Highly conserved motifs in NS1 and PB1-F2 proteins of highly pathogenic avian influenza viruses and their functionalities in virulence, immune responses and pathological alterations like acute lung injury (ALI)
Final Report Abstract
Viral zoonoses are a major problem of our modern society. An important example of such a zoonosis are Influenza A viruses (IAV). IAV primarily circulate in their avian host, nevertheless permanent IAV lineages have been found in multiple different species including humans (seasonal flu). Although these seasonal IAV have certain potential for devastating infections, much more worrisome are newly introduced, zoonotic IAV with severe pathogenic and pandemic potential. In the past, all pandemic IAV carried multiple gene segments of avian IAV. Therefore, molecular signatures potentially mediating the importance of avian IAV gene segments in establishing severe pandemic outbreaks came into focus. In this research project, molecular signatures that are differentially present in seasonal human and avian IAV were studied regarding their pathogenicity mediating potential. A so-called second SH3 binding motif (bm) at aa212-217 (SH3(II)bm) is highly conserved in the nonstructural protein 1 (NS1) of avian but not human IAV. Interestingly, H5N1 and the recent H7N9 2013 strain do not express the motif. In this project, the question was asked if the absence of the functional SH3(II)bm in the H7N9 2013 strain is a potential benefit for this virus to establish robust and severe infections in humans after crossing the species barrier from the avian reservoir. Investigating a human H7N9 isolate revealed a potential benefit to not express the motif for establishing robust infections in the human host, since mutational introduction of the SH3(II)bm into NS1 of this strain gave hints for potentially attenuated pathogenicity in a mammalian host (mouse model). Broadening the investigations, asking for the involvement of the SH3(II)bm to the pathogenicity of human IAV revealed that introduction of the SH3(II)bm into a human IAV resulted in massively increased pathogenicity and priming for bacterial co-infections. Mechanistically, the introduction of the SH3(II)bm resulted in direct interference with lung homeostasis, finally leading to lung injury and fatal outcomes of infections. This data revealed a new, non-canonical mechanism of NS1 protein mediated pathogenicity and therefore increases the understanding of pathogenicity mediating mechanisms in IAV infections in general. In addition, these data on the SH3(II)bm in NS1 revealed the importance for investigating the contribution to pathogenicity for different IAV since strain specific results are possible. Focusing on a pro-inflammatory motif (L62, R75, R79 and L82) within the PB1-F2 protein of a highly pathogenic H5N1 and the potential contribution to pathogenicity revealed that there is also potential for this molecular signature to mediated pathogenicity in a system using viruses expressing a H5N1 PB1 segment with the backbone of a human IAV. This motif was linked to the pathogenicity of the 1968 H3N2 pandemic IAV and the here obtained data give hints for a contribution of this motif to the pathogenicity mediating potential of H5N1 PB1-F2 proteins. Deeper, mechanistic investigations are needed for understanding the specific contribution of this motif to H5N1 pathogenicity. Concluding, the here depicted data revealed that molecular signatures being differently expressed in avian and human IAV can contribute to pathogenicity and should be seen as important guides for more direct surveillance approaches and pandemic planning in the future. Strongly emphasizing this view, working on a molecular signature in the hemagglutinin protein (differences in glycosylation of the globular head between avian and human IAV) revealed that the avian molecular signature has strong pathogenicity boosting potential after introduction into a mammalian host. Taken together, the project revealed the contribution of crucial molecular patterns in different IAV proteins to pathogenicity and resulted in important insights regarding the mechanisms of this pathogenicity regulating motifs.
Publications
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Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway. Cell Rep. 2015 Jun 16;11(10):1591-603
Hrincius ER, Liedmann S, Finkelstein D, Vogel P, Gansebom S, Samarasinghe AE, You D, Cormier SA, McCullers JA
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Nonstructural protein 1 (NS1)-mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections: insights into 1918 H1N1 pandemic? J Infect Dis. 2015 May 1;211(9):1418-28
Hrincius ER, Liedmann S, Finkelstein D, Vogel P, Gansebom S, Ehrhardt C, Ludwig S, Hains DS, Webby R, McCullers JA
