The Control of Porcine Circovirus Diseases (PCVDs)

 Background of the proposal

The members of this consortium have had an active research programme on PCVDs for the last 7 years and their collective research findings and publications in peer reviewed journals (> 100) represent the major advances in PCVD research and the state of the art.

Porcine circovirus:

Porcine circovirus (PCV) was first identified in 1974 as a contaminant of the continuous pig kidney cell line PK/15 [63]. This virus was later shown to contain a single-stranded, circular DNA genome. A "novel" PCV-like virus was first isolated from pigs with a wasting disease in western Canada in 1998 [17]. Shortly thereafter, similar viruses were isolated from diseased pigs in N America and Europe [1, 2, 57]. These isolates were shown to be antigenically and genomically distinct from PCV isolates and were designated PCV2 viruses, to discern from the previous virus, which was named PCV1 [8]. PCV1 and PCV2 are small (17nm) icosahedral, non-enveloped viruses containing a single-stranded, circular DNA genome and are now classified in the circovirus genus of the family Circoviridae [24, 25, 60, 61, 63, 64]. They show an ambisense genome organisation with 2 major open reading frames for replication and packaging of viral DNA [34, 35, 36, 38, 39, 40, 41, 42, 62]. The exact mechanisms of viral replication and interaction with host factors are still not known. Mechanisms of PCV2 replication and the molecular basis of pathogenesis of the virus will be addressed in Work Package 4 of this project.

Field disease:

A wasting syndrome in Canadian and French pigs was first reported in 1996 and named postweaning multisystemic wasting syndrome (PMWS) [13, 33]. PCV nucleic acid and antigen were demonstrated in abundance in the lesions of affected pigs and subsequent isolation and characterisation of a PCV2 virus from diseased pigs was reported [1, 2, 17, 53]. Since these initial reports of PCV2-associated wasting disease in piglets in Canada and France the disease has been reported in almost all pig producing countries around the world [37, 49, 57]. Gross lesions of PCVD/PMWS include generalised lymphadenopathy, hepatitis, nephritis and pneumonia and typical histological lesions include lymphocytic depletion together with histiocytic and multinucleated giant cell infiltration in lymph nodes, degeneration and necrosis of hepatocytes, and multifocal lymphohistiocytic interstitial pneumonia [1, 26, 53]. The criteria used for the diagnosis of PCVD/PMWS include the existence of compatible clinical signs, presence of characteristic microscopic lesions in lymphoid tissues and detection of PCV2 within these lesions [59]. Reagents and SOPs for diagnosis and detection of PCVD/PMWS will be optimised and harmonised in Work Package 1 of this project.

PCV2 is widespread in pigs throughout the world and retrospective analyses of sera from 1969 onwards have shown the presence of antibody to a PCV2 virus in a high percentage of the sera tested [14, 43, 44, 51, 52, 65]. Retrospective analyses of tissue sections from diseased pigs has shown that sporadic cases of classical PCVD/PMWS have occurred as far back as the early 1986 [51, 55]. Evidence is emerging that PCV2 may play a major role in other porcine disease syndromes, including proliferating and necrotising pneumonia [1,48], reproductive disorders in pigs [31, 66] and porcine dermatitis and nephropathy syndrome (PDNS) [1, 20, 59]. PDNS was first described in S America in 1976, but until recently occurred only sporadically in EU member states. However, outbreaks of PDNS over the past 5 years have spiralled to epidemic proportions in EU member states and elsewhere. A recent survey in UK identified 251 cases (9.6 % of larger pig holdings). In many of these incidents, PDNS progressed from a sporadic to an epizootic form, with a case mortality of 25 to 30%. Mortalities can reach 100%, as has been reported for PDNS outbreaks in Spain. The microscopic lesions of PDNS are indicative of an immune complex-mediated disease, typically those of a type III hypersensitivity reaction. Nevertheless, epidemiological evidence suggests that PDNS is an infectious disease. The emergence of epidemic PDNS in recent years parallels the appearance of PCVD/PMWS leading to speculation that this syndrome is also PCV2-related [45]. However, to date, no consistent model of experimental production of PDNS has been developed. This will be addressed in Work Package 5 of this project. PCV2 is not a new virus and PCVD/PMWS is not a new disease. It is not known why sporadic PCVD/PMWS has emerged during the last decade as a global epizootic. Information generated in Work Package 2 of this project will be important in answering this, and other questions related to PCVD/PMWS epizootiology.

