Influenza A virus is one of the major human pathogens. The influenza infection can pass out without any subclinical symptoms or infestation can appear in upper respiratory tract as well as in lower respiratory tract where it can result in lethal outcome. Both innate and adaptive immune responses are activated shortly after infection providing protection against infection. Many activities of the cells of innate and adaptive immunity are coordinated by cytokines. However, inordinate or disbalanced immune response may result in overproduction of cytokines as well as chemokines which can lead to severe inflammation, including excessive recruitment of neutrophils and mononuclear cells at the site of infection. These may damage lung tissue, reduce respiratory capacity, and cause severe disease and mortality. Recently, the role of cytokines induced by virus infection has been reevaluated. While moderate inflammatory response protects against development of severe illness, the hyper-inflammatory response can elevate the disease progression. In this mini-review, we summarized the data on cytokines and chemokines induced in the sera of hospitalized patients infected with human and avian influenza viruses and define their possible role in pathogenesis. Interleukin IL-6 and chemokines CCL-2/MCP-1, CCL-4/MIP-1β, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are associated with pathogenicity of both avian (H5N1 and H7N9) and human (pdmH1N1 and H3N2) viruses. Chemokines CCL-2/MCP-1, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are also related with mortality. These cytokines may be used as targets for new, more complex therapy in the extenuation of unfavorable effects of hyper inflammatory response.

Human dermal fibroblasts and mouse NIH/3T3 cells acquired the transformed phenotype (‘criss-cross' pattern of growth) after infection with ultraviolet-irradiated murine gammaherpesvirus (MuHV-4 strain 68; MHV-68). These cells with changed phenotype could be serially cultured for 5-6 passages (35-40 days), and then they entered into crisis and most of them died. In a small number of cultures, however, foci of newly transformed cells appeared from which two stable cell lines were derived. After 6-9 cell culture passages of the MHV-68 transformed cell lines, MHV-68 DNA and virus antigen could be detected by PCR and immunofluorescence assay along with the disappearance of actin bundles, indicating that both transformed cell lines might be oncogenic.

Influenza viruses are among the most common human pathogens and are responsible for causing extensive seasonal morbidity and mortality. To investigate the immunological factors associated with severe influenza infection, the immune responses in mice infected with nonlethal (LD0) doses of A/PR/8/34 (H1N1) influenza virus were compared with those of mice infected with a lethal dose (LD100) of the virus. The virus titer and activation of retinoic acid-inducible gene (RIG)-I-like receptor signaling pathways were similar in the mice infected with LD0 and LD100 at 2 days post-infection; however, mice infected with LD100 exhibited a greater abundance of cytokines and a more diverse cytokine profile. Infection with LD100 induced the expression of the following factors: Interleukins (ILs), IL-4, IL-7, IL-10, IL-11, IL-12p40, IL-13 and IL-15; inflammatory chemokines, C-C motif chemokine ligand (CCL)2, CCL3/4, CCL12, CCL17, CCL19; and lung injury-associated cytokines, leptin, leukaemia inhibitory factor, macrophage colony stimulating factor, pentraxin (PTX)2 and PTX3, WNT1-inducible-signaling pathway protein 1, matrix metallopeptidase (MMP)-2, MMP-3, proprotein convertase subtilisin/kexin type 9, and T cell immunoglobulin and mucin domain. Switching in macrophage polarization from M1 to M2 was evidenced by the increase in M2 markers, including arginase-1 (Arg1) and early growth response protein 2 (Egr2), in the lungs of mice infected with LD100. Since IL-12 and interferon-γ are the major T helper (Th)1 cytokines, increased expression of interferon regulatory factor 4, IL-4, IL-10 and IL-13 promoted the differentiation of naïve CD4+ T cells into Th2 cells. In conclusion, the present study identified key cytokines involved in the pathogenicity of influenza infection, and demonstrated that lethal influenza virus infection induces a mixed Th1/Th2 response.