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1.  Avian Influenza H7N9/13 and H7N7/13: a Comparative Virulence Study in Chickens, Pigeons, and Ferrets 
Journal of Virology  2014;88(16):9153-9165.
ABSTRACT
Human influenza cases caused by a novel avian H7N9 virus in China emphasize the zoonotic potential of that subtype. We compared the infectivity and pathogenicity of the novel H7N9 virus with those of a recent European avian H7N7 strain in chickens, pigeons, and ferrets. Neither virus induced signs of disease despite substantial replication in inoculated chickens and rapid transmission to contact chickens. Evidence of the replication of both viruses in pigeons, albeit at lower levels of RNA excretion, was also detected. No clear-cut differences between the two H7 isolates emerged regarding replication and antibody development in avian hosts. In ferrets, in contrast, greater replication of the avian H7N9 virus than of the H7N7 strain was observed with significant differences in viral presence, e.g., in nasal wash, lung, and cerebellum samples. Importantly, both viruses showed the potential to spread to the mammal brain. We conclude that efficient asymptomatic viral replication and shedding, as shown in chickens, facilitate the spread of H7 viruses that may harbor zoonotic potential. Biosafety measures are required for the handling of poultry infected with avian influenza viruses of the H7 subtype, independently of their pathogenicity for gallinaceous poultry.
IMPORTANCE This study is important to the field since it provides data about the behavior of the novel H7N9 avian influenza virus in chickens, pigeons, and ferrets in comparison with that of a recent low-pathogenicity H7N7 strain isolated from poultry. We clearly show that chickens, but not pigeons, are highly permissive hosts of both H7 viruses, allowing high-titer replication and virus shedding without any relevant clinical signs. In the ferret model, the potential of both viruses to infect mammals could be demonstrated, including infection of the brain. However, the replication efficiency of the H7N9 virus in ferrets was higher than that of the H7N7 strain. In conclusion, valuable data for the risk analysis of low-pathogenicity avian influenza viruses of the H7 subtype are provided that could also be used for the risk assessment of zoonotic potentials and necessary biosafety measures.
doi:10.1128/JVI.01241-14
PMCID: PMC4136250  PMID: 24899194
2.  Comparative studies on the genetic, antigenic and pathogenic characteristics of Bokeloh bat lyssavirus 
The Journal of General Virology  2014;95(Pt 8):1647-1653.
Bokeloh bat lyssavirus (BBLV), a novel lyssavirus, was isolated from a Natterer’s bat (Myotis nattererii), a chiropteran species with a widespread and abundant distribution across Europe. As a novel lyssavirus, the risks of BBLV to animal and human health are unknown and as such characterization both in vitro and in vivo was required to assess pathogenicity and vaccine protection. Full genome sequence analysis and antigenic cartography demonstrated that the German BBLV isolates are most closely related to European bat lyssavirus type 2 (EBLV-2) and Khujand virus and can be characterized within phylogroup I. In vivo characterization demonstrated that BBLV was pathogenic in mice when inoculated peripherally causing clinical signs typical for rabies encephalitis, with higher pathogenicity observed in juvenile mice. A limited vaccination-challenge experiment in mice was conducted and suggested that current vaccines would afford some protection against BBLV although further studies are warranted to determine a serological cut-off for protection.
doi:10.1099/vir.0.065953-0
PMCID: PMC4103065  PMID: 24828330
3.  Characterization of African Swine Fever Virus Caucasus Isolate in European Wild Boars 
Emerging Infectious Diseases  2011;17(12):2342-2345.
Since 2007, African swine fever has spread from the Caucasus region. To learn more about the dynamics of the disease in wild boars (Sus scrofa), we conducted experiments by using European wild boars. We found high virulence of Caucasus isolates limited potential for establishment of endemicity.
doi:10.3201/eid1712.110430
PMCID: PMC3311204  PMID: 22172247
viruses; African swine fever virus; ASF; vector-borne infections; arboviruses; Caucasus isolate; wild boar; experimental characterization; Europe; arthropod-borne virus
4.  Immunogenicity Studies in Carnivores Using a Rabies Virus Construct with a Site-Directed Deletion in the Phosphoprotein 
Different approaches have been applied to develop highly attenuated rabies virus vaccines for oral vaccination of mesocarnivores. One prototype vaccine construct is SAD dIND1, which contains a deletion in the P-gene severely limiting the inhibition of type-1 interferon induction. Immunogenicity studies in foxes and skunks were undertaken to investigate whether this highly attenuated vaccine would be more immunogenic than the parental SAD B19 vaccine strain. In foxes, it was demonstrated that SAD dIND1 protected the animals against a rabies infection after a single oral dose, although virus neutralizing antibody titres were lower than in foxes orally vaccinated with the SAD B19 virus as observed in previous experiments. In contrast, skunks receiving 107.5 FFU SAD dIND1 did not develop virus neutralizing antibodies and were not protected against a subsequent rabies infection.
