Role of Itk signalling in the interaction between influenza A virus and T-cells

Abstract

Although the T-cell-mediated immune response to influenza virus has been studied extensively, little information is available on the direct interaction between influenza virus and T-cells that pertains to severe diseases in humans and animals. To address these issues, we utilized the BALB/c mouse model combined with primary T-cells infected with A/WSN/33 influenza virus to investigate whether influenza virus has an affinity for T-cells in vivo. We observed that small proportions of CD4+ T-cells and CD8+ T-cells in spleen and thymus expressed viral proteins in infected mice. A significant proportion of mouse primary T-cells displayed expression of α-2,6 sialic acid-linked influenza virus receptor and were infected directly by influenza A virus. These experiments reveal that there exists a population of T-cells that is susceptible to influenza A virus infection. Furthermore, we employed human Jurkat T-cells to investigate the virus–T-cell interaction, with particular emphasis on understanding whether Itk (interleukin-2-inducible T-cell kinase), a Tec family tyrosine kinase that regulates T-cell activation, is involved in virus infection of T-cells. Interestingly, influenza virus infection resulted in an increased recruitment of Itk to the plasma membrane and an increased level of phospholipase C-γ1 (PLC-γ1) phosphorylation, suggesting that Itk/PLC-γ1 signalling is activated by the virus infection. We demonstrated that depletion of Itk inhibited the replication of influenza A virus, whereas overexpression of Itk increased virus replication. These results indicate that Itk is required for efficient replication of influenza virus in infected T-cells.

PLC-γ1 Signaling Plays a Subtype-Specific Role in Postbinding Cell Entry of Influenza A Virus

“…1 to 2). A recent report shows that PLC-␥1 activation is important for WSN infection in T cells, although it did not characterize the mechanism of action (30). Therefore, PLC-␥1 seems to be important for H1N1 infection in various cell types.…”

“…5). In the study by Fan et al, the authors have shown that WSN infection of T cells induces the PLC-␥1 activation through interleukin-2-inducible T-cell kinase (Itk), a T-cell-specific nonreceptor tyrosine kinase, to the plasma membrane (30). Taking these findings together, the mechanism by which influenza virus induces PLC-␥1 activation (and possibly other signaling molecules) may vary by viral subtypes and host cell types but is likely mediated via an upstream receptor or nonreceptor tyrosine kinase that is triggered by virus binding to the cell surface.…”

Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

“…This raises the possibility that ibrutinib may provide benefit in other inflammatory disorders, ranging from allergic asthma and atopic dermatitis to inflammatory bowel disease. 11 Moreover, it was recently demonstrated that ITK activation plays a vital role in the replication of influenza A virus in T cells 46 and is critical for HIV replication and infection cycles, making ITK a valuable target in the development of antiviral therapeutics. 10 Given the global threat of HIV and pandemic influenza, ibrutinib's potential utility as an irreversible ITK inhibitor should be explored further.…”

Propagation of Influenza Virus in Lymphocytes Determine by Antiviral Effects of Honey, Ginger and Garlic Decoction

“…Regardless of the underlying immune mechanisms that protect against various strains of influenza virus, only limited information is available on the direct interaction between influenza virus strains and host T cells [12,13]. Studies with highly virulent influenza A virus strains resulted in the destruction of lymphocytes (e.g.…”

“…Studies with highly virulent influenza A virus strains resulted in the destruction of lymphocytes (e.g. RP9 avian lymphocytes cell line) and histopathological necrosis of lymphoid tissues [12,14,15]. However, whether influenza virus is able to propagate in human lymphocytes remains to be fully elucidated.…”