Reproductive effects of arteriviruses: equine arteritis virus and porcine reproductive and respiratory syndrome virus infections

Balasuriya, Udeni B. R.; Carossino, Mariano

doi:10.1016/j.coviro.2017.11.005

Cited by 37 publications

(27 citation statements)

References 114 publications

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“…For example, the accumulation of data on porcine reproductive and respiratory syndrome virus (PRRSV)infected animals suggests that seminal viruses arise from testicular germ cells during the acute phase of the infection, and from infected macrophages that infiltrate MGT organs during the persistent phase (554). Lifelong MGT infection and seminal shedding was demonstrated for two acute animal viruses, equine arteritis virus (EAV) in horses (37) and bovine viral diarrhea virus (BVDV) in bulls (75). Consequently, the infected male horses and bulls are major viral reservoirs, spreading the disease among cattle herds.…”

Section: What Lessons Can We Learn From Animals?mentioning

confidence: 99%

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

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The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

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Section: What Lessons Can We Learn From Animals?mentioning

confidence: 99%

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

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“…PRRSV infection presents as severe reproductive failure in sows and respiratory distress in piglets and growing pigs ( 9 ). As arteriviruses, EAV and PRRSV share some similar molecular properties, such as their replication strategy, capacity for establishing persistent infection, and ease of transmission from infected animals to naive animals ( 10 , 11 ). These viral characteristics cause the corresponding diseases to be difficult to control.…”

Section: Introductionmentioning

confidence: 99%

Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites

Chen

Wang

Sun

et al. 2019

J Virol

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Equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV) represent two members of the family Arteriviridae and pose major threats for the horse-and swine-breeding industries worldwide. A previous study suggested that PRRSV nsp4, a 3C-like protease, antagonizes interferon beta (IFN-␤) production by cleaving the NF-B essential modulator (NEMO) at a single site, glutamate 349 (E349). Here, we demonstrated that EAV nsp4 also inhibited virus-induced IFN-␤ production by targeting NEMO for proteolytic cleavage and that the scission occurred at four sites: E166, E171, glutamine 205 (Q205), and E349. Additionally, we found that, besides the previously reported cleavage site E349 in NEMO, scission by PRRSV nsp4 took place at two additional sites, E166 and E171. These results imply that while cleaving NEMO is a common strategy utilized by EAV and PRRSV nsp4 to antagonize IFN induction, EAV nsp4 adopts a more complex substrate recognition mechanism to target NEMO. By analyzing the abilities of the eight different NEMO fragments resulting from EAV or PRRSV nsp4 scission to induce IFN-␤ production, we serendipitously found that a NEMO fragment (residues 1 to 349) could activate IFN-␤ transcription more robustly than full-length NEMO, whereas all other NEMO cleavage products were abrogated for the IFN-␤-inducing capacity. Thus, NEMO cleavage at E349 alone may not be sufficient to completely inactivate the IFN response via this signaling adaptor. Altogether, our findings suggest that EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is critical for disarming the innate immune response for viral survival. IMPORTANCE The arterivirus nsp4-encoded 3C-like protease (3CL pro ) plays an important role in virus replication and immune evasion, making it an attractive target for antiviral therapeutics. Previous work suggested that PRRSV nsp4 suppresses type I IFN production by cleaving NEMO at a single site. In contrast, the present study demonstrates that both EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is essential for disruption of type I IFN production. Moreover, we reveal that EAV nsp4 also cleaves NEMO at glutamine 205 (Q205), which is not targeted by PRRSV nsp4. Notably, targeting a glutamine in NEMO for cleavage has been observed only with picornavirus 3C proteases (3C pro ) and coronavirus 3CL pro . In aggregate, our work expands knowledge of the innate immune evasion mechanisms associated with NEMO cleavage by arterivirus nsp4 and describes a novel substrate recognition characteristic of EAV nsp4.KEYWORDS 3C-like protease, equine arteritis virus, NF-B essential modulator, interferon beta, porcine reproductive and respiratory syndrome virus T he family Arteriviridae, which belongs to the order Nidovirales, consists of porcine reproductive and respiratory syndrome virus (PRRSV), equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV) of mice, simian hemorrhagic fever virus RESULTSEAV nsp4-mediated inhibition of IFN-␤ production ...

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“…About 10% to 70% of sexually mature stallions develop persistent infection and become carriers after natural infection (5,20,87). This occurs in the presence of high levels of virus neutralizing antibodies in serum that effectively eliminates systemic infection in body tissues, with the exception of the stallion reproductive tract (5,16,20,81,88,89). While previous studies have shown that natural transmission of EAV can occur by aerosolized respiratory secretions or through insemination with infective semen, the diversity observed during persistent infection contrasts with the relative genetic stability during horizontal transmission in a disease outbreak (30).…”

Section: Fig 14 Fubar Analysis Of Orfs 3 (Gp3) and 5 (Gp5)mentioning

confidence: 99%

Intrahost Selection Pressure Drives Equine Arteritis Virus Evolution during Persistent Infection in the Stallion Reproductive Tract

Nam

Mekuria

Carossino

et al. 2019

J Virol

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Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a reproductive and respiratory disease of horses. Following natural infection, 10 to 70% of infected stallions can become carriers of EAV and continue to shed virus in the semen. In this study, sequential viruses isolated from nasal secretions, buffy coat cells, and semen of seven experimentally infected and two naturally infected EAV carrier stallions were deep sequenced to elucidate the intrahost microevolutionary process after a single transmission event. Analysis of variants from nasal secretions and buffy coat cells lacked extensive positive selection; however, characteristics of the mutant spectra were different in the two sample types. In contrast, the initial semen virus populations during acute infection have undergone a selective bottleneck, as reflected by the reduction in population size and diversifying selection at multiple sites in the viral genome. Furthermore, during persistent infection, extensive genome-wide purifying selection shaped variant diversity in the stallion reproductive tract. Overall, the nonstochastic nature of EAV evolution during persistent infection was driven by active intrahost selection pressure. Among the open reading frames within the viral genome, ORF3, ORF5, and the nsp2-coding region of ORF1a accumulated the majority of nucleotide substitutions during persistence, with ORF3 and ORF5 having the highest intrahost evolutionary rates. The findings presented here provide a novel insight into the evolutionary mechanisms of EAV and identified critical regions of the viral genome likely associated with the establishment and maintenance of persistent infection in the stallion reproductive tract. IMPORTANCE EAV can persist in the reproductive tract of infected stallions, and consequently, long-term carrier stallions constitute its sole natural reservoir. Previous studies demonstrated that the ampullae of the vas deferens are the primary site of viral persistence in the stallion reproductive tract and the persistence is associated with a significant inflammatory response that is unable to clear the infection. This is the first study that describes EAV full-length genomic evolution during acute and long-term persistent infection in the stallion reproductive tract using next-generation sequencing and contemporary sequence analysis techniques. The data provide novel insight into the intrahost evolution of EAV during acute and persistent infection and demonstrate that persistent infection is characterized by extensive genome-wide purifying selection and a nonstochastic evolutionary pattern mediated by intrahost selective pressure, with important nucleotide substitutions occurring in ORF1a (region encoding nsp2), ORF3, and ORF5.

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Reproductive effects of arteriviruses: equine arteritis virus and porcine reproductive and respiratory syndrome virus infections

Cited by 37 publications

References 114 publications

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites

Intrahost Selection Pressure Drives Equine Arteritis Virus Evolution during Persistent Infection in the Stallion Reproductive Tract

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