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\begin{document}

\title{Novel Chinese pseudorabies virus variants undergo extensive
recombination and rapid interspecies transmission}



\author[1]{Jinbiao Liu }%
\author[1]{Changhai Chen}%
\author[2]{Xiangdong  Li}%
\affil[1]{Affiliation not available}%
\affil[2]{Yangzhou University}%


\vspace{-1em}



  
  \date{April 27, 2024}


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\begin{abstract}
Chinese PRV variants have frequent recombination and preferential
interspecies transmission. So far, 23 confirmed PRV-infected human cases
have been reported. In this letter, we discussed the significance of PRV
recombination and its public health issue as an occupational zoonosis.%
\end{abstract}%



\sloppy


\textbf{Novel Chinese pseudorabies virus variants undergo extensive
recombination}

\textbf{and rapid interspecies transmission}

Jinbiao Liu\textsuperscript{1,2}, Changhai Chen\textsuperscript{3},
Xiangdong Li\textsuperscript{1,2}

\textsuperscript{1}Jiangsu Co-innovation Center for Prevention and
Control of Important Animal Infectious Diseases and Zoonoses, College of
Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China.

\textsuperscript{2}Joint International Research Laboratory of
Agriculture and Agri-Product Safety, the Ministry of Education of China,
Yangzhou University, Yangzhou, 225009 China.

\textsuperscript{3}Jiangsu Provincial Center for Animal Disease Control
and Prevention, Nanjing, Jiangsu 210036, China.

\textbf{Correspondence} : Prof. Xiangdong Li, Email: 007352@yzu.edu.cn

Dear Editor,

We have some comments related to the recently published paper
in\emph{Transboundary and Emerging Diseases} titled ``Genetic evolution
analysis of novel recombinant pseudorabies virus strain in Sichuan,
China'' (Huang et al., 2020). A Chinese pseudorabies virus (PRV) isolate
named FJ62 was reported to be a natural recombination of PRV genotype 1
from wild boar and genotype 2 from domestic pigs. Specifically, the gB
gene of PRV FJ62 shared the highest homology (100\%) with Japanese MY-1
strain from wild boar, which shared the same nucleotide sequences with
European and American PRV strains. By contrast, gC, gD and gE genes of
PRV FJ62 were closely related to Chinese PRV variants in domestic pigs
that were far removed from the reference strains in Europe and USA.

Genetically, PRVs could be classified into two genotypes based on
genomic sequence or viral gC gene. PRV strains in China belong to
genotype 2, whereas PRV isolates from other countries belong to genotype
1. Within genotype 2, Chinese PRV isolates are further divided into two
subgenotypes: classical PRV (PRV isolates before 2011) in subgenotype 1
and PRV variants isolated since 2011 in subgenotype 2. As a large DNA
virus, the mutation and recombination rates of PRV are theoretically
slow. However, frequent inter-genotype and intra-genotype recombinations
have been reported. In a recent study, He et al (2019) reported that 29
PRVs had undergone recombination, with more inter- than intra-genotype
recombinations found. The mutation and recombination of viral
glycoproteins - such as gB, gC, gD and some other undefined protective
immunity-elicited proteins - might partially explain the incomplete
protection provided by PRV vaccine strains.

