Human Tibroviruses: Commensals or Lethal Pathogens?

Rhabdoviruses are a large and ecologically diverse family of negative-sense RNA viruses (Mononegavirales: Rhabdoviridae). These viruses are capable of infecting an unexpectedly wide variety of plants, vertebrates, and invertebrates distributed over all human-inhabited continents. However, only a few rhabdoviruses are known to infect humans: a ledantevirus (Le Dantec virus), several lyssaviruses (in particular, rabies virus), and several vesiculoviruses (e.g., Chandipura virus, vesicular stomatitis Indiana virus). Recently, several novel rhabdoviruses have been discovered in the blood of both healthy and severely ill individuals living in Central and Western Africa. These viruses-Bas-Congo virus, Ekpoma virus 1, and Ekpoma virus 2-are members of the little-understood rhabdoviral genus Tibrovirus. Other than the basic genomic architecture, tibroviruses bear little resemblance to well-studied rhabdoviruses such as rabies virus and vesicular stomatitis Indiana virus. These three human tibroviruses are quite divergent from each other, and each of them clusters closely with tibroviruses currently known only from biting midges or healthy cattle. Seroprevalence studies suggest that human tibrovirus infections may be common but are almost entirely unrecognized. The pathogenic potential of this diverse group of viruses remains unknown. Although certain tibroviruses may be benign and well-adapted to humans, others could be newly emerging and produce serious disease. Here, we review the current knowledge of tibroviruses and argue that assessing their impact on human health should be an urgent priority.

Australian bat lyssavirus: implications for public health.

Australian bat lyssavirus (ABLV) infection in humans is rare but fatal, with no proven effective therapy. ABLV infection can be prevented by administration of a post-exposure prophylaxis regimen of human rabies immunoglobulin and rabies vaccine. All Australian bats (flying foxes and microbats) should be considered to be carrying ABLV unless proven otherwise. Any bat-related injury (bite, scratch or mucosal exposure to bat saliva or neural tissue) should be notified immediately to the relevant public health unit - no matter how small the injury or how long ago it occurred. Human-to-human transmission of ABLV has not been reported but is theoretically possible. Standard infection control precautions should be employed when managing patients with suspected or confirmed ABLV infection.

Analysis of the MCMV resistome by ENU mutagenesis.

The mouse cytomegalovirus (MCMV) resistome is the set of host genes with nonredundant functions in resistance to MCMV infection. By screening 3,500 G(3) germline mutant mice ( approximately 1,750 gamete equivalents), we have identified eight transmissible mutations that create MCMV susceptibility in C57BL/6 mice. Among these, a mutation called Domino was noted to cause macrophage susceptibility to vesicular stomatitis virus (VSV) in vitro. This accessory phenotype was not corrected by type I interferon (IFN), which suggested a defect of the type I IFN pathway. Domino corresponds to a point mutation that alters the DNA binding domain of STAT1, leading to a defect of STAT1 activation. Identification of the Domino mutation demonstrates that an in vivo MCMV susceptibility screen is feasible and illustrates how it can provide insight into the resistome. Moreover, some mutations are far more deleterious than Domino in MCMV-infected mice, consistent with the interpretation that certain protein(s) unrelated to IFN production or signaling are more important than IFNs with regard to their net antiviral effects.

Essential role of the NV protein of Novirhabdovirus for pathogenicity in rainbow trout.

Novirhabdovirus, infectious hematopoietic necrosis virus (IHNV), and viral hemorrhagic septicemia virus (VHSV) are fish rhabdoviruses that, in comparison to the other rhabdoviruses, contain an additional gene coding for a small nonvirion (NV) protein of unassigned function. A recombinant IHNV with the NV gene deleted but expressing the green fluorescent protein (rIHNV-Delta NV) has previously been shown to be efficiently recovered by reverse genetics (S. Biacchesi et al., J. Virol. 74:11247-11253, 2000). However, preliminary experiments suggested that the growth in cell culture of rIHNV-Delta NV was affected by the NV deletion. In the present study, we show that the growth in cell culture of rIHNV-Delta NV is indeed severely impaired but that a normal growth of rIHNV-Delta NV can be restored when NV is provided in trans by using fish cell clones constitutively expressing the NV protein. These results indicate that NV is a protein that has a crucial biological role for optimal replication of IHNV in cell culture. Although IHNV and VHSV NV proteins do not share any significant identity, we show here that both NV proteins play a similar role since a recombinant IHNV virus, rIHNV-NV(VHSV), in which the IHNV NV open reading frame has been replaced by that of VHSV, was shown to replicate as well as the wild-type (wt) IHNV into fish cells. Finally, data provided by experimental fish infections with the various recombinant viruses strongly suggest an essential role of the NV protein for the pathogenicity of IHNV. Furthermore, we show that juvenile trout immunized with NV-knockout IHNV were protected against challenge with wt IHNV. That opens a new perspective for the development of IHNV attenuated live vaccines.

