Thogotoviruses/Bourbon Virus

The genus Thogotovirus in the family Orthomyxoviridae contains multiple species, including Araguari, Aransas Bay, Bourbon, Dhori, Jos, Thogoto, and Upolu viruses. Of these viruses, only two have been identified in the United States: Aransas Bay virus (on the southern gulf coast of Texas), from soft ticks found in the nests of seabirds, and Bourbon virus, as a cause of human infection in Kansas and, more recently, in Missouri (although the pathogenesis remains undefined).[1, 2] In the genus Thogotovirus, only 3 have been associated with human disease: Thogoto, Dhori, and Bourbon viruses.[1, 8]

Thogoto and Dhori viruses are transmitted by ticks.[3] Their genome is composed of 6 segments of negative-sense, single-stranded RNA. Replication and transcription occur in the cell nucleus. Polymerase basic subunits 1 and 2, in addition to the polymerase acidic subunit, compose the polymerase complex. These subunits synthesize viral genomic negative-strand DNA, complementary positive-strand RNA, and capped polyadenylated mRNAs.[4]

Electron microscopic images of novel Thogotovirus isolate. Filamentous (A) and spherical (B) virus particles with distinct surface projection are visible in culture supernatant that was fixed in 2.5% paraformaldehyde. Thin-section specimens (C and D), fixed in 2.5% glutaraldehyde, show numerous extracellular virions with slices through strands of viral nucleocapsids. Arrows indicate virus particles that have been endocytosed. Scale bars indicate 100 nm. Courtesy of the CDC.

Thogoto virus initially attaches to sialic acid receptors in host cells through glycoproteins. Subsequently, clathrins from the host cell lead to endocytosis of the virus. The encapsidated RNA segments migrate to the nucleus.[5]

The genome of thogotoviruses consists of 6 segments. Thogotoviruses undergo replication and transcription within the cell nucleus. A viral polymerase complex composed of polymerase basic subunit 1, polymerase basic subunit 2, and polymerase acidic subunit synthesizes negative-strand viral RNA, capped polyadenylated mRNAs, and complementary positive-strand RNA. Segment 5 of the genome encodes nucleoprotein (NP). Segment 6 encodes the matrix protein and an accessory M-long protein that can interfere with the host’s innate immune response.[4] High levels of M1 protein, which is encoded by an alternative splicing of the segment 6 of the viral genome, induces genome segments to be exported from the nucleus of the virion through nuclear export protein (NEP protein). Viral assembly and budding occurs at the plasma membrane.[5]

Murine models of Dhori virus infection, which belongs to the Thogotovirus genus, demonstrate an exaggerated cytokine response, including tumor necrosis factor, interleukin-1, interleukin-6, interleukin-10, macrophage inflammatory protein 1, monocyte chemoattractant protein (MCP)–1, and interferon (IFN). Infected mice also exhibited leucopenia and lymphopenia. On necropsy, pulmonary inflammation, hemorrhage, and edema, as well as hepatic necrosis, apoptosis, and steatosis, were seen. Lymphocytic apoptosis with karyorrhexis was marked in lymph nodes and spleen.[6]

Thogoto virus has been isolated from various species of ticks, including Boophilis species in Kenya and Rhipicephalus species in Sicily. In Nigeria and Egypt, Hyalomma ticks and Amblyomma variegatum have been identified as vectors for Thogoto virus. Thogoto virus has also been isolated in Uganda, Ethiopia, Cameroon, central African Republic, and southern Europe.[7]

Cattle, sheep, donkeys, buffaloes, rats, and camels are also susceptible to Thogoto virus, as suggested by serological evidence.[7]

Dhori virus, another species of the Thogotovirus genus, also infects humans. It has 7 RNA segments, in contrast to Thogoto virus, which has 6 RNA segments. Dhori virus has been found in eastern Russia, Egypt, India, and southern Portugal. It has also been isolated from Hyalomma species ticks.[7]

Bourbon virus was discovered in 2014 in Bourbon County, Kansas, when it caused clinical illness in a single index patient who had had prior exposure to ticks, although the presumptive vector, ticks, has not been clearly established as the vector of disease in this single case.[8] A 2017 case was reported in a 58-year-old female employee of Meramec State Park, Missouri, who was infected via a tick bite. During her course of illness, the woman developed hemophagocytic lymphohistiocytosis (HLH) and died of the infection. The CDC confirmed Bourbon virus as the etiology.[9]

Thogoto virus infection presents as a febrile illness with CNS involvement. Other Thotogovirus infections may also cause meningitis and encephalitis.

