Human encephalitis complicated with bilateral acute retinal necrosis associated with pseudorabies virus infection: A case report

Wang, Yuwei; Nian, Hong; Wang, Wen‐Juan; Wang, Xin; Cui, Yan

doi:10.1016/j.ijid.2019.09.019

Cited by 40 publications

(27 citation statements)

References 14 publications

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“…PrV is the causative agent of Aujeszky's disease in pigs but infects a variety of mammals ranging from ruminants to carnivores, rodents and lagomorphs. Horses and primates resist infection [17], although evidence for rare human infections have been reported recently [18,19]. In adult pigs, the virus causes mostly respiratory illness, abortion or even subclinical infection, whereas piglets usually develop severe neurological signs.…”

Section: Introductionmentioning

confidence: 99%

An improved animal model for herpesvirus encephalitis in humans

et al. 2020

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Herpesviral encephalitis caused by Herpes Simplex Virus 1 (HSV-1) is one of the most devastating diseases in humans. Patients present with fever, mental status changes or seizures and when untreated, sequelae can be fatal. Herpes Simplex Encephalitis (HSE) is characterized by mainly unilateral necrotizing inflammation effacing the frontal and mesiotemporal lobes with rare involvement of the brainstem. HSV-1 is hypothesized to invade the CNS via the trigeminal or olfactory nerve, but viral tropism and the exact route of infection remain unclear. Several mouse models for HSE have been developed, but they mimic natural infection only inadequately. The porcine alphaherpesvirus Pseudorabies virus (PrV) is closely related to HSV-1 and Varicella Zoster Virus (VZV). While pigs can control productive infection, it is lethal in other susceptible animals associated with severe pruritus leading to automutilation. Here, we describe the first mutant PrV establishing productive infection in mice that the animals are able to control. After intranasal inoculation with a PrV mutant lacking tegument protein pUL21 and pUS3 kinase activity (PrV-ΔUL21/US3Δkin), nearly all mice survived despite extensive infection of the central nervous system. Neuroinvasion mainly occurred along the trigeminal pathway. Whereas trigeminal first and second order neurons and autonomic ganglia were positive early after intranasal infection, PrV-specific antigen was mainly detectable in the frontal, mesiotemporal and parietal lobes at later times, accompanied by a long lasting lymphohistiocytic meningoencephalitis. Despite this extensive infection, mice showed only mild to moderate clinical signs, developed alopecic skin lesions, or remained asymptomatic. Interestingly, most mice exhibited abnormalities in behavior and activity levels including slow movements, akinesia and stargazing. In summary, clinical signs, distribution of viral antigen and inflammatory pattern show striking analogies to human encephalitis caused by HSV-1 or VZV not observed in other animal models of disease.

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Section: Introductionmentioning

confidence: 99%

An improved animal model for herpesvirus encephalitis in humans

et al. 2020

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“…In the performed infection assays, HEK293T cells were employed to investigate the effects of BAG3 overexpression or knockdown on lytic infection of PRV. We used HEK293T cells because: (i) Human cell lines are susceptible to PRV, and support the efficient replication of PRV [35,36], (ii) HEK293T cells are highly efficient for overexpression of foreign protein by the transfected plasmid, and (iii) PRV has been reported in several recent case reports to infect humans, which results in encephalitis [37][38][39][40][41][42]. Both overexpression and knockdown assays indicated that BAG3 played a negative regulation role during PRV lytic infection.…”

Section: Discussionmentioning

confidence: 99%

Host BAG3 Is Degraded by Pseudorabies Virus pUL56 C-Terminal 181L-185L and Plays a Negative Regulation Role during Viral Lytic Infection

