The reality in many parts of the world is the coincidence of these well-known diseases together with emerging infections.

Viral infectious diseases in swine account for some of the most devastating health problems in this species, both historically and currently. In addition to the well-known “old” problems like foot-and-mouth disease, pseudo- rabies, classical swine fever or African swine fever (ASF), a significant increase of novel viral diseases appeared in the last 30 years (Fournié et al., 2015).

However, the reality in many parts of the world is the coincidence of these well-known diseases together with emerging infections. The most threatening example in 2019 was ASF, being highly distributed in Africa but also in south-east Asia and eastern Europe.

Swine pathogensIn the last three decades, a number of important world-wide distributed viruses causing significant health prob-lems has been reported (Meng, 2012).

In addition, novel swine pathogens causing different types of disease have been discovered. Although their

Porcine Circovirus 3 (PCV3): an old virus able to cause disease?

Novel swine pathogensSome examples are:

• Porcine deltacoronavirus.

• Senecavirus A.

• Porcine sapelovirus.

• Porcine orthoreovirus.

• Atypical porcine pestivirus.

• HKU2-related coronavirus of bat origin (associated with the so-called swine acute diarrhea syndrome).

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Joaquim Segalés1,2 and Marina Sibila3

1 UAB, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB). Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain2 Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain3 IRTA. Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain

Since Porcine Circovirus 3 was first discovered in 2015, the virus has been found worldwide both in diseased and healthy pigs. This manuscript reviews the most significant features and its putative association with disease causality.

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VirusesAmong others, the list of important worldwide distributed viruses includes:

• Porcine reproductive and respiratory syndrome virus (PRRSV).

• Porcine Circovirus 2 (PCV2).

• Porcine epidemic diarrhea virus (PEDV).

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economic impact might be variable depending on the farm and region, they are considered significant infec-tious agents.

Moreover, other novel infectious agents have been detected in both healthy and diseased animals, and their importance is not yet clarified.

Porcine Circovirus 3 (PCV3)In 2015, a novel member of the Circoviridae family named Porcine Circovirus 3 (PCV3) was discovered through next generation sequencing by two indepen-dent research groups in the USA (Phan et al., 2016; Palinski et al., 2017).

These investigations found the presence of the virus genome in tissues of pigs affected by a number of clin-ical conditions including:• Reproductive failure.• Multisystemic inflammation.• Porcine dermatitis and nephropathy syndrome

(PDNS).

Since then, PCV3 has been found worldwide both in dis-eased and healthy pigs.

ObjectiveThe objective of this manuscript is to review those more significant features of this novel porcine circovirus (PCV) and discuss its putative association with disease causality.

The genome of PCV3PCV3 is a single stranded DNA virus of approximately 2,000 nucleotides in length, which comprises three open reading frames (ORFs) so far identified (Palinski et al., 2017).

The information about ORF2 is important because it has been speculated that vaccines against PCV2 may protect against PCV3 infection. Based on the sequence similar-

Other infectious agentsThe importance of these agents is not clarified:

• Torque teno sus viruses.

• Porcine bocavirus.

• Porcine torovirus.

• Porcine kobuvirus.

• Porcine sapelovirus.

• Hepatitis E virus (HEV) can be considered an exception within this group, since it is apparently quite innocuous for pigs, but considered an important zoonotic agent.

Open reading framesOnly two of the three ORFs have been characterised:

• ORF1: located in the positive viral strand and codes apparently for a single replicase protein of about 296-297 amino acids.

• ORF2: present in the negative DNA viral strand and codes for the capsid protein, which is considered the immunogenic target to neutralise PCV infections. It consists of a 214 amino acid protein (Phan et al., 2016; Palinski et al., 2017) and its nucleotide similarity with that of PCV1 and PCV2 is of 24 % and 26-37 %, respectively (Klaumann et al., 2018a).

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In 2015, a novel member of the Circoviridae family named Porcine Circovirus 3 (PCV3) was discovered through next generation sequencing.

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ity of the ORF2, such cross-protection is not expected at all. Indeed, although PCV3 follows a similar genomic organisation compared to other PCVs, its genome is dis-tantly related to other known circoviruses. In fact, it has been proposed to have a phylogenetic relationship with bat and avian circoviruses (Franzo et al., 2018c).

However, phylogenetic information available to date indi-cates (Franzo et al., 2019a):• A low genetic variability of PCV3 in comparison with

other single stranded-DNA viruses.• That the virus genome has been relatively stable

through the years.

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Based on the low ORF2 homogenity between PCV2 and PCV3 a crossprotection of PCV2 vaccines against PCV3 is not expected at all.

Epidemiology of PCV3 infectionEpidemiological knowledge of PCV3 infection is scarce and fragmented in the existing literature. Importantly, this virus does not appear to be an emerging agent.

