Toscana Virus

Toscana virus (TOSV) is an arthropod-borne phlebovirus responsible for acute febrile illness and neuroinvasive infections, including meningitis and encephalitis, particularly during the summer months in Mediterranean countries. First isolated in 1971 from the sandfly Phlebotomus perniciosus in Tuscany, Italy, TOSV has since emerged as one of the most significant viral pathogens transmitted by sandflies in southern Europe. Unlike many other arboviruses that predominantly cause febrile illness, TOSV exhibits a marked neurotropism, leading to central nervous system (CNS) involvement in a substantial proportion of symptomatic cases. The virus circulates in endemic foci across Italy, France, Spain, Portugal, Greece, Cyprus, Turkey, and North Africa, with increasing reports of travel-associated cases. Despite its public health relevance, TOSV remains underdiagnosed due to limited awareness and diagnostic capacity. This article provides a comprehensive overview of Toscana virus, covering its virology, epidemiology, clinical manifestations, and key molecular targets that underlie its pathogenesis.

Introduction

Toscana virus belongs to the genus Phlebovirus within the family Phenuiviridae (order Bunyavirales). It is classified within the sandfly fever Naples virus species complex, which includes closely related viruses such as sandfly fever Naples virus (SFNV) and sandfly fever Sicilian virus (SFSV). Based on genetic diversity, TOSV is divided into two distinct lineages (A and B), with lineage A prevalent in western Mediterranean countries and lineage B in the eastern Mediterranean. The TOSV genome consists of three negative-sense, single-stranded RNA segments: large (L), medium (M), and small (S). The L segment (approximately 6.4 kb) encodes the RNA-dependent RNA polymerase (RdRp), a multifunctional enzyme essential for viral transcription and genome replication. The M segment (approximately 3.2 kb) encodes a glycoprotein precursor that is co-translationally cleaved into two envelope glycoproteins, Gn and Gc, which form heterodimeric spikes on the virion surface. These glycoproteins mediate receptor binding and pH-dependent membrane fusion during viral entry. The S segment (approximately 1.8 kb) employs an ambisense coding strategy, encoding the nucleoprotein (N) in the genomic sense and a non-structural protein (NSs) in the antigenomic sense. NSs is a major virulence factor that counteracts host innate immune responses.

Clinical Manifestations

The incubation period for TOSV infection ranges from a few days to two weeks. Clinical presentations can be divided into three categories:

• Febrile Illness: Patients may experience sudden onset of fever, headache, myalgia, arthralgia, and gastrointestinal symptoms. This syndrome is indistinguishable from other viral fevers and typically resolves within a week.
• Neuroinvasive Disease: TOSV exhibits a strong neurotropism, causing aseptic meningitis, meningoencephalitis, or encephalitis in up to 50% of symptomatic cases. Symptoms include severe headache, nuchal rigidity, photophobia, confusion, seizures, and focal neurological deficits. Cerebrospinal fluid (CSF) analysis reveals lymphocytic pleocytosis, elevated protein, and normal glucose. Although most patients recover fully, some experience prolonged fatigue, cognitive impairment, or rarely, fatal outcomes.
• Other Manifestations: Rare complications include orchitis, hepatitis, and myocarditis. Immunocompromised individuals may develop severe disseminated disease.

Diagnostic and Therapeutic Approaches

Diagnosis of TOSV infection relies on molecular and serological methods. Reverse transcription-PCR (RT-PCR) targeting conserved regions of the S or L segments is used for early detection in blood or CSF. Serological tests, including ELISA and immunofluorescence assays, detect IgM and IgG antibodies against viral N protein or whole virus. Plaque reduction neutralisation tests (PRNT) are the gold standard for confirming specific antibody responses but are not routinely available.

No specific antiviral therapy is approved for TOSV. Treatment is supportive, focusing on management of fever, pain, and neurological complications. Ribavirin has shown in vitro activity against some phleboviruses but clinical efficacy is unproven. Favipiravir, an RNA polymerase inhibitor, has demonstrated activity against related viruses in animal models and could be repurposed. Immunomodulatory therapies, such as corticosteroids, are sometimes used in severe encephalitis, but their benefit is unclear.

Toscana Virus Antigens