نبذة مختصرة : The mechanisms and consequences of genome evolution on viral fitness following host shifts are poorly understood. In addition, viral fitness -the ability of an organism to reproduce and survive- is multifactorial and thus difficult to quantify. Influenza A viruses (IAVs) circulate broadly among wild birds and have jumped into and become endemic in multiple mammalian hosts, including humans, pigs, dogs, seals, and horses. H3N8 equine influenza virus (EIV) is an endemic virus of horses that originated in birds and has been circulating uninterruptedly in equine populations since the early 1960s. Here, we used EIV to quantify changes in infection phenotype associated to viral fitness due to genome-wide changes acquired during long-term adaptation. We performed experimental infections of two mammalian cell lines and equine tracheal explants using the earliest H3N8 EIV isolated (A/equine/Uruguay/63 [EIV/63]), and A/equine/Ohio/2003 (EIV/2003), a monophyletic descendant of EIV/63 isolated 40 years after the emergence of H3N8 EIV. We show that EIV/2003 exhibits increased resistance to interferon, enhanced viral replication, and a more efficient cell-to-cell spread in cells and tissues. Transcriptomics analyses revealed virus-specific responses to each virus, mainly affecting host immunity and inflammation. Image analyses of infected equine respiratory explants showed that despite replicating at higher levels and spreading over larger areas of the respiratory epithelium, EIV/2003 induced milder lesions compared to EIV/63, suggesting that adaptation led to reduced tissue pathogenicity. Our results reveal previously unknown links between virus genotype and the host response to infection, providing new insights on the relationship between virus evolution and fitness.
Author summary As viruses are obligate intracellular pathogens, their ability to replicate and spread within their hosts is key for survival, even if it leads to severe disease or death of the host. Understanding the consequences of long-term virus adaptation after viral emergence is key for pandemic preparedness. H3N8 equine influenza virus (EIV) originated in birds and has circulated in horses since 1963, thus providing unique opportunities to study virus adaptation. We compared the replication kinetics of two EIVs of the same lineage but with different evolutionary histories: the earliest virus (EIV/63, isolated in 1963), and EIV/2003, which was isolated after 40 years of continuous circulation in horses. Experimental infections of cell lines (MDCK and E.Derm cells) and equine respiratory explants show that EIV evolved towards enhanced replication and cell-to-cell spread; but reduced tissue damage, confirming that viral fitness is adaptive and does not necessarily result in higher virulence.
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