High IFN-αResponses Associated with Depletion of Lymphocytes and Natural IFN-Producing Cells During Classical Swine Fever

Abstract

During the acute phase of the viral hemorrhagic disease, classical swine fever (CSF), a severe hematologic depletion in primary lymphoid organs and depletion of peripheral blood T and B lymphocytes are observed. The onset of these pathologic events is before viremia and independent of leukocyte infection, indicating a host-mediated effect possibly through a cytokine storm. Here, we show that high serum levels of interferon- alpha (IFN-alpha) were found during this phase of CSF, detectable as early as 2 days postinfection and reaching maximum levels 3-5 days postinfection (250-1300 U/mL). This IFN-alpha response was related to the virulence of the viral strain used, with avirulent virus not inducing any detectable serum IFN-alpha. A progressive depletion of natural IFN-producing cells/plasmacytoid dendritic cells (pDC), the likely in vivo source of IFN-alpha, was also induced by the viral infection. An important finding was that the onset of severe lymphopenia was concomitant with the IFN-alpha responses, and all animals with serum IFN-alpha had depleted B and T lymphocytes. A statistically significant correlation between lymphocyte depletion and serum IFN-alpha indicates a relationship between the two events, which is supported by the known hematologic effects of high IFN-alpha doses in vivo.

Classical swine fever virus induces activation of plasmacytoid and conventional dendritic cells in tonsil, blood, and spleen of infected pigs

“…As a consequence of the huge amounts of DC expressing IFN-α and TNF-α in secondary lymphoid organs and blood after infection, IFN-α and TNF-α productions in serum were uncommonly high, in accordance with previous reports [36,43]. By contrast, IL-12 level remained constant in serum after infection, probably because of the high IFN-α concentration known to inhibit IL-12 production [2].…”

“…We did not find any significant variation in blood pDC number, despite a jagged curve, but a strong transient decrease in spleen at 48 hpi. Altogether, these results revealed a rapid turn-over of pDC in the spleen, implying a migration of stimulated NIPC between blood and spleen, as previously demonstrated in mice [1] and hypothesized in pigs [43]. These data also showed that cDC, unlike pDC, disappeared permanently from blood after infection, preventing an efficient turn-over of these DC subset in the spleen.…”

“…They were statistically correlated to the lymphocyte depletion, thus a relationship between both events was hypothesized, supported by the known adverse haematological effects of high IFN-α doses in vivo [3]. The authors reported that the infection also induces a progressive depletion of NIPC in blood, and thus suggested that IFN-α expression does not occur in the peripheral blood but in the lymphoid tissue [43].…”

“…These authors implicated macrophages as TNF-α producing cells, but our data showed that DC could also play a role in this phenomenon. Similarly, the high IFN-α level in serum was recently correlated to leucopoenia [43]. As described in other viral infections, IFN-α and TNF-α expressions by pDC could have an inhibitory effect in IL-12 expression by cDC becoming unable to induce efficient cellular immune responses [2].…”

“…To date, these in vitro findings could not be correlated to observations made in infected animals. Interestingly, high serum levels of IFN-α were recently found during the acute phase of CSF [43]. They were statistically correlated to the lymphocyte depletion, thus a relationship between both events was hypothesized, supported by the known adverse haematological effects of high IFN-α doses in vivo [3].…”