In the case of PRRSV the infection can be divided clearly in two successive phases:
1- a viraemic phase, lasting from days to several weeks depending on the age of the affected animal and on the strain, and
2- a non-viraemic phase of persistence of the virus in the lymphoid tissues that can last for months. How the virus persists is not clear. It is probably the result of several factors including at least the interplay of the virus with the immune system of the host, the genetic background of the animal and the particular strain of the virus that is infecting the pig.
PRRSV and the innate immune response
PRRSV targets are differentiated macrophages and probably myeloid dendritic cells –both central players in in the bridge between innate and adaptive immune responses. Recent studies suggest that susceptibility of macrophages to the infection depends on the genotype of the virus and on the polarization of the macrophage. It is thought that PRRSV may manipulate or interfere with some critical elements of these cell types. From early studies it is known that PRRSV inhibits type I interferon responses in macrophages.
PRRSV may replicate in several types of dendritic cells causing inhibition of type I interferons along with many other alterations in the phenotype, functionality or cytokine responses of the examined dendritic cells. Interestingly, these effects seem to be partially dependent on the strain of PRRSV. This inhibition of type I interferons is attributable at least in part to the interaction of non structural proteins of the virus with the interferon pathways of the cell.
In contrast, plasmacytoid dendritic cells are refractory to the infection. Interestingly, the capacity for inhibiting interferon alpha responses in plasmacytoid dendritic cells seems to be dependent on the strain with genotype 1 isolates being lowly inhibitory.
Further, it has been demonstrated that immunosuppressive cytokines may be produced upon infection, such as IL10 although the precise role of this cytokine in PRRSV infection is not understood completely. A full picture of which immune mechanisms are altered or regulated by PRRSV is lacking but there is clear evidence that the innate immune response is affected.
PRRSV and the adaptive immune response
The pig’s adaptive immune response against PRRSV is characterized by being delayed and defective. Following a natural infection, it takes at least 3 months to reach immunity peak levels and it does not appear to be solid enough to prevent reinfection, especially if the reinfection is caused by antigenically heterologous PRRSV strains. Pigs infected with PRRSV fail to generate any significant inflammatory cytokine expression in the lungs, including the type I interferons (IFN-α/β), interleukin (IL)-1, and TNF-α. The expression of type I interferon is important for the activation of innate immune response. The downregulation of INF-α can be a crucial step in PRRSV pathogenesis as INF-α has been shown to inhibit PRRSV replication, hence the weak initial innate immune response may lead to longer survival of the virus in the infected animal.
Following infection, the earliest and strongest antibody response is directed against the N protein which is measureable 5-9 days PI. Antibodies against the two non-structural proteins nsp1 and nsp2 are evident at 14 days PI, and reach peak levels at 28- 35 days PI. All these early produced antibodies are non-neutralizing whereas the neutralizing antibodies first appear 4 weeks PI or even later. The neutralizing antibody response against the GP5 neutralizing epitope is weak and delayed, and some animals fail to make a detectable antibody response against GP5. The mechanism for the weak antibody response towards GP5 is linked to the N-glycosylations surrounding the neutralizing epitope, a phenomenon called N-glycan shielding. Furthermore, for Type 2 PRRSV, GP5 encodes a decoy epitope at position aa27-30 which is not neutralizing but may function to distract the humoral immune response hence delaying the induction of neutralizing antibodies against PRRSV.
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