**1. Introduction**

Classical swine fever virus (CSFV) is one of the most relevant viruses in the Pestivirus genus, being the causative agent of classical swine fever (CSF), a highly impactful disease for the porcine industry worldwide [1]. The capacity of pestiviruses to generate persistent infection by trans-placental transmission has already been described [2–6]. Particularly, low virulence CSFV strains have been related to the development of congenital viral persistence in their offspring when infection of the sows occurs between 50 and 90 days of gestation [1–5]. Piglets that develop this form of infection

are born infected, showing high viral replication and shedding in the absence of specific antibody response [3,4,7]. This type of viral persistence has been explained by the immunotolerance mechanism, due to a lack of CSFV recognition by the immature immune system of the foetus [5].

CSF still remains endemic in countries in Asia, the Caribbean, and Central and South America [1]. Previous studies have demonstrated the evolutionary capacity of CSFV towards less virulent strains in endemic situations under inefficient vaccination programs [8,9]. In this type of scenario, a recent study showed that CSF persistence was the predominant form, favoring virus prevalence and hampering the control tools [10].

CSFV also has the ability to generate viral persistence after postnatal infection, although unlike the congenital persistence forms, the generation of postnatal persistence has been associated with the CSFV moderate virulence strains [11,12]. Previous studies have also shown that moderate virulence strains are widely distributed [13–15]. In this regard, the strain of CSFV that recently caused an epidemic in Japan after 26 years has been characterised to be of moderate virulence [16,17].

Despite the known capacity of CSFV to be transmitted by the trans-placental route and to induce persistent congenital infection, few scientific works have dealt with the immunopathogenesis of this form of the disease, especially from a virus–host interaction standpoint. Considering this background, the aim of this work is to evaluate the capacity of CSFV strains with different virulence degrees to infect pregnant sows and its relation with the vertical transmission by trans-placental infection of fetuses. Likewise, the implication of the virulence degree in the generation of CSFV congenital persistent infection is also assessed. The levels of viral replication, as well as the immune response, in terms of cytokine production and changes in immune system cell populations were evaluated in foetuses and piglets from the infected sows.

## **2. Results**
