Venezuelan Equine Encephalitis Virus Capsid—The Clever Caper

Abstract

Venezuelan equine encephalitis virus (VEEV) is a New World alphavirus that is vectored by mosquitos and cycled in rodents. It can cause disease in equines and humans characterized by a febrile illness that may progress into encephalitis. Like the capsid protein of other viruses, VEEV capsid is an abundant structural protein that binds to the viral RNA and interacts with the membrane-bound glycoproteins. It also has protease activity, allowing cleavage of itself from the growing structural polypeptide during translation. However, VEEV capsid protein has additional nonstructural roles within the host cell functioning as the primary virulence factor for VEEV. VEEV capsid inhibits host transcription and blocks nuclear import in mammalian cells, at least partially due to its complexing with the host CRM1 and importin α/β1 nuclear transport proteins. VEEV capsid also shuttles between the nucleus and cytoplasm and is susceptible to inhibitors of nuclear trafficking, making it a promising antiviral target. Herein, the role of VEEV capsid in viral replication and pathogenesis will be discussed including a comparison to proteins of other alphaviruses.

Venezuelan Equine Encephalitis Virus Capsid Implicated in Infection-Induced Cell Cycle Delay in vitro

“…Our data coupled with other previous findings led us to our model (Figure 7) where in VEEV infected cells, capsid binds to the host karyopherins CRM1 and importin α/β1, blocking the nuclear pore complex and shutting down host transcription. Transcriptional suppression is directly correlated with the block in nucleocytoplasmic trafficking although the exact mechanism is unknown (Garmashova et al, 2007; Lundberg et al, 2017). Capsid mediates transcriptional suppression of cyclins (A, E, G, and B) and cdks (cdk1 and cdk2), due at least in part to the depletion of host cell import and export proteins (Figure 7).…”

“…Incubation is typically 2–5 days, and acute disease persists for 4–6 days; occasionally the disease becomes biphasic 4–8 days later with neurological and systemic involvement such as brain hemorrhaging and edema, necrotizing vasculitis, lymphocyte destruction, neutrophilic infiltration, and neuronal degradation (Weaver et al, 2004). There are many research gaps surrounding the process of VEEV neuroinvasion (especially from sites of peripheral inoculation), target cell populations, host/virus interactions, and the molecular impact of infection on host cell processes such as cell cycle, proliferation, antiviral responses, and apoptosis (Weaver et al, 2004; Steele et al, 2007; Reichert et al, 2009; Lundberg et al, 2017).…”

Mitochondrial-Directed Antioxidant Reduces Microglial-Induced Inflammation in Murine In Vitro Model of TC-83 Infection

“…While it is important to elucidate the inflammatory cytokines produced by directly infected microglia cells, we hypothesize that these microglia will not contribute as greatly to the overall inflammatory burden given the ability of VEEV capsid protein to inhibit host transcriptional machinery [ 43 ]. Instead, we hypothesize that bystander microglia will contribute more greatly to the overall inflammatory burden.…”

Epidemic Alphaviruses: Ecology, Emergence and Outbreaks

“…In humans, VEEV has an incubation period of 1-5 days, which is nearly always followed by rapid onset of symptoms including fever, headache, myalgia, ocular pain, nausea, back pains, vomiting and diarrhea [8][9][10]. This initial clinical picture is similar to that of many viral infections, but in 4-14% of the cases, it can progress to a more serious encephalitic disease characterized by photophobia, confusion, seizures, convulsions, stupor, behavioral changes, alterations of consciousness, unilateral paralysis and coma [11][12][13]. Laboratory exams may show leukopenia, lymphopenia and elevated transaminases [14], renal failure [13], and cerebrospinal fluid may show elevated proteins and increase in lymphocyte counts [14].…”