Comparison of cytokine profiles induced by nonlethal and lethal doses of influenza A virus in mice

Abstract

Influenza viruses are among the most common human pathogens and are responsible for causing extensive seasonal morbidity and mortality. To investigate the immu- nological 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-infec- tion; 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 chemo- kine 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, Correspondence to: Dr Tatiana Betáková, Biomedical Research Center-Slovak Academy of Sciences, Institute of Virology, Dubravska Cesta 9, 84505 Bratislava, Slovak Republic E-mail: virubeta@savba.sk Key words: influenza virus, cytokine, interleukin, chemokine, immune response, lungs, mice and demonstrated that lethal influenza virus infection induces a mixed Th1/Th2 response.