Inhibiting Powassan Virus Persistence and Spread to Neuronal Compartments
Abstract
Powassan virus (POWV) is transmitted to humans in the saliva of deer ticks during a 15-minute tick bite. POWV spreads to the brain, where it kills brain cells (neurons) and causes severe damage to the central nervous system (CNS). POWV is fatal in 10% of patients (causing encephalitis, coma, and death). In 50% of surviving patients POWV has long-term effects on brain function with memory loss, muscle wasting, and long term neurologic deficits. POWV has emerged in tick populations in the northeastern United States, along with lethal human POWV disease that has increased in New York, Connecticut, New Jersey, and other northeastern states. Deer ticks are reservoirs for POWV and a number of additional tick-borne human diseases, most notably Lyme disease. Deer ticks that carry POWV are maintained in small and large animals including white-footed mice, deer, skunks, woodchucks, and squirrels. We found that POWV is present in 2% of ticks surveyed on Long Island, a highly populated area of approximately 3 million, adjacent to New York City. Transmission of POWV to humans requires just a 15-minute tick bite, as the virus is present in tick saliva and injected into humans during tick attachment. Thus, removing ticks just hours after attachment will not prevent POWV infection. The short attachment period for POWV transmission contrasts with the greater than 24 hours required for Borrelia transmission (Lyme disease), and antibiotics used for resolving Lyme disease have no effect on POWV infection or disease. Currently there are no vaccines, prophylactics, or therapeutics to prevent or treat POWV disease. We found that POWV infects cells that form a blood-brain-barrier (BBB) and normally protect the CNS from viral infections. These protective cells are called brain endothelial cells. Brain endothelial cells form a complex with brain pericytes that are across the BBB in the CNS and the interactions of these cells normally prevents viruses from entering the brain and killing neurons. We have found that POWV infects BBB endothelial cells and pericytes. POWV does not kill brain endothelial cells or pericytes but instead, infects these cells for long periods of days to weeks. This provides a reservoir for POWVs to replicate and spread across the BBB to kill neurons. We isolated POWV from LI and developed an attenuated POWV that fails to infect human endothelial cells or cause lethal neurovirulent disease in a mouse model. We have defined potential prophylactics and therapeutics that target POWV-infected BBB cells and prevent viral spread and clear virus from infected cells. We propose evaluating existing compounds for their ability to therapeutically target POWV-infected endothelial cells and pericytes to preventing POWV persistence and spread across the BBB, and as a result, prevent POWV from killing of neurons and neurologic disease. Our findings show that IFNs and CCL5 inhibitors can block POWV spread and to clear viral infections from the brain endothelial cells. These findings suggest potential therapeutic approaches to block POWV infection and CNS damage. In addition to therapeutic approaches, we have developed an attenuated POWV that we will assess as a potential POWV vaccine. We have defined elements of the virus that determine its attenuation that we apply to generating recombinant attenuated POWVs and which permit the design of additional vaccines and therapeutic targeting. TBDRP Focus Areas: Proposed studies evaluate pre- and postexposure prophylactic, therapeutic, and vaccine approaches to preventing POWV persistence, spread to the CNS and lethal neuronal damage. Our findings are likely to rationalize therapeutics, using existing clinical compounds that are directly applicable as postexposure therapies that prevent POWV infection and damage to neurons. Ultimate Applicability: Studies proposed will evaluate therapeutic and postexposure preventive treatments for POWV infections that prevent ne
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210702
Entities
People
- Erich R Mackow
Organizations
- Stony Brook University
- United States Army