How PCV2 Interferes with the Immune System

A story of porcine circovirus type 2 (PCV2) and PCV-associated disease (PCVD), could be subtitled 'PCV2 and PCVD – when immunology goes wrong'. Dr Kenneth McCullough, head of research at Switzerland's Institute of Virology and Immunoprophylaxis explained how PCV2 affects the pig's immune response at this year's PCVD Forum. Jackie Linden reports for ThePigSite.

4 December 2009

5 minute read

One of the critical points in understanding the pathogenesis of PCV2 infection is the balance between the host immune defences responding to the presence of the virus, and the capacity of the virus to interfere with immune defence development.

From Gnotobiotic to SPF Piglet Models

A major insight into this balance between immune recognition and immune impairment came from work with gnotobiotic piglets.

PCV2-infected gnotobiotic piglets do not develop clinical signs: their immune system may be impaired but the lack of challenge by what is effectively their sterile environment means that there is no disease development.

Only when a 'danger signal' is introduced into the environment does disease develop. Examples of this 'second signal' representing 'danger' – a potential threat to the host – are immune stimulation, as seen with Freud's adjuvant together with an antigen, or co-infection, as seen with parvovirus.

PCV2 infection has also been studied in specific pathogen-free (SPF) piglets by a number of research laboratories. Piglets that develop porcine multisystemic wasting syndrome (PMWS)-like signs and lesions show a collapse of the immune system, particularly of the adaptive immune system (B and T cell lymphopenia). The innate immune system (NK cells and monocytes) is also affected although this can often be seen as impaired activation. In these animals, both adaptive and innate cytokine responsiveness is impaired. Although this is not a general knock-down of all cytokine activities – while 1L-1β and IL-2 response may be weakened, IFN-responses can appear intact. Nevertheless, piglets with such immune defences are an easy target for any opportunistic pathogen in the environment.

Quest for PCV2's Target Cell

The immune cell targeted by PCV2 has long been a matter of debate. While PCV2 antigen or DNA can be found in lymphocytes, this appears to be a transient event. On the contrary, monocytic cells can effectively internalise the virus but seem to be incapable of clearing it with respect to the persistence of the virus in these cells with time.

In-vitro observations have confirmed that macrophages and dendritic cells are major targets for virus infection, and do indeed accumulate infectious virus, allowing its persistence. However, virus does not replicate efficiently in these cells. Endothelial cells and gut epithelial cells are permissive to PCV2 infection and replication without demonstrating an obvious dysfunction. This is important considering that endothelial cells are in contact with the blood in every tissue. Even a low replication in a limited proportion of the body's endothelial cells could produce a large amount of PCV2.

Dendritic Cells Attack on Several Fronts

PCV2 infection of dendritic cells (DCs) poses a major problem for the host's immune defences. The DCs are critical immune controllers: they are the pillars ensuring homeostasis, together with the correct and efficient development of adaptive immune responses. PCV2 can infect both immature and mature dendritic cells (the so-called conventional DCs or cDCs).

Although infected immature DCs are still able to mature - and become professional antigen-presenting cells - it is the induction of this maturation that is highly susceptible to the presence of PCV2 infection. DC maturation is triggered by signals mediated by 'danger' recognition, exemplified by the maturation factors secreted by Natural Interferon-Producing Cells (NIPCs; also known as plasmacytoid DCs or pDCs) to recognise 'danger' is down-regulated in the presence of PCV2, wherein the main culprit is viral DNA, particularly the dsDNA replicative form.

In this way, PCV2 infection has the capacity to limit the proportion of immature DCs reaching maturity. A number of in-vitro trials have shown that the accumulation of PCV2 observed with DCs can prove deleterious for the DCs, resulting in erroneous signalling to other effectors of the immune response (B- and T-cells). The final outcome may be anergy, i.e. absence of response, and immunopathology.

At Pig Level

When PCV2 infects piglets still protected by maternal immunity: either the virus infection is prevented by the maternal immunity or residual immunity can enhance the ability of the piglet to resist infection and develop its own immune response.

In the latter case, a 'normal' activation of the immune system occurs: the innate defences remain intact, DCs function and mature normally and the animal will mount an effective immune response against PCV2 and other pathogens. This contrasts with PCV2 in an unprotected piglet. Therein, the infection of DCs will reduce the ability to recognise 'danger' (detect pathogen-associated molecular patterns), resulting in reduced innate defence competence.

Consequently, the DCs' ability to promote adaptive immunity by detecting and presenting antigens, as well as communicating appropriately with the adaptive defences, are impaired leading to anergy or immunosuppression. As a result, the immune system as a whole is no longer capable of responding efficiently to pathogen attack, setting the scenario for the development of diseases such as PMWS and PCVD.