A tick-borne flavivirus known as the Powassan virus (POWV), linked to human infections in the US, Canada, and Russia, is endemic to North America. Lineage I of the virus is spread by Ixodes cookei ticks across the Great Lakes area of the United States, whereas Ixodes scapularis spread lineage II ticks in the Northeast. After a tick attaches, humans can get an infection within 15-30 minutes.   

Ixodes ticks have three life phases (larva, nymph, & adult), each requiring a blood meal to develop. The principal stage for I. scapularis to transfer infections is the nymph stage, which regularly bites humans. White-footed mice and white-tailed deer are the most common reservoirs for I. scapularis, while I. cookei feeds on skunks, woodchucks, and squirrels. Ticks do not rely on humans for survival but may feed on them for their next blood meal; hence, humans are known as accidental hosts.   

In the United States, Minnesota & Wisconsin have the greatest incidences of POWV, with Massachusetts and New York also having greater incidences than other states in the Great Lakes or Northeast region. The CDC added POWV to the list of nationally notifiable illnesses in 2002. Though still uncommon, Powassan virus incidences have grown in recent years.

From 1958 to 1998, 27 instances were documented in the United States; however, in 1999 – 2016, 98 cases were reported, with most cases happening in New York, Minnesota, Wisconsin, Massachusetts, & New Hampshire. From 2009 – 2015, 16 instances were documented in Canada, predominantly in Ontario & Quebec. From 1978 – 2004, 11 cases were documented in Russia, most of which occurred in Primorsky Krai.   

Powassan virus has an excessive mortality rate of 10% and a severe morbidity rate of 50%. Survivors of severe disease may develop long-term neurological issues such as memory loss, muscle weakness, and paralysis. The CDC received reports of 133 instances of neuroinvasive POWV & 12 instances of non-neuroinvasive POWV between 2010 and 2018.

POWV has been linked to 150 recorded human diseases since its discovery in 1958. From 1958 to 2005, the incidence rate in the United States was about one case per year, but it has since climbed to an average of ten cases yearly. Powassan virus disease is still uncommon, with roughly 200 occurrences recorded in the United States in 2012 and 33 confirmed instances between 2001 and 2010.   

Classification and Structure: 

Kingdom: Virus 

Phylum: Kitrinoviricota  

Class: Flasuviricetes  

Order: Amarillovirales  

Family: Flaviviridae  

Genus: Flavivirus  

Species: Powassan virus 

Powassan virus has a single-stranded positive-sense RNA genome that is approximately 11,000 nucleotides long. The genome has a single open reading frame (ORF) that encodes a polyprotein. Powassan virus has a spherical or icosahedral shape, characterized by 20 triangular faces and 12 vertices. 

The powassan virus is approximately 50 nm in diameter. The capsid has a diameter of about 30 nm and comprises 180 capsid protein copies. The envelope is approximately 20 nm thick and derived from the host cell membrane. The spike is about 10 nm high and comprises 60 dimers of E proteins.   

The polyprotein is cleaved into three structural proteins and seven non-structural proteins. The structural proteins include the capsid, premembrane/membrane (prM/M), and envelope (E) proteins.  

The capsid comprises 180 copies of the capsid protein arranged in an icosahedral symmetry. It forms the inner shell of the virus and interacts with the RNA genome. The capsid protein has an N-terminal region that interacts with the RNA and a C-terminal region that anchors the capsid to the envelope. 

The envelope is a lipid bilayer derived from the host cell membrane. It contains two types of glycoproteins: premembrane/membrane (prM/M) and envelope (E) proteins. The E protein forms spike-like protrusions on the surface of the virus, And the prM/M protein assists in the proper folding of the E protein and plays a role in virus assembly. 

The spike is composed of 60 dimers of E proteins arranged in a herringbone pattern. Each dimer consists of two E proteins oriented in an antiparallel fashion. The spike protrudes from the surface of the viral envelope. 

Lineage I & Lineage II are the two antigenic subgroups of the Powassan virus. Isolated for the first time in 1958, Lineage I is the original lineage & is connected to ticks, including Ixodes cookeri, Ixodes marxi, & Ixodes scapularis. It has been recorded in Canada, the USA, & Russia and can infect humans, rats, birds, and other animals.

