Pathogenesis of porcine reproductive and respiratory syndrome virus

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Porcine reproductive and respiratory syndrome virus (PRRSV) is the most costly viral pathogen facing a modern pig industry. A unique feature of the virus is the ability to cause severe clinical disease and maintain a life-long subclinical infection. Persistence at the population level poses the biggest challenge for the successful control and elimination of the disease. A mechanistic basis for persistence includes the evasion of innate and adaptive immune responses. Recent advances include the study of how the non-structural proteins (nsp's) inhibit the induction of type 1 interferon genes.

Highlights

► Persistence is a critical component of PRRSV pathogenesis. ► Mechanism of persistence includes subversion of the innate and humoral responses. ► Evasion of the humoral response is through glycan shielding and genetic variation. ► PRRSV can block the early induction of type I interferons.

Introduction

Porcine reproductive and respiratory syndrome (PRRS) is currently the most economically significant disease impacting pig production worldwide. Clinical outcomes following infection include reproductive failure and increased mortality in young pigs as a result of severe respiratory disease and poor growth performance [1]. However, within a production system, PRRSV infection predominantly exists as a subclinical infection, participating as a co-factor in various polymicrobial disease syndromes, such as porcine respiratory disease complex (PRDC) and porcine circovirus associated disease (PCVAD).

The etiological agent, PRRS virus (PRRSV), was identified in Europe in 1991 and termed Lelystad virus [2]. PRRSV was subsequently isolated in the U.S. and assigned the name VR-2332 [3]. Based on nucleotide sequence comparisons of European and North American isolates, PRRSV is divided into type 1 and type 2 genotypes, respectively. Even though type 1 and type 2 viruses appeared simultaneously and produce similar clinical signs, the two groups share only about 70% identity at the nucleotide level [4, 5, 6]. PRRSV is an enveloped, positive sense, single-stranded RNA virus. The 15.4 kb genome codes for at least 10 open reading frames (ORFs). The structure and composition of the virion are reviewed elsewhere [7]. The nucleocapsid (N) protein forms a polymer surrounding the viral genome. The surface of the virion is dominated by glycoprotein (GP) 5 disulfide linked to the matrix (M) protein. Minor surface glycoproteins form a trimer composed of GP2, GP3, and GP4. Additional envelope proteins include E and ORF5a [8, 9].

The arteriviruses, which include PRRSV, lactate dehydrogenase-elevating virus (LDV), simian hemorrhagic fever virus (SHFV), and equine arteritis virus (EAV), possess several novel properties related to viral pathogenesis, including cytopathic replication in macrophages, the capacity to establish a persistent infection, as well as cause severe disease. As a group, the arteriviruses represent the absolute extremes in mammalian pathogenesis. For example, SHFV is nearly 100% fatal in Asian monkeys [1]. In contrast, LDV rapidly reaches levels close to 1010 virions per ml in the blood with no apparent clinical signs in mice.

The different outcomes following PRRSV infection are a consequence of a complex set of interactions between the virus and the pig host. The acute phase of viremia covers approximately 28 days and primarily targets alveolar macrophages. The mechanistic basis for acute disease, such as respiratory distress is likely a consequence of the release of inflammatory cytokines in the lung. Following the initial clearance from the blood, viremia periodically re-appears [10••], with lymphoid tissues as the primary site of virus replication. Virus can be isolated from lymph nodes for more than 100 days after infection and virus is easily shed to sentinel pigs during the asymptomatic period. Replication levels gradually decay until the virus eventually becomes extinct [11, 12••]. The mechanism for extinction is not clear, but probably relates to the gradual disappearance of permissive cells combined with only a partially effective immune response. By definition, PRRSV is not a ‘persistent’ virus. However, since the average lifetime of a production pig is approximately 180 days, PRRSV infection is ‘life-long’ for the vast majority of pigs. The mechanistic basis for persistence is dependent on a combination of factors including; (1) a complex virion structure that possesses a heavily glycosylated surface, (2) re-direction of the humoral response towards non-surface proteins, (3) antigenic and genetic drift, and (4) subversion of interferon gene induction. This review primarily focuses on recent advances, reported during the past ten years, related to understanding the processes that contribute to persistence.

Section snippets

Humoral immune response and the role of glycan shielding

An example of the humoral response to PRRSV structural and non-structural proteins during experimental infection is shown in Figure 1. Following infection, the earliest and strongest antibody response is against the N protein. In contrast, the antibody response against the major surface component, the GP5-M heterodimer, is weak and delayed. In fact, some animals fail to make a detectable antibody response against GP5. The neutralizing antibody response, which is also weak and delayed, follows a

The role of genetic and antigenic drift in persistence

A recent analysis of approximately 8500 ORF5 (GP5) nucleotide sequences indicates that type 2 viruses can be divided into at least nine distinct groups or lineages [27]. The capacity of PRRSV to rapidly change is illustrated in our previous work investigating the emergence of European type 1 isolates in the US [28]. Type 1 isolates of European origin first appeared in North America around 1999 [29, 30, 31] and are designated as North American (NA) type 1 PRRSV isolates. Phylogenetic analyses

Subversion of the type 1 interferon response by non-structural proteins

A number of studies have shown that pretreatment of cells with type 1 interferon (IFN) inhibits PRRSV replication [37, 38, 39, 40•]. Therefore, the study of the escape of PRRSV from the innate immune response has primarily focused on the subversion of IFN gene activation. The principal observation is the downregulation of IFN type 1 synthesis during virus infection in cultured primary porcine macrophages and other cell lines. After uncoating and entry of the virus genome in the cytoplasm of the

Conclusion

The persistent nature of PRRSV presents significant challenges for the control and elimination of disease. As summarized in Figure 3, subversion of the innate and humoral responses contribute to PRRSV persistence within a population. The strategies that PRRSV utilizes to evade host defenses have placed similar limitations on the effectiveness of the current modified live virus (MLV) vaccines, such as delayed and weak neutralizing antibody response, persistent infection, and the inability to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work was supported by the PRRS CAP, USDA NIFA Award 2008-55620-19132.

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