In 1966, 2 cases of Thogoto virus infection were reported in Nigeria. One of them presented in an adult as a febrile syndrome and optic neuromyelitis. The second case manifested in a 14-year-old boy as meningitis and resulted in death within a week as a result of complications from underlying sickle cell disease.[8]

Five cases of Dhori virus infection were described in laboratory workers infected accidentally while preparing cultural agents. In 3 cases, the infection manifested as acute fever (of up to 4 days’ duration) and severe toxic symptoms. The other 2 patients had central nervous system involvement manifesting as encephalitis with subcortical symptoms, pyramidal signs, and encephalopolyradiculoneuritis with paresthesia.[10]

In 2014, the newest member of the genus, Bourbon virus, was isolated when it infected a 50-year-old man with a known history of recent prior tick exposure in Bourbon County, Kansas, United States. He presented with obtundation, fever, leukopenia, and thrombocytopenia. He eventually developed multiorgan failure and cardiopulmonary arrest despite treatment with doxycycline for presumptive tick-borne infection. In a specimen that was sent to the Centers for Disease Control and Prevention (CDC) to evaluate for Heartland virus, the presence of a novel virus was noted in traditional viral isolation cell culture, as well as plaque reduction neutralization tests. Subsequent next-generation sequencing and phylogenetic analysis revealed a virus with significant resemblance to Thogoto virus.[8, 11]

A subsequent case of fatal Bourbon virus infection, reported in Missouri in 2017, included hemophagocytic lymphohistiocytosis (HLH) as a manifestation. The CDC confirmed Bourbon virus as the etiology.[9]

Physical examination may reveal several manifestations, such as fever, papular rash, lymphadenopathy, altered mental status, meningismus, and pyramidal signs.[8]

Thogotoviral infection may manifest as nonspecific symptoms such as the following:

• Nausea
• Vomiting
• Weakness
• Diarrhea
• Fever
• Papular rash
• Lymphadenopathy

Most viruses from the genus Thogotovirus affect the central nervous system, causing altered mental status, meningismus, headaches, and pyramidal signs. Infection may also manifest as sensitivity abnormalities and polyradiculoneuropathy.[8, 10]

Laboratory evaluation in most cases shows normal blood counts; however, Bourbon virus has been reported to cause leukopenia, lymphopenia, and thrombocytopenia, in addition to mild hyponatremia, hypokalemia, and increased levels of liver enzymes.[8]

Dhori virus infection in mice showed fulminant systemic illness, leukopenia, and increased levels of liver enzymes.[6]

The following laboratory tests may be used in the workup of infections caused by viruses from the genus Thogotovirus:

• Complete blood cell (CBC) count, which is described only as abnormal in the single case report of Bourbon virus infection ^[8]
• Liver function tests
• Complete metabolic panel
• Blood and urine cultures to rule out bacterial infections
• Polymerase chain reaction (PCR) of blood to evaluate for other tick-related illnesses like ehrlichiosis or anaplasmosis
• Advanced molecular studies (ie, next-generation sequencing for viral genome sequencing, reverse-transcriptase PCR [RT-PCR], phylogenetic analyses) have been used in the workup of Bourbon virus infection ^[8]

Chest radiography may be used to detect complications as seen cases with multiorgan failure and potential lung injury.

No specific diagnostic test is used to evaluate suspected Bourbon virus infection. The CDC recommends that the healthcare practitioner contact the state health department regarding the possibility of pursuing an investigational protocol for this purpose.[12]

Infections caused by viruses from the Thogotovirus genus are treated with supportive care. No vaccine or antiviral therapy has been reported to be effective in treating infections with these viruses.[12]

An infectious disease specialist should be consulted.

Infection by viruses from the genus Thogotovirus are transmitted by ticks. The following measures serve to avoid transmission:

• Use insect repellents that contain 20-30% DEET (N,N-diethyl-meta-toluamide) on skin and clothing. Insect repellents that contain 0.5% permethrin may be used on clothing and outdoor gear.
• Wear long sleeves.
• Avoid bushy and wooded areas. ^[8]