After the first description reported from the USA in 2015, several countries located in Asia, Europe and South America (figure 1) have demonstrated the presence of PCV3 genome in domestic pigs (Klaumann et al., 2018a).

In fact, the perception is that the viral genome has been found in pigs as long as proper investigations have been conducted in a given country or region. In consequence, it is believed that PCV3 is, similarly to other PCVs, a ubiquitous virus.

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The perception is the that viral genome has been found in pigs as long as proper investigations have been conducted in a given country or region.

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PCV3Data to support the view that PCV3 does not appear to be an emerging infectious agent, is as follows:

• Retrospective studies have detected its genome in Sweden as early as 1993 (Ye et al., 2018) and Spain and China in 1996 (Klaumann et al., 2018b; Sun et al., 2018).

• It is likely that studies with older samples may potentially detect PCV3 even earlier, since those mentioned studies showed positivity by PCR within the first year of investigation.

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PCV3 genomePCV3 genome has been detected in pigs of all ages, including sows, mummified fetuses and stillborn (Pal-inski et al., 2017; Klaumann et al., 2018b; Tochetto et al., 2018).

In a very recent work performed on longitudinally sam-pled pigs in Spain (Klaumann et al., 2019a), PCV3 DNA was found at all age-groups in four tested farms and the frequency of infection was not dominant at any age; therefore, no particular infection dynamics could be inferred in this study.

PCV3 DNAPCV3 DNA has been found in many different matrices including serum, tissues, oral fluids, nasal swabs, feces, semen and colostrum (Collins et al., 2017; Ku et al., 2017; Kwon et al., 2017; Stadejek et al., 2017; Franzo et al., 2018a,b; Kedkovid et al., 2018a; Klaumann et al., 2019b).

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Figure 1. PCV3 is distributed worldwide.

Countries in red are those in which PCV3 PCR positive samples in domestic pigs and/or wild boar have been so far reported.

Detection of PCV3 genomeAlthough some studies show a lower frequency of PCV3 PCR positivity in lactating pigs when compared with nursery and fattening pigs, the highest prevalence has been found in animals after weaning (Kwon et al., 2017; Stadejek et al., 2017; Fux et al., 2018). However, most published studies included different pigs from limited age-groups and not the same animals over time.

Spanish studyIn these farms, pigs were healthy during the follow up period (weaning-to-slaughter) and the viral load was low in all cases, suggesting a subclinical infection.

However, certain percentages of pigs were found to be PCR positive at different and consecutive sampling points, suggesting the existence of long-lasting infections with this virus (Klaumann et al., 2019a).

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No studies have been performed on virus detection in the environment, but one study found the PCV3 genome in 2 out of 4 sponges used for sampling pig transporting trucks after sanitation (Franzo et al., 2018a).

In addition to domestic pigs, PCV3 infects wild boar (Franzo et al., 2018d; Klaumann et al., 2019b; Prinz et al., 2019), which to be expected taking into account the epidemiology of PCV2.

Historically, circoviruses were considered to be spe-cies-specific. However, a number of years ago the debate was raised whether mice were considered sus-ceptible to PCV2 infection (Kiupel et al., 2001; Quintana et al., 2002). These discussion continue with regard to PCV3 infections. Curiously, PCV-3 has been also found

in dogs, cattle, mice, wild ruminants and ticks (Ouyang et al., 2019).

Further studies are needed to confirm the suggested wider circulation of PCV3 among non-Suidae species.

Disease association with PCV3The first descriptions of PCV3 in USA suggested a link to disease association, the viral genome was then identified (Phan et al., 2016; Palinski et al., 2017) in the following cases:• Myocarditis.• Systemic inflammation.• PDNS.

In all these cases other usual pathogens were ruled out.

These initial studies ensured that the lesions of the affected animals were analysed for the presence of PCV3 genomic material. Although the complete genome was not achieved, the presence of the PCV3 virus within the lesions was proven.

However, since then, most of the published studies on putative disease association (table) have been based on the simple detection of the virus genome in serum or tissues of sick pigs and, eventually, along with a negative control group of healthy animals.

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PCV3 infects wild boar, this was to be expected considering the epidemiology of PCV2 and the fact that its prevalence is similar or higher than in domestic pigs.

There was no solid evidence of PCV3 as a real causative agent of disease in most of these descriptions.

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PCV3 in wild boarViral DNA sequences retrieved from wild boar showed more than 98 % similarity with the available sequences from domestic pigs.

The prevalence in wild boar is similar or higher than that found in domestic pigs (30-45 %).

In fact, a potential reservoir role of the wild boar with respect to PCV3 infection has been suggested by those studies.