doi:10.4061/2011/898171
PMCID: PMC3177460  PMID: 21991446
5.  Novel Lyssavirus in Natterer’s Bat, Germany 
Emerging Infectious Diseases  2011;17(8):1519-1522.
A virus isolated from a Natterer’s bat (Myotis nattererii) in Germany was differentiated from other lyssaviruses on the basis of the reaction pattern of a panel of monoclonal antibodies. Phylogenetic analysis supported the assumption that the isolated virus, Bokeloh bat lyssavirus, may represent a new member of the genus Lyssavirus.
doi:10.3201/eid1708.110201
PMCID: PMC3381583  PMID: 21801640
rabies; bats; lyssavirus; Natterer’s bat; Myotis nattereri; sequence analysis; zoonosis; Germany; viruses; dispatch
6.  Ultrastructural Analysis of Virion Formation and Intraaxonal Transport of Herpes Simplex Virus Type 1 in Primary Rat Neurons▿  
Journal of Virology  2010;84(24):13031-13035.
After primary replication at the site of entry into the host, alphaherpesviruses infect and establish latency in neurons. To this end, they are transported within axons retrograde from the periphery to the cell body for replication and in an anterograde direction to synapses for infection of higher-order neurons or back to the periphery. Retrograde transport of incoming nucleocapsids is well documented. In contrast, there is still significant controversy on the mode of anterograde transport. By high-resolution transmission electron microscopy of primary neuronal cultures from embryonic rat superior cervical ganglia infected by pseudorabies virus (PrV), we observed the presence of enveloped virions in axons within vesicles supporting the “married model” of anterograde transport of complete virus particles within vesicles (C. Maresch, H. Granzow, A. Negatsch, B.G. Klupp, W. Fuchs, J.P. Teifke, and T.C. Mettenleiter, J. Virol. 84:5528-5539, 2010). We have now extended these analyses to the related human herpes simplex virus type 1 (HSV-1). We have demonstrated that in neurons infected by HSV-1 strains HFEM, 17+ or SC16, approximately 75% of virus particles observed intraaxonally or in growth cones late after infection constitute enveloped virions within vesicles, whereas approximately 25% present as naked capsids. In general, the number of HSV-1 particles in the axons was significantly less than that observed after PrV infection.
doi:10.1128/JVI.01784-10
PMCID: PMC3004319  PMID: 20943987
7.  Ultrastructural Analysis of Virion Formation and Anterograde Intraaxonal Transport of the Alphaherpesvirus Pseudorabies Virus in Primary Neurons▿  
Journal of Virology  2010;84(11):5528-5539.
A hallmark of alphaherpesviruses is their capacity to be neuroinvasive and establish latent infections in neurons. After primary replication in epithelial cells at the periphery, entry into nerve endings occurs, followed by retrograde transport of nucleocapsids to the nucleus where viral transcription, genome replication, and nucleocapsid formation take place. Translocation of nucleocapsids to the cytoplasm is followed by axonal transport to infect synaptically linked neurons. Two modes of intraaxonal anterograde herpesvirus transport have been proposed: transport of complete, enveloped virions within vesicles (“married model”), and separate transport of capsids and envelopes (“subassembly model”). To assess this in detail for the alphaherpesvirus pseudorabies virus (PrV), we used high-resolution transmission electron microscopy of primary neuronal cultures from embryonic rat superior cervical ganglia after infection with wild-type and gB-deficient PrV. Our data show that intranuclear capsid maturation, nuclear egress and cytoplasmic secondary envelopment occur as in cultured nonpolarized cells (H. Granzow, F. Weiland, A. Jöns, B. G. Klupp, A. Karger, and T. C. Mettenleiter, J. Virol. 71:2072-2082, 1997). PrV virions were present in axons as enveloped particles within vesicles associated with microtubules and apparently leave the neuron by exocytosis primarily at the growth cone. Only a few nonenveloped nucleocapsids were found in the axon. The same picture was observed after infection by phenotypically complemented gB-deficient PrV, which is able to complete only a single round of replication. Our data thus support intraaxonal anterograde transport of enveloped PrV virions within vesicles following the “married model.”
doi:10.1128/JVI.00067-10
PMCID: PMC2876598  PMID: 20237081
8.  Highly Pathogenic H5N1 Influenza Viruses Carry Virulence Determinants beyond the Polybasic Hemagglutinin Cleavage Site 
PLoS ONE  2010;5(7):e11826.