The role of interleukin-18 in vesicular stomatitis virus infection of the CNS.

Intranasal application of vesicular stomatitis virus (VSV) results in the initial infection of the olfactory receptor neurons and a rapid progression of the virus through the mouse central nervous system (CNS). Interleukin-18 (IL-18) is an 18.3-kd cytokine that induces interferon gamma (IFN-gamma) production in mice. IL-18 is synthesized as an inactive precursor that is cleaved and activated by caspase-1/interleukin-1beta converting enzyme (ICE). IL-18 shares several biological properties with IL-12, including the ability to induce IFN-gamma production in T lymphocytes and natural killer (NK) cells. In the CNS, microglia and astrocytes produce IL-18 and IL-12. We have previously shown that IL-12 promotes recovery from VSV encephalitis. This led us to examine the potential role of IL-18 in the pathogenesis of VSV encephalitis. We show that both IL-18 and caspase-1 mRNA are consistently present in the CNS of mice. The addition of exogenous IL-18 to cell cultures does not affect the production of VSV, and addition of exogenous IL-18 at the time of infection does not alter the morbidity or mortality of BALB/c mice. In vitro studies with neutralizing monoclonal antibody to IL-18 had no effect. From these results we conclude that in this system and under the experimental conditions used, unlike IL-12 and IFN-gamma, IL-18 does not play a significant role in the host response to VSV infection.

Management factors affecting the risk for vesicular stomatitis in livestock operations in the western United States.

OBJECTIVE: To identify management factors affecting the risk of animals developing vesicular stomatitis (VS). DESIGN: Case-control study. ANIMALS: Horses, cattle, and sheep with suspected vesicular stomatitis on 395 premises in Colorado, New Mexico, Utah, and Arizona. PROCEDURE: Data were collected during the VS outbreak of 1997. Diagnosticians interviewed livestock owners and completed a supplemental questionnaire. Cases were defined as those premises that had a completed questionnaire and had > or = 1 animal positive for VS. Control premises were all premises investigated that had a completed questionnaire and on which the animals had been tested but VS was not detected. RESULTS: Animals that had access to a shelter or barn had a reduced risk of developing VS (OR, 0.6; 95% confidence interval [CI], 0.35 to 0.99). This effect was more pronounced for equine premises (OR, 0.5; 95% CI, 0.3 to 0.9). Conversely, during an adjusted analysis on equine premises, risk of developing disease was increased slightly where animals had access to pasture (OR, 2.01; 95% CI, 1.1 to 3.7). On all premises where owners reported insect populations were greater than normal, odds of developing disease were significantly increased (OR, 2.5; 95% CI, 1.47 to 4.47). Premises with animals housed < 0.25 miles from running water were more than twice as likely to have clinical signs of VS (OR, 2.6; 95% CI, 1.32 to 5.0). CONCLUSIONS AND CLINICAL RELEVANCE: These results support reports of others that suggest biting insects are a vector in VS virus transmission. Management practices to reduce exposure to biting insects might reduce the risk of VS.