Besides frequent recombination, Chinese PRV variants undergo
preferential interspecies transmission including cows, dogs, cats,
sheep, minks, foxes, racoons, and even humans (Wong et al., 2019, Li et
al., 2020). PRV utilizes its glycoprotein gD to bind to cells via the
nectin-1 receptor, which shares conserved amino acid residues among
different species (Li et al., 2017). Zheng et al recently reported a
human severe pseudorabies encephalitis in \emph{Transboundary and
Emerging Diseases} (Zheng et al., 2019). Besides that, another 22 PRV
variants-infected human cases have been reported (Table 1). There are
several distinct characteristics of patients infected with PRV variants
versus those infected with classical PRV. First, humans infected with
classical PRV had fever, weakness and pruritus before progressing to
neurological signs, including dysphagia and paresthesia. The clinical
signs of patients can last several months, but all eventually recovered
without any treatment. By contrast, humans infected with PRV variants
suffered severe central nervous system disorders and fatal encephalitis.
Besides encephalitis, 12 out of 23 patients also suffered from
endophthalmitis, causing loss of vision. How PRV variants invade the
ocular nerve system and leads to endophthalmitis warrants further
investigation. Second, humans infected with classical PRVs had close
contact with diseased dogs, cats or cattle (Wong et al., 2019). By
contrast, all patients infected with PRV variants had close contact with
pigs. This suggested that pigs have become the etiological source of PRV
for human infection. Third, PRV variants have been successfully isolated
on cells from cerebrospinal fluid samples of patients. Most recently,
human PRV hSD-1/2019 strain was, for the first time, isolated from
cerebrospinal fluid samples on PK-15 cells (Liu et al., 2020). The virus
was shown to be a PRV variant by next-generation sequencing; it induced
acute neurological signs in pigs, and caused high mortality.

The above reported cases suggest that PRV could be an important
neglected occupational zoonotic pathogen in humans. Therefore, PRV
should be screened for in unexplained fever and encephalitis cases in
human, especially when patients have a history of close contact with
pigs or pig products. The mechanisms by which PRV variants lead to
encephalitis and endophthalmitis should be further explored in non-human
primate models.

\textbf{ACKNOWLEDGEMENTS}

The authors were supported by Development of Jiangsu Higher Education
Institutions (PADD) and Ten-thousand Talents Program, and grants from
Jiangsu Co-innovation Center for Prevention and Control of Important
Animal Infectious Diseases and Zoonoses.

\textbf{CONFLICT OF INTEREST}

The author declares no conflict of interest relevant to this article.

\textbf{ETHICAL APPROAL}

Not applicable to this comment.

\textbf{Data Availability Statement}

There is no experimental data available in this letter.

\textbf{REFERENCES}

Huang, J., L. Zhu, J. Zhao, X. Yin, Y. Feng, X. Wang, X. Sun, Y. Zhou
and Z. Xu, 2020: Genetic evolution analysis of novel recombinant
pseudorabies virus strain in Sichuan, China. \emph{Transboundary and
emerging diseases,} 67, 1428-1432.

Li, A., G. Lu, J. Qi, L. Wu, K. Tian, T. Luo, Y. Shi, J. Yan and G. F.
Gao, 2017: Structural basis of nectin-1 recognition by pseudorabies
virus glycoprotein D. \emph{PLoS pathogens,}13, e1006314.

Li, X. D., S. H. Fu, L. Y. Chen, F. Li, J. H. Deng, X. C. Lu, H. Y. Wang
and K. G. Tian, 2020: Detection of Pseudorabies Virus Antibodies in
Human Encephalitis Cases.\emph{Biomedical and environmental sciences :
BES,} 33, 444-447.

Liu, Q., X. Wang, C. Xie, S. Ding, H. Yang, S. Guo, J. Li, L. Qin, F.
Ban, D. Wang, C. Wang, L. Feng, H. Ma, B. Wu, L. Zhang, C. Dong, L.
Xing, J. Zhang, H. Chen, R. Yan and W. Li, 2020: A novel human acute
encephalitis caused by pseudorabies virus variant strain. \emph{Clinical
infectious diseases,} doi: 10.1093/cid/ciaa987.

Wong, G., J. Lu, W. Zhang and G. F. Gao, 2019: Pseudorabies virus: a
neglected zoonotic pathogen in humans?\emph{Emerging microbes \&
infections,} 8, 150-154.

Zheng, L., X. Liu, D. Yuan, R. Li, J. Lu, X. Li, K. Tian and E. Dai,
2019: Dynamic cerebrospinal fluid analyses of severe pseudorabies
encephalitis. \emph{Transboundary and emerging diseases,} 66, 2562-2565.