Humans, deer, rats, and other animals can contract the 1997-discovered Lineage II infection linked to Ixodes scapularis ticks. In both the US & Canada, reports of Lineage II have been made. The two lineages’ nucleotide and amino acid sequences are comparable by 84% & 94%, respectively, indicating a high degree of genetic similarity.   

Within these lineages, several Powassan virus strains have been discovered. The Powassan virus‘s prototype strain is known as the LB strain. It was discovered in a patient with encephalitis in 1958 in Powassan, Ontario, Canada. It is a lineage I strain linked to Ixodes cookeri ticks, and cases of it have been documented in both Canada and the US. In Partizansk, Russia, in 2006, the lineage I strain Partizansk-2006 was discovered in a sample of human blood. This strain has only been documented in Russia & is linked to Ixodes persulcatus ticks.   

Ixodes scapularis ticks collected at Shelter Island, New York, USA, yielded the Deer tick virus (DTV) strain, a member of lineage II in 1997. DTV has been recorded in both Canada & the US & is connected to Ixodes scapularis ticks. Other lineage II strains include Anoka-2008, isolated from a human serum sample in Anoka County, Minnesota, USA, in 2008, & Maine-1999, which was isolated from a human cerebrospinal fluid sample in Maine, USA, in 1999. Ixodes scapularis ticks are linked to both the Maine-1999 & Anoka-2008 outbreaks, which have only been recorded in the United States.   

The pathogenicity of the Powassan virus is aided by various genes and virulent proteins that it encodes. Hexameric protein, known as non-structural protein 1 (NS1), controls RNA replication and assembly by interacting with viral and host factors. It also engages in interactions with toll-like receptors, plasminogen, complement proteins, and proteoglycans made of heparan sulfate.

A multifunctional protein containing protease, helicase, & NTPase activity is known as non-structural protein 3 (NS3). NS3 participates in several interactions within the host cell and aids in the replication of viral RNA. Another crucial protein with interferon antagonist action, known as non-structural protein 5 (NS5), enables the virus to elude the host’s immune response.

Important elements of the host’s innate immune system, STAT1 & STAT2, are inhibited by NS5 from being phosphorylated to propagate into the nucleus. The virus’s principal surface protein, the envelope (E) protein, is essential for viral attachment, entry, & fusion with host cells. Domain I (DI), Domain II (DII), & Domain III (DIII) make up this structure. These domains let the virus connect with the receptors on the host cell, allowing viral entrance & infection. 

Although partially acknowledged, the pathogenesis of the Powassan virus involves numerous critical features. The virus enters the human body via the bite of an infected tick. Unlike other tick-borne infections, the Powassan virus may require extended feeding for transmission and can be spread in as little as a few minutes of tick attachment. 

Powassan virus replicates in a variety of locations within the host, including the skin, lymph nodes, & circulation. The virus can evade the blood-brain barrier and infiltrate the central nervous system. This invasion can cause brain inflammation or inflammation in the brain & spinal cord). 

The presence of the Powassan virus in the CNS causes the host to mount an immunological response. This immune response is thought to play a role in the infection’s observed tissue damage & neurological symptoms. Cross-reactivity with other flaviviruses, like West Nile or dengue viruses, might lead to immune-mediated problems. 

Powassan virus infection in humans can result in severe and occasionally fatal sickness. The infection is so severe that the mortality rate is believed to be around 10%. Furthermore, roughly 50% of severe disease survivors endure long-term neurological consequences such as memory loss, fatigue, muscle paralysis, & seizures. 

B cells generate antibodies, referred to as immunoglobulins, that recognize and attach to the virus. Natural Killer Cells secrete cytotoxic granules containing granzymes and perforin, causing infected cells to be destroyed. T lymphocytes identify viral antigens on infected cells & produce cytotoxic chemicals like perforin and granzymes to kill the infected cells. 

The POWV-SEV vaccine stimulates both cellular & humoral immune responses. Vaccination with POWV-SEV resulted in significant levels of detectable antibodies specific to the POWV envelope protein in mice.

These antibodies have the potential to attach to the viral envelope protein & neutralize the virus. When stimulated with POWV peptides, the vaccination also generated POWV-specific T cells, as demonstrated by an increase in the number of T cells generating interferon-gamma (IFN-γ). It shows that cellular immune responses to viral antigens have been activated. 