Lyu

Shu-wen

et al. 2020

IJMS

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Bcl2-associated athanogene (BAG) 3, which is a chaperone-mediated selective autophagy protein, plays a pivotal role in modulating the life cycle of a wide variety of viruses. Both positive and negative modulations of viruses by BAG3 were reported. However, the effects of BAG3 on pseudorabies virus (PRV) remain unknown. To investigate whether BAG3 could modulate the PRV life cycle during a lytic infection, we first identified PRV protein UL56 (pUL56) as a novel BAG3 interactor by co-immunoprecipitation and co-localization analyses. The overexpression of pUL56 induced a significant degradation of BAG3 at protein level via the lysosome pathway. The C-terminal mutations of 181L/A, 185L/A, or 181L/A-185L/A in pUL56 resulted in a deficiency in pUL56-induced BAG3 degradation. In addition, the pUL56 C-terminal mutants that lost Golgi retention abrogated pUL56-induced BAG3 degradation, which indicates a Golgi retention-dependent manner. Strikingly, BAG3 was not observed to be degraded in either wild-type or UL56-deleted PRV infected cells as compared to mock infected ones, whereas the additional two adjacent BAG3 cleaved products were found in the infected cells in a species-specific manner. Overexpression of BAG3 significantly suppressed PRV proliferation, while knockdown of BAG3 resulted in increased viral yields in HEK293T cells. Thus, these data indicated a negative regulation role of BAG3 during PRV lytic infection. Collectively, our findings revealed a novel molecular mechanism on host protein degradation induced by PRV pUL56. Moreover, we identified BAG3 as a host restricted protein during PRV lytic infection in cells.

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“…This patient got endophthalmitis 3 days after her eyes were exposed directly to the sewage of the farm (Ai et al, 2018). Another case was reported in 2019, in which the patient suffered from encephalitis and PRV gene fragments were detected in the cerebrospinal fluid and vitreous humor using next-generation sequencing (Wang et al, 2019), after which more cases of encephalitis resulting from PRV infection have been reported in China; most of the patients worked as farmers or veterinarians Yang X. et al, 2019;Fan et al, 2020;Li et al, 2020;Liu et al, 2020;Ou et al, 2020;Wang et al, 2020), suggesting that PRV infection in humans should not be neglected in the future (Wong et al, 2019).…”

Section: Introductionmentioning

confidence: 91%

Implication of the Identification of an Earlier Pseudorabies Virus (PRV) Strain HLJ-2013 to the Evolution of Chinese PRVs

et al. 2020

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Pseudorabies viruses (PRVs) pose a great threat to the pig industry of many countries around the world. Human infections with PRV have also been reported occasionally in China. Therefore, understanding the epidemiology and evolution of PRVs is of great importance for disease control in the pig populations and humans as well. In this study, we isolated a PRV designated HLJ-2013 from PRV-positive samples that had been collected in Heilongjiang, China, in 2013. The full genome sequence of the virus was determined to be ∼143 kbp in length using high-throughput sequencing. The genomic sequence identities between this isolate and 21 other previous PRV isolates ranged from 92.4% (with Bartha) to 97.3% (with SC). Phylogenetic analysis based on the full-length genome sequences revealed that PRV HLJ-2013 clustered together with all the Chinese strains in one group belonging to Genotype II, but this virus occurred phylogenetically earlier than all the other Chinese PRV strains. Phylogenetic trees based on both protein-coding genes and non-coding regions revealed that HLJ-2013 probably obtained its genome sequences from three origins: a yet unknown parent virus, the European viruses, and the same ancestor of all Chinese PRVs. Recombination analysis showed that HLJ-2013-like virus possibly donated the main framework of the genome of the Chinese PRVs. HLJ-2013 exhibited cytopathic and growth characteristics similar to that of the Chinese PRV strains SC and HeN1, but its pathogenicity in mice was higher than that of SC and lower than that of HeN1. The identification of HLJ-2013 takes us one step closer to understanding the origin of PRVs in China and provides new knowledge about the evolution of PRVs worldwide.

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Human encephalitis complicated with bilateral acute retinal necrosis associated with pseudorabies virus infection: A case report

Cited by 40 publications

References 14 publications

An improved animal model for herpesvirus encephalitis in humans

An improved animal model for herpesvirus encephalitis in humans

Host BAG3 Is Degraded by Pseudorabies Virus pUL56 C-Terminal 181L-185L and Plays a Negative Regulation Role during Viral Lytic Infection

Implication of the Identification of an Earlier Pseudorabies Virus (PRV) Strain HLJ-2013 to the Evolution of Chinese PRVs

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