Arboviruses Pathogenic for man in Brazil

Os mais importantes aspectos clinicicos e ecoepidemiologicos e aspectos preventivos acerca das arboviroses associadas com doenca humana no Brasil sao discutidos.Trinta e seis arbovirus dentre os tipos presentemente isolados no Pais tem sido incriminados como causadores de doenca humana. Destes, cinco sao importantes em termos de saude publica pois estao associados com epidemias , sao os virus Dengue (DEN), Mayaro(MAY), Oropouche (ORO), Rocio (ROC) e Febre amarela (FA). DEN e ORO estao associados com doenca humana epidemica em areas urbanas enquanto MAY, ROC e FA especialmente em areas rurais. Basicamente, o virus ORO determina um quadro febril algumas vezes acmpanhado por meningite asseptica. MAY e DEN sao responsaveis por quadros exantematicos, sendo que DEN, nos ultimos anos tem sido associado com quadros de febre hemorragica, o que sabidamente e o mecanismos pelo qual o virus FA determinaa sua apresentacao clinica classica e o ROC esta associado com graves quadros de encefalite. Trinta e um outros arbovirus tem sido associados com doenca febril benigna em poucos e esporadicos casos. Afora DEN e os Arenavirus Flexal e Sabia ( nao sao arbovirus), todos os arbovirus envolvidos com doenca humana na AmazoniaBrasileira, sao mantidos em natureza atraves de um ciclo silvestre desenvolvido na floresta, onde diversas especies de insetos hematofagos e vertebrados silvestres atuam como vetores e hospedeiros, respectivamente.O virus DEN tem um ciclo urbano em que o mosquito Aedes aegypti e o vetor e o homem atua como hospedeiro. Os arenavirus sao transmitidos diretamente ao homen atraves de excretas de roedores que sao seus principais hospedeiros.Excetuando os cinco virus associados com epidemias que causam um grande impacto socio-economico, inclusive levando a morte, casos verificados com FA, DEN e ROC, o verdadeiro papel dessesvirus como agentes sistematicos de doencas humanas e ainda puco conhecido. Novos estudos sao necessarios para esclarecer aspectos ainda obscuros acerca da epidemiologia da maioria desses arbovirus

Pathogenesis of murine encephalitis limited by defective interfering particles. An immunohistochemical study.

To determine whether defective interfering (DI) particles alter viral encephalitis BALB/c mice were inoculated intranasally with standard vesicular stomatitis virus (VSV) and its DI particles. Addition of 10(7) PFU equivalents of DI particles to 10(5) PFU of VSV reduced morbidity but did not delay disease onset. Less mortality was also observed. When 10(3) PFU equivalents of DI particles or UV-irradiated DI particles were substituted, these effects were absent. Attempts to correlate mortality with virus recovered from the brain could not be made due to considerable variations in the few surviving mice. Immunohistochemical analysis obtained from 121 mice showed that inoculation of DI particles limited the specific pathways of VSV antigen dissemination within the central nervous system, and new pathways were not substituted. In the group of mice with reduced mortality due to DI particles, at day 4 post inoculation VSV antigen was limited to the outer layers of the glomeruli of the olfactory bulb and to the accessory olfactory bulb, whereas there was deeper invasion of the olfactory bulb and olfactory ventricular system with mice infected with standard VSV alone. Correlation between mortality and extent of invasion became more difficult to make from 8 days on, when VSV antigens were found in discrete areas of the brain. By 12 days, few surviving mice contained any detectable VSV antigen in their brains. These results demonstrate that DI particles have potential as therapeutic agents. Also, mortality resulting from VSV-induced encephalitis, although poorly understood, may be determined very early, possibly while the virus is replicating at the site of inoculation.

The earliest events in vesicular stomatitis virus infection of the murine olfactory neuroepithelium and entry of the central nervous system.

After intranasal instillation of mice with vesicular stomatitis virus (VSV), olfactory receptor neurons are infected. By 12 to 24 hr postinfection, VSV antigens are observed in adjoining supporting and basal cells and in other structures of the olfactory epithelium and lamina propria. Peripheral deafferentation of the olfactory epithelium with Triton X-100 or bilateral surgical bulbectomy does not prevent spread of VSV to the central nervous system (CNS); the route of spread differs considerably from the route taken when the olfactory nerve is intact. In contrast to rabies virus and HSV-1, VSV does not use the trigeminal nerve for entry into the brain, as the trigeminal ganglion remains virus-free following intranasal infection. These results indicate that VSV has a strong tropism for olfactory receptor cells, using them for entry into the CNS. Both retrograde and anterograde transneuronal and nonneuronal (ependymal cells and cerebrospinal fluid) pathways are utilized by VSV within the CNS.