The Timing and Magnitude of the Type I Interferon Response Are Correlated with Disease Tolerance in Arbovirus Infection
Alexandra Hardy, Siddharth Bakshi, Wilhelm Furnon, Oscar A. MacLean, Quan Gu, Margus Varjak, Mariana Varela, Muhamad Afiq Aziz, Andrew E. Shaw, Rute Maria Pinto, Natalia Cameron Ruiz, Catrina Mullan, Aislynn Taggart, Ana da Silva Filipe, Richard E. Randall, Sam J. Wilson, Meredith Stewart, Massimo Palmarini
Abstract
The host immune response usually aims to inhibit virus replication in order to avoid cell damage and disease. In some cases, however, the infected host avoids the deleterious effects of infection despite high levels of viral replication. This strategy is known as disease tolerance, and it is used by animal reservoirs of some zoonotic viruses. Here, using a virus of ruminants (bluetongue virus [BTV]) as an experimental system, we dissected virus-host interactions in cells collected from species that are susceptible (sheep) or tolerant (cow) to disease. We show that (i) virus modulation of the host antiviral type I interferon (IFN) responses, (ii) viral replication kinetics, and (iii) virus-induced cell damage differ in tolerant and susceptible BTV-infected cells. Understanding the complex virus-host interactions in disease tolerance can allow us to disentangle the critical balance between protective and damaging host immune responses.