Furthermore, the POWV-SEV vaccine showed specificity in its immune responses. The antibodies generated by POWV-SEV-immunized mice did not cross-react with envelope antigens of other flaviviruses like West Nile virus (WNV), Zika virus (ZIKV), or dengue serotypes 1 through 4. This specificity is crucial as it ensures the immune response is targeted specifically against the Powassan virus. 

Powassan virus disease is a rare illness transmitted to humans through tick bites. While most infections result in mild or no symptoms, severe cases can occur where the virus spreads to the brain, leading to encephalitis, a potentially life-threatening condition. 

Initial symptoms: The onset of Powassan virus infection may be marked by typical symptoms such as fever, headache, vomiting, and weakness. These symptoms can resemble those of other viral illnesses and may not initially raise suspicion of a severe infection. 

Neurological symptoms: As the disease progresses, more severe symptoms associated with neurological involvement may develop. These can include confusion, altered mental state, difficulty speaking, and seizures. These neurological manifestations indicate the virus’s impact on the brain and surrounding structures. 

Paralysis: In some rare cases, Powassan virus infection can lead to paralysis. This paralysis can be partial or complete, affecting various muscle groups and resulting in motor impairments. 

It is crucial to remember that roughly 1 in 10 individuals with severe Powassan virus sickness may pass away because of the infection. Even among those who survive, nearly half may endure long-term health consequences, such as persistent headaches, a loss of muscular mass and strength, and cognitive impairments.

The incubation period, or the interval between a tick bite & the onset of symptoms, can last anywhere between a week and a month. Suppose you have symptoms after being bitten by a tick. In that case, it is imperative to see a doctor, especially if you reside in or have recently visited places where the Powassan virus is known to exist. 

Blood Tests: Blood tests are included to detect the presence of the Powassan virus or the immune response against the virus. These tests can include: 

• Antibody Detection: Blood tests can detect the presence of antibodies released by the immune system in response to the Powassan virus. The most common test is the IgM antibody capture ELISA or IgM immunofluorescence antibody (IFA) assay. These tests can identify recent or acute infections. 

• Viral RNA Detection: Blood tests can also detect the genetic material (RNA) of the Powassan virus using techniques such as reverse transcription-polymerase chain reaction (RT-PCR). This test can help confirm an active infection and is particularly useful during the early stages of the disease. 

Spinal Tap (Lumbar Puncture): A spinal tap or lumbar puncture collects cerebrospinal fluid (CSF) from the space around the brain and spinal cord. CSF tests can help determine if the central nervous system is affected by the Powassan virus. The collected CSF can be tested for the presence of antibodies or viral RNA using similar methods as blood tests. 

Imaging Tests: Imaging tests, such as CT scans (computed tomography scans) or MRI (magnetic resonance imaging), may be conducted if a person presents with neurological symptoms. These tests can provide detailed brain images and help identify signs of inflammation or damage caused by Powassan virus infection. 

Specific Powassan virus assays, like IgM antibody capture ELISA, PRNT, & viral RNA detection, can only be conducted in specialized facilities. The CDC has established diagnostic criteria for Powassan virus disease, which include living in an endemic area, reporting tick exposure, and exhibiting symptoms like fever, mental retardation, seizures, and focal neurological deficits. Positive Powassan IgM or Powassan PRNT test results in blood, tissue, or CSF samples also corroborate the diagnosis. 

• Keep the grass mowed no shorter than 5 inches to limit tick habitat. Stay on well-marked paths and avoid strolling through woodland or grassy areas where ticks are prevalent. On exposed skin and clothing, apply insect repellents that include DEET or other proven tick-repellent chemicals. 

• If a tick is found adhered to the skin, use fine-tipped tweezers to remove it carefully and quickly. Grasp the tick at the skin’s surface & pull it up with firm pressure. Avoid squeezing or twisting the tick to reduce the chance of mouthpart rupture and virus transfer. 

• Individuals proven to have Powassan virus infections should refrain from donating blood for four months due to the possibility of virus transmission via blood transfusions. 

Powassan Virus > Fact Sheets > Yale Medicine 

Powassan Virus | Powassan | CDC 

Powassan Virus: Causes, Symptoms, Diagnosis & Treatment (clevelandclinic.org)