Highly pathogenic avian influenza viruses (HPAIV) originate from avirulent precursors but differ from all other influenza viruses by the presence of a polybasic cleavage site in their hemagglutinins (HA) of subtype H5 or H7. In this study, we investigated the ability of a low-pathogenic avian H5N1 strain to transform into an HPAIV. Using reverse genetics, we replaced the monobasic HA cleavage site of the low-pathogenic strain A/Teal/Germany/Wv632/2005 (H5N1) (TG05) by a polybasic motif from an HPAIV (TG05poly). To elucidate the virulence potential of all viral genes of HPAIV, we generated two reassortants carrying the HA from the HPAIV A/Swan/Germany/R65/06 (H5N1) (R65) plus the remaining genes from TG05 (TG05-HAR65) or in reversed composition the mutated TG05 HA plus the R65 genes (R65-HATG05poly). In vitro, TG05poly and both reassortants were able to replicate without the addition of trypsin, which is characteristic for HPAIV. Moreover, in contrast to avirulent TG05, the variants TG05poly, TG05-HAR65, and R65-HATG05poly are pathogenic in chicken to an increasing degree. Whereas the HA cleavage site mutant TG05poly led to temporary non-lethal disease in all animals, the reassortant TG05-HAR65 caused death in 3 of 10 animals. Furthermore, the reassortant R65-HATG05poly displayed the highest lethality as 8 of 10 chickens died, resembling “natural” HPAIV strains. Taken together, acquisition of a polybasic HA cleavage site is only one necessary step for evolution of low-pathogenic H5N1 strains into HPAIV. However, these low-pathogenic strains may already have cryptic virulence potential. Moreover, besides the polybasic cleavage site, the additional virulence determinants of H5N1 HPAIV are located within the HA itself and in other viral proteins.
doi:10.1371/journal.pone.0011826
PMCID: PMC2910732  PMID: 20676399
9.  Acquisition of a Polybasic Hemagglutinin Cleavage Site by a Low-Pathogenic Avian Influenza Virus Is Not Sufficient for Immediate Transformation into a Highly Pathogenic Strain▿  
Journal of Virology  2009;83(11):5864-5868.
Highly pathogenic avian influenza viruses (HPAIV) differ from all other strains by a polybasic cleavage site in their hemagglutinin. All these HPAIV share the H5 or H7 subtype. In order to investigate whether the acquisition of a polybasic cleavage site by an avirulent avian influenza virus strain with a hemagglutinin other than H5 or H7 is sufficient for immediate transformation into an HPAIV, we adapted the hemagglutinin cleavage site of A/Duck/Ukraine/1/1963 (H3N8) to that of the HPAIV A/Chicken/Italy/8/98 (H5N2), A/Chicken/HongKong/220/97 (H5N1), or A/Chicken/Germany/R28/03 (H7N7) and generated the recombinant wild-type and cleavage site mutants. In contrast to the wild type, multicycle replication of these mutants in tissue culture was demonstrated by positive plaque assays and viral multiplication in the absence of exogenous trypsin. Therefore, in vitro all cleavage site mutants resemble an HPAIV. However, in chicken they did not exhibit high pathogenicity, although they could be reisolated from cloacal swabs to some extent, indicating enhanced replication in vivo. These results demonstrate that beyond the polybasic hemagglutinin cleavage site, the virulence of HPAIV in chicken is based on additional pathogenicity determinants within the hemagglutinin itself or in the other viral proteins. Taken together, these observations support the notion that acquisition of a polybasic hemagglutinin cleavage site by an avirulent strain with a non-H5/H7 subtype is only one among several alterations necessary for evolution into an HPAIV.
doi:10.1128/JVI.02649-08
PMCID: PMC2681970  PMID: 19297482
10.  Migratory Status Is Not Related to the Susceptibility to HPAIV H5N1 in an Insectivorous Passerine Species 
PLoS ONE  2009;4(7):e6170.
