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The presence of the endogenous Leishmania RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured Leishmania guyanensis ( LgyLRV1 - ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing ( LgyLRV1 + ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with L. guyanensis and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of L. guyanensis infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the LgyLRV1 + metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from L. guyanensis infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World Leishmania parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis., Competing Interests: The authors declare no conflict of interest.

Toscana Virus (TOSV) is a Phlebovirus responsible for central nervous system (CNS) injury in humans. The TOSV non-structural protein (NSs), which interacting with RIG-I leads to its degradation, was analysed in the C terminus fragment in order to identify its functional domains. To this aim, two C-terminal truncated NSs proteins, Δ1C-NSs (aa 1-284) and Δ2C-NSs (aa 1-287) were tested. Only Δ1C-NSs did not present any inhibitory effect on RIG-I and it showed a greater stability than the whole NSs protein. Moreover, the deletion of the TLQ aa sequence interposed between the two ΔC constructs caused a greater accumulation of the protein with a weak inhibitory effect on RIG-I, indicating some involvement of these amino acids in the NSs activity. Nevertheless, all the truncated proteins were still able to interact with RIG-I, suggesting that the domains responsible for RIG-I signaling and RIG-I interaction are mapped on different regions of the protein., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Toscana virus is the main phlebovirus circulating in Tuscany during the warm season, thus, a seroprevalence study was performed in the same area to estimate the antibody prevalence rates for sandfly fever Sicilian virus (SFSV) that is endemic in the Mediterranean countries. The low seroprevalence observed in this study shows that this virus does not play an important role in the etiology of febrile illness in central Italy.

Objective: The present study aimed to assess seroprevalence of and risk factors for Toscana (TOSV) and Sicilian (SFSV) virus infections in a sample of Sicilian subjects., Methods: A cross-sectional seroepidemiological study was conducted on 271 individuals. Each participant completed a self-administrated questionnaire and provided a serum sample which was analyzed for the presence of IgG specific anti-TOSV and anti-SFSV viruses., Results: Overall, 90 subjects (33.2%) were positive for TOSV IgG, 25 (9.2%) were positive for SFSV IgG and 11 (4%) were positive for both the viruses. A higher risk for TOSV seropositivity was found in participants who were older (adjOR = 1.02 per year; 95% CI = 1.01-1.03), having a pet living outdoors (adjOR = 2.62; 95% CI = 1.42-4.83) and being obese (adjOR = 2.37; 95% CI = 1.06-5.30)., Conclusions: TOSV seroprevalence appears to be relatively high in Sicilian general population, especially in older adults, representing a potential public health concern. The observations that seropositivity for TOSV was not significantly associated with SFSV seropositivity, and none of the risk factors associated with TOSV were associated with SFSV seem to suggest that these two phleboviruses may have different ecology and transmission pathways., (Copyright © 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Toscana virus (TOSV) infection is a frequent cause of meningitis in central Italy during summer. The disease generally has a benign course. Rarely, the infection produces a severe disease, with encephalitis and signs of systemic involvement, including lymphadenopathy. Since there is no clinical necessity of performing lymph node biopsy in such cases, the histopathological feature of TOSV-related lymphadenitis is not known. We herein present a case in which lymphadenopathy preceded the onset of meningitis. The excised lymph node showed a non-specific mixed-type lymphoid hyperplasia, with follicular hyperplasia, sinusal expansion and paracortical involvement. We also demonstrated the presence of viral protein and viral RNA in the lymph node tissue., (Copyright © 2010. Published by Elsevier GmbH.)

Toscana virus (TosV), a sandfly fever virus, is one of the main causes of the aseptic meningitis that occurs during the summer in some Mediterranean regions, and whose epidemiology is largely unknown. We used a Bayesian Markov Chain Monte Carlo approach and a relaxed molecular clock to estimate the demographic history of the TosV infection in a series of isolates sampled between 1980 and 2003. The estimated mean evolutionary rate was 2.5 x 10(-4) substitutions per site per year (95% HPD: 0.31-5.44 x 10(-4)subs/site/year). Bayesian skyline plot revealed a sharp decline in the effective number of infections over the last 30 years. In conclusion, our data suggest that continuous and prolonged perturbations of vector/phlebovirus interactions due to the relatively recent climate changes may have contributed to gradually reducing the viral population in endemic areas.

