The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs

Abstract

This paper reviews in vivo studies on the interaction between porcine reproductive and respiratory syndrome virus (PRRSV) and LPS performed in the authors' laboratory. The main aim was to develop a reproducible model to study the pathogenesis of PRRSV-induced multifactorial respiratory disease. The central hypothesis was that respiratory disease results from an overproduction of proinflammatory cytokines in the lungs. In a first series of studies, PRRSV was shown to be a poor inducer of TNF-alpha and IFN-alpha in the lungs, whereas IL-1 and the anti-inflammatory cytokine IL-10 were produced consistently during infection. We then set up a dual inoculation model in which pigs were inoculated intratracheally with PRRSV and 3-14 days later with LPS. PRRSV-infected pigs developed acute respiratory signs for 12-24h upon intratracheal LPS inoculation, in contrast to pigs inoculated with PRRSV or LPS only. Moreover, peak TNF-alpha, IL-1 and IL-6 titers were 10-100 times higher in PRRSV-LPS inoculated pigs than in the singly inoculated pigs and the cytokine overproduction was associated with disease. To further prove the role of proinflammatory cytokines, we studied the effect of pentoxifylline, a known inhibitor of TNF-alpha and IL-1, on PRRSV-LPS induced cytokine production and disease. The clinical effects of two non-steroidal anti-inflammatory drugs (NSAIDs), meloxicam and flunixin meglumine, were also examined. Pentoxifylline, but not the NSAIDs, significantly reduced fever and respiratory signs from 2 to 6h after LPS. The levels of TNF-alpha and IL-1 in the lungs of pentoxifylline-treated pigs were moderately reduced, but were still 26 and 3.5-fold higher than in pigs inoculated with PRRSV or LPS only. This indicates that pathways other than inhibition of cytokine production contributed to the clinical improvement. Finally, we studied a mechanism by which PRRSV may sensitize the lungs for LPS. We hypothesized that PRRSV would increase the amount of LPS receptor complex in the lungs leading to LPS sensitisation. Both CD14 and LPS-binding protein, two components of this complex, increased significantly during infection and the amount of CD14 in particular was correlated with LPS sensitisation. The increase of CD14 was mainly due to infiltration of strongly CD14-positive monocytes in the lungs. The PRRSV-LPS combination proved to be a simple and reproducible experimental model for multifactorial respiratory disease in pigs. To what extent the interaction between PRRSV and LPS contributes to the development of complex respiratory disease is still a matter of debate.

Lack ofIn VitroandIn VivoEffects of Lipopolysaccharide on Porcine Circovirus Type 2 Infection

“…LPS has been used in swine models of infection with PRRSV (61,60) and porcine respiratory coronavirus (PRCV) (62). In all these works, the aim was to repro-FERNANDES ET AL.…”

“…It has been reported that LPSs of Escherichia coli and Salmonella spp. have stronger endotoxic activity than those of other bacteria (60). Therefore, based on this fact and due to the fact that one of the best in vitro results for the Stoon-1010 isolate (the same phylogenetic group as the Burgos isolate) was with the LPS from Salmonella enterica serotype typhimurium, this LPS was chosen for the in vivo study.…”

Vaccination with a genotype 1 modified live vaccine against porcine reproductive and respiratory syndrome virus significantly reduces viremia, viral shedding and transmission of the virus in a quasi-natural experimental model

“…In contrast, vaccination of piglets is more controversial. Firstly, because respiratory disease caused by PRRSV, particularly by genotype 1 isolates, is not always overt (Martínez-Lobo et al, 2011) and depends on the interaction with other pathogens (Van Gucht et al, 2004). Therefore, the beneficial effect of vaccination is more difficult to evaluate.…”

Development of an experimental inactivated PRRSV vaccine that induces virus-neutralizing antibodies

“…PRRSV can cause severe reproductive failure in sows, characterized by late term abortion, early farrowing, stillbirth and the birth of weak piglets, and is associated with the porcine respiratory disease complex in combination with secondary infections [3,4,[26][27][28]30]. The virus is present in a majority of swine producing countries around the world and gives rise to enormous economic losses in the swine industry [17].…”