There was no solid evidence of PCV3 as a real causative agent of disease in most of these descriptions. In fact, a recent paper indicated specifically lack of association between respiratory and digestive disorders with PCV3 infection, since the prevalence and viral loads in dis-eased animals was similar than to age-matched healthy pigs (Saporiti et al., 2019).

Therefore, it is important to note that the presence of a given viral agent in a tissue of a diseased animal does not imply this virus is the cause of the clinical signs or observed lesions.

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The presence of viral agents in tissuesIn the literature there are many infectious viral agents infecting swine which have never been demonstrated (so far) as true pathogens (Meng, 2012).

Consequently, care must be taken in the interpretation of PCV3 detected PCR results, regardless of the sample type from a diseased animal, investigated for diagnostic purposes.

Putative disease associationIn this context, PCV3 has been found (table) in cases of:

• Reproductive disease.

• Respiratory disorders.

• Enteric problems.

• Systemic inflammation.

• Congenital tremors.

• Periweaning failure-to-thrive syndrome (table).

Disorders Production phase Clinical signs – Disease – Syndrome Control group –

Healthy animals References

Reproductive Sows

• Increase in the sow mortality; decrease in the conception rates; mummified fetuses

• Aborted fetuses, stillborn• Abortion, mummified fetuses; reproductive

failure; decrease of neonatal rate• Abortion, reproductive failure• Stillbirths• Non-specified reproductive problems• Abortions, weak-born piglets

NANANANANANANA

Palinski et al., 2017Faccini et al., 2017

Ku et al., 2017Kim et al., 2018

Tochetto et al., 2018Zou et al., 2018

Deim et al., 2019

Respiratory

LactationWeaningWeaningFatteningFattening

• Dyspnea• Anorexia, fever, jaundice, abdominal breathing• Cough, softly panting, abdominal breathing• Respiratory signs• Porcine respiratory disease complex (PRDC)• Respiratory distress

NANA

Yes*NANANA

Phan et al., 2016Shen et al., 2017Zhai et al., 2017

Phan et al., 2016; Fux et al., 2018Kedkovid et al., 2018

Kim et al., 2018

CardiovascularLactation, weaning

• Anorexia, weight loss, swollen joints• Non-suppurative myocarditis

NANA

Phan et al., 2016Arruda et al., 2019;

Williamson et al., 2019

Weaning • Diarrhea Yes* Zhai et al., 2017

Systemic Lactation, weaning

• Wasting• Periweaning failure-to-thrive syndrome (PFTS)• Non-suppurative systemic inflammation

Yes*Yes*NA

Stadejek et al., 2017Franzo et al., 2019bArruda et al., 2019;

Williamson et al., 2019

Neurological LactationLactation

• Neurological signs• Congenital tremors

NANA

Phan et al., 2016 Chen et al., 2017

Others FatteningSows

• Rectal prolapse• Congenital malformations• PDNS

NANANA

Phan et al., 2016Williamson et al., 2019

Palinski et al., 2017; Arruda et al., 2019; Jiang et al., 2019

Studies on detection of PCV3 by PCR according to production phase and different clinical/pathological scenarios

NA: not available in the published study. *PCV3 positivity in lower frequency than diseased animal.Adapted from: Klaumann et al. (2018a).

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EvidenceProbably the best evidence of disease association has been demonstrated recently in the United States of America and in the United Kingdom.

These cases were strongly positive by means of PCV3 in situ hybridisation (figure 2), further emphasizing the causal association of the virus with observed lesions. All these cases from both USA and United Kingdom were negative for PCV2 detection.

Another important issue, not yet resolved, is to determine in which conditions and frequency, PCV3 is able to cause obvious clinical disease. Moreover, although PCV3 has been found in co-infection with multiple endemic patho-gens (Klaumann et al., 2018a), it is not understood if such concurrent infection potentiates PCV3 virulence or degree of replication and, therefore, its pathogenic possibilities.

Furthermore, it is still unknown if:• The likelihood of disease association with this novel

virus depends on its presence only.• Whether other infectious or non-infectious factors

may serve as triggers to disease.

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Another important issue, not yet resolved, is to determine in which conditions and frequency PCV3 is able to cause obvious clinical disease.

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United States of AmericaA group of researchers and diagnosticians from USA has described diagnostic investigations of 36 field cases from 9 different states, detecting PCV3 genome within lesions by in situ hybridisation (Arruda et al., 2019).

Viral detection was accomplished in fetuses with myocarditis, weak-born neonatal piglets with encephalitis and myocarditis, PDNS cases, and in weaned pigs with systemic periarteritis.

United KingdomDiagnosticians from United Kingdom reported stillborns (with some level of limb deformity) and 18-day old piglets with post-natal tremor from one farm, showing very significant lesions of multisystemic inflammation with very low Ct values of PCV3 by quantitative PCR (Williamson et al., 2019).