Migratory birds have evolved elaborate physiological adaptations to travelling, the implications for their susceptibility to avian influenza are however unknown. Three groups of stonechats (Saxicola torquata) from (I) strongly migrating, (II) weakly migrating and (III) non-migrating populations were experimentally infected with HPAIV H5N1. The different bird groups of this insectivorous passerine species were infected in autumn, when the migrating populations clearly exhibit migratory restlessness. Following infection, all animals succumbed to the disease from 3 through 7 days post inoculation. Viral shedding, antigen distribution in tissues, and survival time did not differ between the three populations. However, notably, endothelial tropism of the HPAIV infection was exclusively seen in the group of resident birds. In conclusion, our data document for the first time the high susceptibility of an insectivorous passerine species to H5N1 infection, and the epidemiological role of these passerine birds is probably limited due to their high sensitivity to HPAIV H5N1 infection. Despite pronounced inherited differences in migratory status, the groups were generally indistinguishable in their susceptibility, survival time, clinical symptoms and viral shedding. Nevertheless, the migratory status partly influenced pathogenesis in the way of viral tropism.
doi:10.1371/journal.pone.0006170
PMCID: PMC2703776  PMID: 19584935
11.  Immunohistochemistry for detection of avian infectious bronchitis virus strain M41 in the proventriculus and nervous system of experimentally infected chicken embryos 
Virology Journal  2009;6:15.
Background
Infectious bronchitis virus primarily induces a disease of the respiratory system, different IBV strains may show variable tissue tropisms and also affect the oviduct and the kidneys. Proventriculitis was also associated with some new IBV strains. Aim of this study was to investigate by immunohistochemistry (IHC) the tissue tropism of avian infectious bronchitis virus (IBV) strain M41 in experimentally infected chicken embryos.
Results
To this end chicken embryos were inoculated in the allantoic sac with 103 EID50 of IBV M41 at 10 days of age. At 48, 72, and 120 h postinoculation (PI), embryos and chorioallantoic membranes (CAM) were sampled, fixed, and paraffin-wax embedded. Allantoic fluid was also collected and titrated in chicken embryo kidney cells (CEK). The sensitivity of IHC in detecting IBV antigens in the CAM of inoculated eggs matched the virus reisolation and detection in CEK. Using IHC, antigens of IBV were detected in nasal epithelium, trachea, lung, spleen, myocardial vasculature, liver, gastrointestinal tract, kidney, skin, sclera of the eye, spinal cord, as well as in brain neurons of the inoculated embryos. These results were consistent with virus isolation and denote the wide tissue tropism of IBV M41 in the chicken embryo. Most importantly, we found infection of vasculature and smooth muscle of the proventriculus which has not seen before with IBV strain M41.
Conclusion
IHC can be an additional useful tool for diagnosis of IBV infection in chickens and allows further studies to foster a deeper understanding of the pathogenesis of infections with IBV strains of different virulence. Moreover, these results underline that embryonic tissues in addition to CAM could be also used as possible source to generate IBV antigens for diagnostic purposes.
doi:10.1186/1743-422X-6-15
PMCID: PMC2657138  PMID: 19196466
12.  Mutagenesis of the Active-Site Cysteine in the Ubiquitin-Specific Protease Contained in Large Tegument Protein pUL36 of Pseudorabies Virus Impairs Viral Replication In Vitro and Neuroinvasion In Vivo ▿  
Journal of Virology  2008;82(12):6009-6016.
Herpesviruses specify a ubiquitin-specific protease activity located within their largest tegument protein. Although its biological role is still largely unclear, mutation within the active site abolished deubiquitinating (DUB) activity and decreased virus replication in vitro and in vivo. To further elucidate the role of DUB activity for herpesvirus replication, the conserved active-site cysteine at amino acid position 26 within pUL36 of Pseudorabies virus (PrV) (Suid herpesvirus 1), a neurotropic alphaherpesvirus, was mutated to serine. Whereas one-step growth kinetics of the resulting mutant virus PrV-UL36(C26S) were moderately reduced, plaque size was decreased to 62% of that of the wild-type virus. Ultrastructural analysis revealed large accumulations of unenveloped nucleocapsids in the cytoplasm, but incorporation of the tegument protein pUL37 was not abolished. After intranasal infection with PrV-UL36(C26S) mice showed survival times two times longer than those of mice infected with wild-type or rescued virus. Thus, the DUB activity is important for PrV replication in vitro and for neuroinvasion in mice.
doi:10.1128/JVI.00280-08
PMCID: PMC2395145  PMID: 18400848
13.  Pathogenicity of Highly Pathogenic Avian Influenza Virus (H5N1) in Adult Mute Swans 
Emerging Infectious Diseases  2008;14(8):1267-1270.
