unmet need. Here I present a novel approach utilizing human antimicrobial peptides (AMPs), including the cathelicidin LL-37 as well as designed synthetic derivatives, to combat VEEV infections. AMPs are a key component of the innate immune response and exhibit immunomodulatory activity that regulates signaling cascades to decrease inflammatory events. The data presented here demonstrated that AMPs exhibit antiviral activity against attenuated and wild-type strains of VEEV. The peptides exhibit dual activities: 1) antiviral activity by inhibiting viral entry and 2) immunomodulatory activity inhibiting inflammatory responses during VEEV infection. I have screened a library of synthetic peptides derived from a cathelicidin and identified a number of these agents that demonstrated efficacy against VEEV. Two candidate synthetic peptides inhibited VEEV replication by approximately 1000-fold and decreased the expression of inflammatory mediators such as IL1α, IL1β, IFNᵧ, and TNFα at both the gene and protein expression levels. Furthermore, an increase in expression levels of genes involved in chemotaxis of leukocytes and anti-inflammatory genes such as IL1RN was also observed. These peptides also decreased inflammation in cells of the BBB while increasing the expression of tight junction proteins in VEEV-infected cells. Overall, I conclude that cathelicidin-derived synthetic peptides and LL-37 inhibit VEEV replication and the inflammatory burden associated with VEEV infection.