Figure 2. PCV3 in situ hybridisation of a piglet kidney with arteritis and periarteritis showing massive viral DNA in the wall of pelvic arterioles (red dark color). The presence of virus genome within the lesion represents a strong evidence of potential lesion causality.

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Tools to detect PCV3Detection of a ubiquitous virus in a pig or herd does not preclude the causation of disease despite the presence of clinical signs. In fact, the simple detection of a num-ber of pathogens mentioned in the introduction does not discriminate between subclinical infections or obvious clinical disease.

It is known that PCV2 may cause overt disease or sub-clinical infection and there are also economical losses attributed to this condition, which is especially evident when pigs are not vaccinated (Segalés, 2015).

The current knowledge on PCV3 is very scarce com-pared to PCV2, and at this point very few studies have demonstrated disease causality with the novel virus.

In situ hybridisationIn fact, the presence of PCV3 associated with lesions has been demonstrated by means of in situ hybridisation in very few studies (Phan et al., 2016; Arruda et al., 2019; own unpublished data). However, so far, this technique is the one that better establishes a putative association between the agent and the disease problem.

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The current knowledge on PCV3 is very scarce compared to PCV2.

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AssociationsBased on these data, PCV3 should be considered a potential cause of:

• Reproductive failure.

• Multisystemic inflammation.

• Encephalitis and myocarditis in perinatal piglets.

• PDNS.

• Periarteritis in weaned swine.

DiagnosisA sound diagnosis of an infectious disease must include:

• Clinical signs or evidence of a poor performance situation.

• Assessment of factors involved in the triggering of the problem.

• Detection of the given pathogen associated to the lesions in affected pigs at the time of disease occurrence. This latter point is crucial, especially for certain infectious agents such as PCVs.

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Molecular methodsSince the discovery of PCV3, new molecular methods have been developed; PCR methods, especially real-time PCR, are now used to detect a Ct value (cycle threshold) or to quantify the amount of viral DNA in a given sample (Ouyang et al., 2019).

However, the pathogenesis of this viral infection is virtually unknown and it is still unknown what the presence of lev-els of PCV3 DNA in a sample, means in terms of infection.

Consequently, these molecular methods are excellent tools for virus monitoring, but not yet the best methods to ascertain disease association.

Antibody monitoringAnother important aspect in diagnosis is the possibility of antibody monitoring. So far there are no commercial ELISA kits to detect antibodies against PCV3.

In literature, few tests have been proposed (Ouyang et al., 2019), but the difficulties in:• Isolating the virus (not yet published), and• getting viral recombinant proteins (Cap protein) at

large scale…

…pose complications to the short term availability of such antibody tests.

As a parallel with PCV2, it is very likely that PCV3 anti-body detection will be a great monitoring tool but not an aid to establish a diagnosis of disease causality.

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Molecular methods are excellent tools for virus monitoring, but not yet the best methods to ascertain disease association.

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Ct value or the amount of viral DNADue to the fact that the higher the viral load, the higher likelihood of disease association (at least for a number of pathogens including PCV2), then:

• A high amount of viral DNA copies, or

• a low Ct value for PCV3…

…are stronger indications of potential link with disease occurrence.

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PCV3 epidemiology

PCV3 is a recently discovered virus, now considered to have been in existence for many decades prior to its discovery and which:• Is widespread in both domestic pigs and wild boar.• Has been found in several non-Suidae species.

Whether these species are fully susceptible to the infection and play a role in the epidemiology of the virus is still to be determined.

PCV3 at all ages

PCV3 can be found at all ages in domestic pig and some animals may suffer from persistent infections.The virus has been found in several clinical and pathological conditions, but a definitive proof of its pathogenicity is still lacking.Only recent studies using in situ hybridisation have given a clue regarding disease cau-sality, since PCV3 DNA was found in inflammatory lesions of sick animals.The frequency of disease caused by PCV3 and the trigger conditions are still unknown and pose important questions.

Conclusions

Lack of a PCV3 isolate

Importantly, to date, the lack of a readily available virus isolate prevents the develop-ment of an animal model, which in turn, would advance our understanding of PCV3 pathogenesis and immunity.It is very likely that these aspects will be resolved in the future, but they will depend on the research effort dedicated to this new pathogenic agent in the next few years.Moreover, depending on the demonstrated impact of PCV3 on pig health, putative vaccine development will follow.

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AcknowledgementsAuthors would like to acknowledge the funding of the E-RTA2017-00007-00-00 project, from the Instituto Nacional de Investigación y Tecnologia Agraria y Alimentaria (Spanish Government).

The funding from CERCA Programme/Generalitat de Catalunya to IRTA is also acknowledged.

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PCV

Respig 3rd edition12