Research areas: Biochemistry, Signal Transduction, Virology
Influenza A viruses are characterized by a high degree of genomic plasticity which enables them to quickly adapt to new environmental conditions and to cross species barriers, causing epidemics and occasional pandemics. In the first funding period, CRISPR-Cas9-mediated gene editing was employed to generate mouse lung epithelial cells deficient in specific key proteins of the NF-B pathway. The functional analysis of these cells revealed that NF-κB was not relevant for replication of a mouse-adapted SC35M, while the absence of NF-κB activity increased replication of the non-adapted SC35 virus. The analysis of reassortant viruses showed that the anti-viral effect of NF-B is determined by the IAV genotype. In addition, the group has identified thousands of IAV-regulated phosphorylation sites of host cell and viral proteins were identified in a phospho-proteomic screen, which led to the discovery of new IAV-regulated kinase pathways, phosphorylation motifs, and cellular processes. This first comprehensive phospho-proteomic screen now allows to study the contribution of key phosphorylation sites and newly discovered pathways for IAV replication.
Project-related publications of the investigators:
- Schloer S, Goretzko J, Pleschka S, Ludwig S, Rescher U. 2020. Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection. Viruses 12:703.
- Mostafa A, Mahmoud SH, Shehata M, Muller C, Kandeil A, El-Shesheny R, Nooh HZ, Kayali G, Ali MA, Pleschka S. 2020. PA from a Recent H9N2 (G1-Like) Avian Influenza a Virus (AIV) Strain Carrying Lysine 367 Confers Altered Replication Efficiency and Pathogenicity to Contemporaneous H5N1 in Mammalian Systems. Viruses 12: E1046.
- Harbig A, Mernberger M, Bittel L, Pleschka S, Schughart K, Steinmetzer T, Stiewe T, Nist A, Bottcher-Friebertshauser E. 2020. Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways. J Biol Chem 295:11388-11407.
- Weber A, Dam S, Saul VV, Kuznetsova I, Muller C, Fritz-Wolf K, Becker K, Linne U, Gu H, Stokes MP, Pleschka S, Kracht M, Schmitz ML. 2019. Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks. J Virol 93: e00528-19.
- Seibert M, Kruger M, Watson NA, Sen O, Daum JR, Slotman JA, Braun T, Houtsmuller AB, Gorbsky GJ, Jacob R, Kracht M, Higgins JMG, Schmitz ML. 2019. CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation. J Cell Biol 218:1164-1181.
- Saul VV, Seibert M, Kruger M, Jeratsch S, Kracht M, Schmitz ML. 2019. ULK1/2 Restricts the Formation of Inducible SINT-Speckles, Membraneless Organelles Controlling the Threshold of TBK1 Activation. iScience 19:527-544.
- Schmitz ML, Shaban MS, Albert BV, Gokcen A, Kracht M. 2018. The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-kappaB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection. Biomedicines 6:59.
- Poppe M, Wittig S, Jurida L, Bartkuhn M, Wilhelm J, Muller H, Beuerlein K, Karl N, Bhuju S, Ziebuhr J, Schmitz ML, Kracht M. 2017. The NF-kappaB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. PLoS Pathog 13:e1006286.
- Haasbach E, Muller C, Ehrhardt C, Schreiber A, Pleschka S, Ludwig S, Planz O. 2017. The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Res 142:178-184.
- Dam S, Kracht M, Pleschka S, Schmitz ML. 2016. The Influenza A Virus Genotype Determines the Antiviral Function of NF-kappaB. J Virol 90:7980-90.