Differential pathogenesis of Usutu virus isolates in mice

Abstract

Usutu virus (USUV; Flavivirus), a close phylogenetic and ecological relative of West Nile virus, is a zoonotic virus that can cause neuroinvasive disease in humans. USUV is maintained in an enzootic cycle between Culex mosquitoes and birds. Since the first isolation in 1959 in South Africa, USUV has spread throughout Africa and Europe. Reported human cases have increased over the last few decades, primarily in Europe, with symptoms ranging from mild febrile illness to severe neurological effects. In this study, we investigated whether USUV has become more pathogenic during emergence in Europe. Interferon α/β receptor knockout (Ifnar1-/-) mice were inoculated with recent USUV isolates from Africa and Europe, as well as the historic 1959 South African strain. The three tested African strains and one European strain from Spain caused 100% mortality in inoculated mice, with similar survival times and histopathology in tissues. Unexpectedly, a European strain from the Netherlands caused only 12% mortality and significantly less histopathology in tissues from mice compared to mice inoculated with the other strains. Viremia was highest in mice inoculated with the recent African strains and lowest in mice inoculated with the Netherlands strain. Based on phylogenetics, the USUV isolates from Spain and the Netherlands were derived from separate introductions into Europe, suggesting that disease outcomes may differ for USUV strains circulating in Europe. These results also suggest that while more human USUV disease cases have been reported in Europe recently, circulating African USUV strains are still a potential major health concern.

Analysis of avian Usutu virus infections in Germany from 2011 to 2018 with focus on dsRNA detection to demonstrate viral infections

“…In particular, neurovirulence was found to be increased in the Europe 2 lineage compared to the other lineages in one study 39 . Since these experiments were performed in the mouse model 28 , 39 , 58 on the one hand and under in-vitro conditions 39 on the other hand, the results should be interpreted cautiously in the context of the present study.…”

“…Recent studies have shown that there are significant differences in the virulence of different lineages in both mouse models and in vitro cell culture experiments 28 , 39 , 58 . In particular, neurovirulence was found to be increased in the Europe 2 lineage compared to the other lineages in one study 39 .…”

Pathology and Pathogenesis of Eurasian Blackbirds (Turdus merula) Naturally Infected with Usutu Virus

“…Regarding USUV tissue and cell tropism, the same reports highlight the presence of the viral antigen in the major affected organs (liver, spleen, heart, brain) [ 5 , 21 , 22 , 23 ]. Despite the identification of different circulating virus lineages [ 17 ], studies investigating their pathogenetic potential in naturally-infected birds are lacking and it has only been partially studied in vitro and in experimental in vivo studies in mice [ 24 , 25 , 26 , 27 , 28 ]. Consequently, due to the small number of animals examined in previous studies, knowledge on the pathology and the complete cell and tissue tropism of the virus, as well as the pathogenetic potential of different circulating viral lineages, are still fragmentary.…”

Pathogenesis and shedding of Usutu virus in juvenile chickens

“…[ 44 ], and SAAR1776 (South Africa 1959, Africa 2 lineage, MN813492, passage 9, isolated from Culex neavei ) [ 3 ]. These strains have been previously sequenced by our lab [ 28 ].…”