Experimental infections:

Clinical disease, and gross and histological lesions consistent with PCVD/PMWS have been reproduced following experimental infection of gnotobiotic, colostrum-deprived (CD) and colostrum-fed (CF) piglets with PCV2 [3, 4, 5, 6, 7, 9, 10, 11, 12, 18, 21, 22, 26, 28, 29, 30, 50, 54]. Consistent reproduction of clinical disease in an experimental model seems to require PCV2 infection plus modulation of the immune system by either co-infection with other viruses (porcine parvovirus (PPV)/porcine reproductive and respiratory disease virus (PRRSV) or the use of non-infectious immune modulators [3, 4, 5, 22, 26, 28, 29, 30, 50]. Recent studies using a gnotobiotic model have shown that inoculation of pigs with PCV2 alone plus a non-specific stimulation of immune system results in clinical PCVD/PMWS in 100% of the inoculates [28]. To date, this remains the only 100% disease model, which uses PCV2 as the only infectious agent. However, reproducible clinical disease can be achieved by the co-inoculation of CD pigs with PCV2 and PPV [3, 7], or cloned PCV2 DNA with PPV [unpublished]. Also experimental in-utero infection of porcine foetuses has resulted in gross and histological lesions in the inoculated foetuses, that vary in severity, dependent on the state of gestation of the foetus when inoculated [56]. Stimulation of the immune system of young pigs in current husbandry practises can be multifactorial and PCVD/PMWS is now considered as a multifactorial syndrome where PCV2 is essentially. Mechanisms of PCV2 pathogenesis will be elucidated in Work Packages 5 and 6 of this project.

Immunology and Immunopathogenesis:

Infected pigs seroconvert to PCV2, however the specific roles of the different immune compartments in protection against disease is unknown [27]. Studies have shown that PCV2 accumulates in macrophages and dendritic cells. This is likely to be a pivotal event in the pathogenesis of the disease. In-vivo studies on tissues from PMWS-affected pigs have shown that macrophages and/or dendritic cells contain large amounts of PCV2 antigen [18, 28, 29, 53]. Recent in-vitro studies have confirmed that PCV2 does not replicate in these cell types [19]. However, importantly, PCV2 infectivity was not reduced following infection of macrophages and in-vitro culture for up to 8 days. In vitro studies have revealed potentially immunoregulatory sequences in the genome of PCV2 that inhibits induction of IFN-alpha production [23].

Field and experimental studies have shown significant changes in the subpopulations of blood peripheral mononuclear cells of diseased pigs. These changes were characterised by lymphopenia, increase of circulating monocytes, reduction of T cells (mainly CD4+ and/or CD8+, as well as double positive cells) and B lymphocytes when compared with clinically healthy, non-PCV2 infected pigs [16, 47, 58]. In addition, more recent work have shown cytokine mRNA alterations in PMWS affected pigs, which were characterized by an over expression of IL-10 mRNA in thymus and IFN-gamma mRNA in tonsils, and by decreases of several cytokines in other lymphoid tissues [15].

All together, these immunopathological findings in PMWS affected pigs suggest an inability to mount an effective immune response. However, it still remains unclear how this virus acts upon the immune system of infected pigs, especially during the early phases of infection. This will be addressed in Work Packages 5 and 6 of this project.

Control of PCVDs:

Currently very little is known about control of PCVDs. Recent field studies have indicated that a "20-point plan" of improved husbandry measures may sometimes, but not always, limit the disease impact in affected herds [32]. Importantly, field observations by veterinarians and producers suggest that susceptibility/resistance to PCVD/PMWS may be influenced by the genetics or breed of the host, specifically in regard to the boar lines used. None of these “observations” have been scientifically evaluated or assessed. This will be addressed in Work Package 3 of this project. In addition, on some farms the use of feed additives and alterations in feeding regimes have had a beneficial effect on PCVD/PMWS. However, on other farms this has had no effect. This will be addressed in Work Package 7 of this project. To date, no commercial vaccines are available for PCVD. Strategies for the control of PCVDs will be developed through the collaborative efforts of all partners and particularly through data obtained from Work Packages 2, 3, 5, 6, 7 and 8. Information generated within all of the above Work Packages will be disseminated through Work Package 9 of the project.

Summary:

Since the initiation of the two research projects on PCVD under Framework 5, a great deal of basic information on the pathogenesis, epidemiology and replication of PCV2 has been generated and a new generation of biological and procedures for the study of this disease have been prepared. This information and these biological and procedures will serve as a sound platform for further research in this proposed project by an enhanced new multidisciplinary consortium. The new consortium combines the existing strengths of the partners from the two previous projects with expertise in epizootiology, nutrition, porcine genetics, bacteriology and information dissemination.

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