Adult, healthy mute swans were experimentally infected with highly pathogenic avian influenza virus A/Cygnus cygnus/Germany/R65/2006 subtype H5N1. Immunologically naive birds died, whereas animals with preexisting, naturally acquired avian influenza virus–specific antibodies became infected asymptomatically and shed virus. Adult mute swans are highly susceptible, excrete virus, and can be clinically protected by preexposure immunity.
doi:10.3201/eid1408.080078
PMCID: PMC2600380  PMID: 18680652
Mute swan; avian influenza; subtype H5N1; epidemiology; pathogenicity; preexposure immunity; dispatch
14.  Experimental Infection and Natural Contact Exposure of Dogs with Avian Influenza Virus (H5N1) 
Emerging Infectious Diseases  2008;14(2):308-310.
Experiments that exposed influenza virus (H5N1)–infected cats to susceptible dogs did not result in intraspecies or interspecies transmission. Infected dogs showed increased body temperatures, viral RNA in pharyngeal swabs, and seroconversion but not fatal disease.
doi:10.3201/eid1402.070864
PMCID: PMC2600189  PMID: 18258127
highly pathogenic avian influenza (H5N1) virus; dog; cat; canine; feline; susceptibility; dispatch
15.  Protection and Virus Shedding of Falcons Vaccinated against Highly Pathogenic Avian Influenza A Virus (H5N1) 
Emerging Infectious Diseases  2007;13(11):1667-1674.
Virus shedding by vaccinated birds was markedly reduced.
Because fatal infections with highly pathogenic avian influenza A (HPAI) virus subtype H5N1 have been reported in birds of prey, we sought to determine detailed information about the birds’ susceptibility and protection after vaccination. Ten falcons vaccinated with an inactivated influenza virus (H5N2) vaccine seroconverted. We then challenged 5 vaccinated and 5 nonvaccinated falcons with HPAI (H5N1). All vaccinated birds survived; all unvaccinated birds died within 5 days. For the nonvaccinated birds, histopathologic examination showed tissue degeneration and necrosis, immunohistochemical techniques showed influenza virus antigen in affected tissues, and these birds shed high levels of infectious virus from the oropharynx and cloaca. Vaccinated birds showed no influenza virus antigen in tissues and shed virus at lower titers from the oropharynx only. Vaccination could protect these valuable birds and, through reduced virus shedding, reduce risk for transmission to other avian species and humans.
doi:10.3201/eid1311.070705
PMCID: PMC3375792  PMID: 18217549
Keywords: Birds of prey; falcon hybrids; highly pathogenic avian influenza; challenge; antibody titer; histopathology; H5N1; zoonosis; human risk; fowl plague; virus shedding; research
16.  Influence of Pseudorabies Virus Proteins on Neuroinvasion and Neurovirulence in Mice 
Journal of Virology  2006;80(11):5571-5576.
Neurotropism is a distinctive feature of members of the Alphaherpesvirinae. However, its molecular basis remains enigmatic. In the past, research has been focused mainly on the role of viral envelope proteins in modulating herpesvirus neuroinvasion and neurovirulence (T. C. Mettenleiter, Virus Res. 92:192-206, 2003). To further analyze the molecular requirements for neuroinvasion of the alphaherpesvirus pseudorabies virus (PrV), adult mice were infected intranasally with a set of single- or multiple-deletion mutants lacking the UL3, UL4, UL7, UL11, UL13, UL16, UL17, UL21, UL31, UL34, UL37, UL41, UL43, UL46, UL47, UL48, UL51, US3, US9, glycoprotein E (gE), gM, UL11/US9, UL11/UL16, UL16/UL21, UL11/UL16/UL21, UL11/gE, UL11/gM, UL43/gK, UL43/gM, or UL43/gK/gM genes. Neurovirulence was evaluated by measuring mean survival times compared to that after wild-type virus infection. Furthermore, by immunohistochemical detection of infected neurons, the kinetics of viral spread in the murine central nervous system was investigated.
doi:10.1128/JVI.02589-05
PMCID: PMC1472135  PMID: 16699038
17.  In Vitro and In Vivo Relevance of Infectious Laryngotracheitis Virus gJ Proteins That Are Expressed from Spliced and Nonspliced mRNAs 
Journal of Virology  2005;79(2):705-716.