\textbf{Table 1} . Summary of reported human PRV cases.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\textbf{Case} & \textbf{Year} & \textbf{Sex} & \textbf{Age} &
\textbf{Province} & \textbf{Occupation} & \textbf{Clinical signs} &
\textbf{Clinical signs} & \textbf{Outcome} &
\textbf{Reference}\tabularnewline
\midrule
\endhead
& & & & & & Encephalitis & Endophthalmitis & &\tabularnewline
1 & 2018 & Male & 25 & Hubei & Veterinary & Yes & Yes & Survived & Liu
QY, et al. Clin Infect Dis. 2020.\tabularnewline
2 & 2019 & Male & 35 & Henan & Pig butcher & Yes & No & Survived
&\tabularnewline
3 & 2019 & Male & 49 & Henan & Pig butcher & Yes & No & Survived
&\tabularnewline
4 & 2018 & Male & 43 & Shandong & Veterinary & Yes & No & Survived
&\tabularnewline
5 & 2018 & Male & Mid-aged & Shandong & Butcher & Yes & No & Died & Fan
SY, et al.J Neurovirol. 2020.\tabularnewline
6 & 2018 & Male & Mid-aged & Hebei & Swineherd & Yes & Yes & Survived
&\tabularnewline
7 & 2018 & Male & Young & Guangdong & Driver & Yes & Yes & Survived
&\tabularnewline
8 & 2011 & Female & Young & Beijing & Pork dealer & Yes & No & Died
&\tabularnewline
9 & 2017 & Male & 55 & Inner Mongolia & Pork dealer & Yes & Yes & Died &
Zhao WL, et al. Zhonghua Yi Xue Za Zhi. 2018.\tabularnewline
10 & 2017 & Male & 51 & Inner Mongolia & Cook & Yes & No & Died
&\tabularnewline
11 & 2017 & Male & 38 & Shandong & Butcher & Yes & No & Survived
&\tabularnewline
12 & 2016 & Female & 42 & Hebei & Unknown & Yes & Yes & Survived
&\tabularnewline
13 & 2019 & Male & 44 & Anhui & Pork dealer & Yes & Yes & Survived &
Wang D, et al. J Neurovirol. 2020.\tabularnewline
14 & 2019 & Male & 44 & Shandong & Pork dealer & Yes & Yes & Survived &
Wang Y, et al. Int J Infect Dis. 2019.\tabularnewline
15 & 2018 & Male & 50 & Shandong & Pig slaughterer & Yes & No & Survived
& Yang X, et al. Int J Infect Dis. 2019.\tabularnewline
16 & 2018 & Female & 50 & Shandong & Pork cutter & Yes & No & Survived
&\tabularnewline
17 & 2018 & Male & 43 & Shandong & Pig handler & Yes & Yes & Survived
&\tabularnewline
18 & 2018 & Male & 59 & Shandong & Pork cutter & Yes & No & Survived
&\tabularnewline
19 & 2018 & Male & 50 & Shandong & Pork cutter & Yes & Yes & Survived
&\tabularnewline
20 & 2018 & Male & 59 & Hebei & Swineherd & Yes & Yes & Survived & Zheng
LH, et al. Transbound Emerg Dis. 2019.\tabularnewline
21 & 2019 & Male & 43 & Shandong & Veterinary & Yes & No & Survived &
Yang H, et al. Front Neurol. 2019.\tabularnewline
22 & 2019 & Male & 49 & Anhui & Pig slaughterer & Yes & Yes & Survived &
Hu F, et al. Ocul Immunol Inflamm. 2020.\tabularnewline
23 & 2017 & Female & 46 & Jiangxi & Swineherd & Yes & Yes & Survived &
Ai JW, et al. Emerg Infect Dis. 2018.\tabularnewline
\bottomrule
\end{longtable}

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