Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

Varani, Stefania; Gelsomino, Francesco; Bartoletti, Michele; Viale, Pierluigi; Mastroianni, Antonio; Briganti, Elisabetta; Ortolani, Patrizia; Albertini, Francesco; Carlo, Calzetti; Prati, Francesca; Cenni, P.; Castellani, Gastone; Morini, Silvia; Rossini, Giada; Landini, Maria Paola; Sambri, Vittorio

doi:10.3390/v7112909

Cited by 7 publications

(8 citation statements)

References 42 publications

(48 reference statements)

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“…Similarly, our results showed no association of inflammatory markers in the CSF and disease severity. A high intrathecal production of IL-6, IFN-γ, and IL-10 suggests the activation of a selective antiviral and anti-inflammatory response in the CNS of TOSV-infected patients which is in correlation with observations in some other neuroinvasive arboviral infections (flaviviruses) where a strong inflammatory immune response in the CNS was found [23][24][25].…”

Section: Discussionsupporting

confidence: 85%

“…In the other study, no difference was observed in the plasma levels of IL-6, IL-10, TNF-α, IFN-α, and IFN-γ between TOSV-infected patients and controls, however, levels of cytokines in the CSF was significantly higher in TOSV-infected patients. No difference was found in the CSF cytokine production in patients with meningitis and meningoencephalitis [23]. Similarly, our results showed no association of inflammatory markers in the CSF and disease severity.…”

Section: Discussionsupporting

confidence: 55%

“…Data on cytokine levels during TOSV infection are scarce [22,23]. In this study, a very high levels of IL-6, IFN-γ, and IL-10 were found in all three CSF samples, while in serum samples levels of cytokines were significantly lower.…”

Section: Discussionmentioning

confidence: 40%

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Clinical, Virological, and Immunological Findings in Patients with Toscana Neuroinvasive Disease in Croatia: Report of Three Cases

et al. 2020

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Toscana virus (TOSV) is an arthropod-borne virus, transmitted to humans by phlebotomine sandflies. Although the majority of infections are asymptomatic, neuroinvasive disease may occur. We report three cases of neuroinvasive TOSV infection detected in Croatia. Two patients aged 21 and 54 years presented with meningitis, while a 22-year old patient presented with meningoencephalitis and right-sided brachial plexitis. Cerebrospinal fluid (CSF), serum, and urine samples were collected and tested for neuroinvasive arboviruses: tick-borne encephalitis, West Nile, Usutu, TOSV, Tahyna, and Bhanja virus. In addition, CSF and serum samples were tested for the anti-viral cytokine response. High titers of TOSV IgM (1000–3200) and IgG (3200−10,000) antibodies in serum samples confirmed TOSV infection. Antibodies to other phleboviruses (sandfly fever Sicilian/Naples/Cyprus virus) were negative. CSF samples showed high concentrations of interleukin 6 (IL-6; range 162.32−2683.90 pg/mL), interferon gamma (IFN-γ; range 110.12−1568.07 pg/mL), and IL-10 (range 28.08−858.91 pg/mL), while significantly lower cytokine production was observed in serum. Two patients recovered fully. The patient with a brachial plexitis improved significantly at discharge. The presented cases highlight the need of increasing awareness of a TOSV as a possible cause of aseptic meningitis/meningoencephalitis during summer months. Association of TOSV and brachial plexitis with long-term sequelae detected in one patient indicates the possibility of more severe disease, even in young patients.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 55%

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Clinical, Virological, and Immunological Findings in Patients with Toscana Neuroinvasive Disease in Croatia: Report of Three Cases

et al. 2020

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“…Japanese encephalitis virus (JEV) infection elicits an elevation of inflammatory cytokine expression through TLR7 signaling to cause neuroinflammation [15]. Meningitis caused by Toscana virus (TOSV) is associated with a strong TLR7-mediated antiviral response in the CNS [16]. Upon EV71 infection, TLR7 usually acts as an inflammatory response modulator in intestinal epithelial cells and immune cells [17–20].…”