The positional homologue in the infectious laryngotracheitis virus (ILTV) genome of the glycoprotein gJ gene of herpes simplex virus and the gp2 gene of equine herpesvirus 1 is expressed into four proteins of 85, 115, 160, and 200 kDa (J. Veits, B. Köllner, J. P. Teifke, H. Granzow, T. C. Mettenleiter, and W. Fuchs, Avian Dis. 47:330-342, 2003). RNA analyses revealed that these proteins are expressed from two different late (γ2) transcripts, an unspliced 5.5-kb and a spliced 4.3-kb mRNA that are translated into proteins of 985 and 611 amino acids, respectively. ILTV gJ is incorporated into virions and is modified by N- and O-linked glycosylation. After cotransfection of chicken cells with genomic DNA of a pathogenic ILTV strain and transfer plasmids, gJ-negative ILTV mutants could be isolated. In vitro growth studies demonstrated that deletion of the gJ gene has only minor effects on direct cell-to-cell spread as measured by plaque size. However, progeny virus titers of ILTV-ΔgJ were significantly reduced in comparison to those of the parental virus and a gJ rescue mutant. After experimental infection of chickens the gJ rescue mutant, like wild-type ILTV, caused severe disease and considerable mortality, whereas ILTV-ΔgJ was significantly attenuated. All immunized animals were protected against subsequent challenge infection with virulent ILTV. In sera collected after immunization with the gJ-rescue mutant or with wild-type ILTV, gJ-specific antibodies were detectable by immunofluorescence on cells that had been transfected with a gJ expression plasmid. As expected, no gJ-specific antibodies were found in sera obtained from chickens immunized with ILTV-ΔgJ. Thus, gJ deletion mutants of ILTV might be usable as attenuated live-virus vaccines. Furthermore, the gJ gene might constitute a reliable marker for serological discrimination between vaccinated and field virus-infected chickens.
doi:10.1128/JVI.79.2.705-716.2005
PMCID: PMC538576  PMID: 15613298
18.  Influence of Tegument Proteins of Pseudorabies Virus on Neuroinvasion and Transneuronal Spread in the Nervous System of Adult Mice after Intranasal Inoculation 
Journal of Virology  2004;78(6):2956-2966.
Pseudorabies virus (PrV) is a neurotropic alphaherpesvirus that, after intranasal infection of adult mice, enters peripheral neurons and propagates to the central nervous system. In recent years we have analyzed the contribution of virus-encoded glycoproteins to neuroinvasion and transneuronal spread (reviewed in T. C. Mettenleiter, Virus Res. 92:197-206, 2003). We now extend our studies to analyze the role of tegument proteins in these processes. To this end, PrV mutants unable to express the UL11, UL37, UL46, UL47, and UL48 tegument proteins, as well as the corresponding rescued viruses, were intranasally instilled into 6- to 8-week-old CD1 strain mice. First, mean survival times were determined which showed that mice infected with the UL46 deletion mutant succumbed to the disease as early as wild-type PrV-infected animals. Survival times increased in the order: PrV-ΔUL47-, PrV-ΔUL11-, and PrV-ΔUL48-infected animals, a finding which parallels the growth phenotype of these viruses in cell culture. In contrast, none of the PrV-ΔUL37-infected animals died. Upon closer histological examination, all viruses except PrV-ΔUL37 were able to infect the nasal cavity and propagate to first- and second-order neurons as shown by two-color immunofluorescence. However, neuroinvasion was delayed in PrV-ΔUL47, PrV-ΔUL11, and PrV-ΔUL48, a finding that correlated with the extended survival times. Surprisingly, whereas PrV-ΔUL48 and PrV-ΔUL37 replicated to similar titers in cell culture which were ∼500-fold lower than those of wild-type virus, after intranasal infection of mice PrV-ΔUL48 was able to infect areas of the brain like wild-type PrV, although only after a considerably longer time period. In contrast, PrV-ΔUL37 was not able to enter neurons and was restricted to the infection of single cells in the nasal respiratory epithelium. Thus, our data demonstrate the importance of herpesviral tegument proteins in neuronal infection and show a different contribution of tegument proteins to the neuroinvasion phenotype of a neurotropic alphaherpesvirus.
doi:10.1128/JVI.78.6.2956-2966.2004
PMCID: PMC353730  PMID: 14990714

Results 1-18 (18)