Browsing by Subject "influenza A virus"

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  • Luukkainen, Annika; Puan, Kia Joo; Yusof, Nurhashikin; Lee, Bernett; Tan, Kai Sen; Liu, Jing; Yan, Yan; Toppila-Salmi, Sanna; Renkonen, Risto; Chow, Vincent T.; Rotzschke, Olaf; Wang, De Yun (2018)
    Background: We established an in vitro co-culture model involving H3N2-infection of human nasal epithelium with peripheral blood mononuclear cells (PBMC) to investigate their cross-talk during early H3N2 infection. Methods: Nasal epithelium was differentiated from human nasal epithelial stem/progenitor cells and cultured wtih fresh human PBMC. PBMC and supernatants were harvested after 24 and 48 h of co-culture with H3N2-infected nasal epithelium. We used flow cytometry and Luminex to characterize PBMC subpopulations, their activation and secretion of cytokine and chemokines. Results: H3N2 infection of the nasal epithelium associated with significant increase in interferons (IFN-alpha, IFN-gamma, IL-29), pro-inflammatory cytokines (TNF-alpha, BDNF, IL-3) and viral-associated chemokines (IP-10, MCP-3, I-TAC, MIG), detectable already after 24 h. This translates into rapid activation of monocytes, NK-cells and innate T-cells (MAIT and gamma delta T cells), evident with CD38+ and/or CD69+ upregulation. Conclusions: This system may contribute to in vitro mechanistic immunological studies bridging systemic models and possibly enable the development of targeted immunomodulatory therapies.
  • Scharenberg, Marlena; Vangeti, Sindhu; Kekäläinen, Eliisa; Bergman, Per; Al-Ameri, Mamdoh; Johansson, Niclas; Sonden, Klara; Falck-Jones, Sara; Färnert, Anna; Ljunggren, Hans-Gustaf; Michaelsson, Jakob; Smed-Sörensen, Anna; Marquardt, Nicole (2019)
    NK cells in the human lung respond to influenza A virus-(IAV-) infected target cells. However, the detailed functional capacity of human lung and peripheral blood NK cells remains to be determined in IAV and other respiratory viral infections. Here, we investigated the effects of IAV infection on human lung and peripheral blood NK cells in vitro and ex vivo following clinical infection. IAV infection of lung- and peripheral blood-derived mononuclear cells in vitro induced NK cell hyperresponsiveness to K562 target cells, including increased degranulation and cytokine production particularly in the CD56(bright)CD16(-) subset of NK cells. Furthermore, lung CD16(-) NK cells showed increased IAV-mediated but target cell-independent activation compared to CD16(+) lung NK cells or total NK cells in peripheral blood. IAV infection rendered peripheral blood NK cells responsive toward the normally NK cell-resistant lung epithelial cell line A549, indicating that NK cell activation during IAV infection could contribute to killing of surrounding non-infected epithelial cells. In vivo, peripheral blood CD56(dim)CD16(+) and CD56(bright)CD16(-) NK cells were primed during acute IAV infection, and a small subset of CD16(-) CD49a(+)CXCR3(+) NK cells could be identified, with CD49a and CXCR3 potentially promoting homing to and tissue-retention in the lung during acute infection. Together, we show that IAV respiratory viral infections prime otherwise hyporesponsive lung NK cells, indicating that both CD16(+) and CD16(-) NK cells including CD16(-)CD49a(+) tissue-resident NK cells could contribute to host immunity but possibly also tissue damage in clinical IAV infection.
  • Ylosmaki, Leena; Fagerlund, Riku; Kuisma, Inka; Julkunen, Ilkka; Saksela, Kalle (2016)
    The non-structural protein-1 (NS1) of many influenza A strains, especially those of avian origin, contains an SH3 ligand motif, which binds tightly to the cellular adaptor proteins Crk (Chicken tumor virus number 10 (CT10) regulator of kinase) and Crk-like adapter protein (CrkL). This interaction has been shown to potentiate NS1-induced activation of the phosphatidylinositol 3-kinase (PI3K), but additional effects on the host cell physiology may exist. Here we show that NS1 can induce an efficient translocation of Crk proteins from the cytoplasm into the nucleus, which results in an altered pattern of nuclear protein tyrosine phosphorylation. This was not observed using NS1 proteins deficient in SH3 binding or engineered to be exclusively cytoplasmic, indicating a physical role for NS1 as a carrier in the nuclear translocation of Crk. These data further emphasize the role of Crk proteins as host cell interaction partners of NS1, and highlight the potential for host cell manipulation gained by a viral protein simply via acquiring a short SH3 binding motif.
  • Ianevski, Aleksandr; Yao, Rouan; Zusinaite, Eva; Lello, Laura Sandra; Wang, Sainan; Jo, Eunji; Yang, Jaewon; Ravlo, Erlend; Wang, Wei; Lysvand, Hilde; Loseth, Kirsti; Oksenych, Valentyn; Tenson, Tanel; Windisch, Marc P.; Poranen, Minna M.; Nieminen, Anni I.; Nordbo, Svein Arne; Fenstad, Mona Hoysaeter; Grodeland, Gunnveig; Aukrust, Pal; Troseid, Marius; Kantele, Anu; Lastauskiene, Egle; Vitkauskiene, Astra; Legrand, Nicolas; Merits, Andres; Bjoras, Magnar; Kainov, Denis E. (2021)
    Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFN alpha, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFN alpha-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFN alpha combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFN alpha can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.