Section: Introductionmentioning

confidence: 99%

EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

Luo

Wang

et al. 2019

PLoS Pathog

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As a neurotropic virus, human Enterovirus 71 (EV71) infection causes hand-foot-and-mouth disease (HFMD) and may develop severe neurological disorders in infants. Toll-like receptor 7 (TLR7) acts as an innate immune receptor and is also a death receptor in the central nervous system (CNS). However, the mechanisms underlying the regulation of TLR7-mediated brain pathogenesis upon EV71 infection remain largely elusive. Here we reveal a novel mechanism by which EV71 infects astrocytes in the brain and induces neural pathogenesis via TLR7 and interleukin-6 (IL-6) in C57BL/6 mice and in human astroglioma U251 cells. Upon EV71 infection, wild-type (WT) mice displayed more significant body weight loss, higher clinical scores, and lower survival rates as compared with TLR7-/- mice. In the cerebral cortex of EV71-infected mice, neurofilament integrity was disrupted, and inflammatory cell infiltration and neurodegeneration were induced in WT mice, whereas these were largely absent in TLR7-/- mice. Similarly, IL-6 production, Caspase-3 cleavage, and cell apoptosis were significantly higher in EV71-infected WT mice as compared with TLR7-/- mice. Moreover, EV71 preferentially infected and induced IL-6 in astrocytes of mice brain. In U251 cells, EV71-induced IL-6 production and cell apoptosis were suppressed by shRNA-mediated knockdown of TLR7 (shTLR7). Moreover, in the cerebral cortex of EV71-infected mice, the blockade of IL-6 with anti-IL-6 antibody (IL-6-Ab) restored the body weight loss, attenuated clinical scores, improved survival rates, reduced the disruption of neurofilament integrity, decreased cell apoptotic induction, and lowered levels of Caspase-3 cleavage. Similarly, in EV71-infected U251 cells, IL-6-Ab blocked EV71-induced IL-6 production and cell apoptosis in response to viral infection. Collectively, it’s exhibited TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Taken together, we propose that EV71 infects astrocytes of the cerebral cortex in mice and human and triggers TLR7 signaling and IL-6 release, subsequently inducing neural pathogenesis in the brain.

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“…The outcome of infection is usually good and there is no recurrence of symptoms. The virus, however, has the potential to cause severe aseptic meningitis, meningoencephalitis, and severe infections beyond the currently known geographical range of the virus [32][33][34][35][36][37][38][39][40][41][42][43][44]. Keeping preparedness in focus, it is important to develop tools to study such viruses.…”

Section: Introductionmentioning

confidence: 99%

Development of a Reverse Genetics System for Toscana Virus (Lineage A)

Alexander

Confort

Desloire

et al. 2020

Viruses

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Toscana virus (TOSV) is a Phlebovirus in the Phenuiviridae family, order Bunyavirales, found in the countries surrounding the Mediterranean. TOSV is an important cause of seasonal acute meningitis and encephalitis within its range. Here, we determined the full sequence of the TOSV strain 1500590, a lineage A virus obtained from an infected patient (Marseille, 2007) and used this in combination with other sequence information to construct functional cDNA plasmids encoding the viral L, M, and S antigenomic sequences under the control of the T7 RNA promoter to recover recombinant viruses. Importantly, resequencing identified two single nucleotide changes to a TOSV reference genome, which, when corrected, restored functionality to the polymerase L and made it possible to recover infectious recombinant TOSV (rTOSV) from cDNA, as well as establish a minigenome system. Using reverse genetics, we produced an NSs-deletant rTOSV and also obtained viruses expressing reporter genes instead of NSs. The availability of such a system assists investigating questions that require genetic manipulation of the viral genome, such as investigations into replication and tropism, and beyond these fundamental aspects, also the development of novel vaccine design strategies.

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Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

Cited by 7 publications

References 42 publications

Clinical, Virological, and Immunological Findings in Patients with Toscana Neuroinvasive Disease in Croatia: Report of Three Cases

Clinical, Virological, and Immunological Findings in Patients with Toscana Neuroinvasive Disease in Croatia: Report of Three Cases

EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

Development of a Reverse Genetics System for Toscana Virus (Lineage A)

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