Toscana virus (TOSV) is an emerging virus, circulating in the Mediterranean area, that is responsible for aseptic meningitis, meningoencephalitis, and encephalitis. The development of a vaccine that could provide complete protection from TOSV infection is needed. In this study we investigated the capacity of TOSV structural proteins, nucleocapsid protein N and the two Gc and Gn glycoproteins, produced as recombinant proteins, in an animal model. In particular, we investigated their role in inducing specific and protective immune responses against virus infection. Mice were immunized intraperitoneally using TOSV antigens singly or in combination. The results show that only the N-Gc combination was able to protect 100% of animals from a lethal challenge with a neurovirulent strain of TOSV. This potential vaccine induces high serum antibody titres with neutralizing activity and it is safe for animals. Moreover, immunization induces a virus specific cell-mediated immune response, in particular a CD8+ T cell response associated with a marked expression of interferon gamma. These results indicate that the N+Gc viral antigen combination could be useful for future development of a vaccine controlling the spread of this emerging virus that could pose a new threat for humans.

Toscana virus (Bunyaviridae family, Phlebovirus genus) is a sandfly fever virus responsible for human neurological infections. Sandfly viruses are transmitted by insect vectors (Phlebotomus species) and the infection is present in climatic areas that allow the life cycle of the vector. The arthropode-borne Toscana virus is the etiologic agent of meningitis, meningoencephalitis, and encephalitis. The frequency of this neuropathic infection increases in the summer months, peaking in August in the endemic Mediterranean areas (Italy, Portugal, Spain, and Cyprus). Infection diagnosis is carried out by molecular assays and immunoenzymatic tests, which are rapid and sensitive. Recent studies have investigated the antigenic properties of the viral proteins (nucleoprotein N and surface glycoproteins G1 and G2), to better understand their immunogentic role.

Toscana virus is the most important agent responsible for meningitis in central Italy. We report a serosurveillance study, using an immunoenzymatic assay, of 360 serum samples harvested from a high-risk population occupationally exposed to Toscana virus in two regions of Italy, Tuscany and Piedmont. The results indicates a seroprevalence of Toscana virus of 77.2% in the forestry workers, particularly in the Tuscany region. This fact is strictly correlated with the ecological niches specific for the survival of Toscana virus arthropod vector.

The role of Toscana (TOS) virus in producing encephalitis without meningitis is uncertain. We studied 2 cases of TOS virus encephalitis without meningitis by means of nested polymerase chain reaction assay and DNA sequencing. Findings confirm that TOS virus may directly cause encephalitis and suggest the usefulness of DNA sequencing in investigating relationships between TOS virus molecular patterns and the spectrum of neurological involvement.

A recombinant enzyme immunoassay (rEIA) to detect serum immunoglobulin M (IgM) and IgG to Toscana virus (TOSV) was developed with the aim of establishing a simple and easily available assay for diagnosing acute and/or previous infections. The rEIA, based on the recombinant nucleoprotein of TOSV expressed in Escherichia coli, was evaluated with 97 serum samples collected in an area where TOSV is endemic and compared to an analogous assay based on cell-derived TOSV. Discordant results were resolved by immunoblotting (IB). Twenty-two of these samples, obtained from subjects hospitalized during the summer season with meningitis of suspected TOSV etiology, were further characterized by indirect immunofluorescence and IB, and detection of specific TOSV RNA sequences in the cerebrospinal fluid of these patients was attempted by nested PCR. The results indicated that rEIA was able to diagnose acute TOSV infection by detection of specific serum IgM in all of the subjects with TOSV meningitis confirmed by nested PCR or serology. The overall sensitivity and specificity of rEIA were both 100% for IgM detection and 100 and 96.6%, respectively, for IgG detection. Thus, rEIA appears to be a simple and reliable laboratory test for the diagnosis of acute TOSV infection and for the assessment of immune status.