Tissue tropism and mRNA expression profiles of selected innate immunity-related genes following experimental tick-borne encephalitis virus and louping ill virus infection of sheep.

Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are genetically and antigenically closely related tick-borne flaviviruses responsible for different disease outcomes in sheep. In order to determine whether key components of the innate immunity could contribute to the observed difference in virus dissemination and disease outcome, 8-month-old sheep were inoculated intradermally with TBEV Neudoerfl strain or LIV LI/31 strain. Only LIV-infected sheep developed fever and clinical signs. No TBEV RNA was detected in serum and examined tissues, except for low amounts in the skin, prescapular lymph nodes, and spleen. In contrast, high LIV RNA load and infectious virus were found in serum and various tissues, indicating a tropism for lymphoid organs and the brain. The highest LIV viral loads were found in the brain stem, the cerebellum, and the thalamus. The analysis of mRNA expression profiles of selected cytokines and chemokines showed a weak to moderate innate antiviral immune response in the prescapular lymph nodes of TBEV-infected sheep. Conversely, a strong upregulation of several interferon-stimulated genes, chemokines, and pro-inflammatory cytokines was induced in the prescapular lymph nodes, tonsils, medulla oblongata, cerebellum, and thalamus of LIV-infected animals. Neutralizing antibodies were detected in both LIV- and TBEV-infected sheep. These data suggest that the innate and humoral immune responses were sufficient to block TBEV replication early after infection but insufficient to stop LIV entry and replication in the brain, as supported by the high viral loads at euthanasia, and likely contribute to the induced clinical symptoms. Although LIV and TBEV are closely related tick-borne flaviviruses, the outcome of an infection in sheep is considerably different. Here, we show that the effectiveness of the innate immune response to limit virus replication corresponds to a specific clinical outcome. TBEV infection seemed to be efficiently controlled at the level of the prescapular lymph node by a moderate interferon-related cytokine response. This early control prevented likely further TBEV spread and entry in the CNS. In contrast, LIV was capable of replicating to high viral loads in prescapular lymph nodes, tonsils, and brain tissues despite the strong innate immune responses induced in these tissues, which probably contributed to the observed clinical signs. This further suggests that LIV has adapted to better circumvent innate immune responses than TBEV and that the clinical manifestations can be attributed to a dysregulated response.