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)

• Antragsteller: Dr. Eike-Roman Hrincius
• Fachliche Zuordnung: Virologie
• Förderung: Förderung von 2013 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 237780743

As estimated by the World Health Organization, infections of the respiratory tract are responsible for more than 6 percent of all deaths worldwide. Importantly, among all pathogens having the capability to infect the respiratory tract, influenza A viruses (IAV) are among the most common and devastating. In addition to millions of hospitalizations and thousands of deaths, these pathogens lead to enormous economic losses during the seasonal influenza each year. Even more worrisome, IAV have the potential to cause pandemic outbreaks with several million victims, such as the Spanish flu outbreak in 1918 and IAV are discussed as potential causative agent for upcoming life-threatening pandemics. The zoonotic potential of IAV is fundamental for the occurrence of pandemic outbreaks in humans and the ongoing, sporadic transmission of highly pathogenic avian IAV (HPAI) of the subtype H5N1 to humans since 1997. The high case fatality rate of 60%, emphasizes the need to understand the biology of HPAI infection of humans. To understand this high case fatality rate, multiple approaches focusing on different viral proteins have been conducted. Beside the contribution of the hemagglutinin protein of HPAI to their virulence and finally transmission, the polymerase proteins have been studied for their role in increasing replication efficiency of H5N1 IAV. Less effort has been put into study of the non-structural proteins NS1 and PB1-F2 to this point. Both proteins carry immune modulatory and interferon antagonistic properties and are described as virulence determinants. In general, amino-acid motifs, which are differentially present in seasonal human and HPAI came into focus of interest for understanding the severeness of HPAI infections. Regarding the NS1 protein, a SH3 binding motif (aa212-217) is present in almost all avian IAV isolates with a special position of H5N1 isolates in contrast to seasonal human IAV lacking this motif. In the context of PB1-F2, four amino acids (pro-inflammatory motif; L62, R75, R79 and L82) have been identified as contributor to cytokine release and inflammatory responses and are highly present in avian IAV, including a high prevalence in human H5N1 isolates.In this study, the impact of the depicted motifs in NS1 and PB1-F2 on virulence of HPAI, modulation of immune responses and finally immune pathology and acute lung injury in different hosts (avian and mammalian) will be broadly investigated. Understanding the basal mechanisms of HPAI virulence in humans and the impact of these motifs potentially strengthen the ability of more guided surveillance and set up of additional treatment options for HPAI infections.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Dr. Jonathan A. McCullers