title: Influenza A whole virion vaccine induces a rapid reduction of peripheral blood leukocytes via interferon-α-dependent apoptosis.
abstract: Infection with single strand RNA (ssRNA) viruses, such as influenza A virus, is known to induce protective acquired immune responses, including the production of neutralizing antibodies. Vaccination also causes a reduction in the number of peripheral blood leukocytes (PBL) shortly after inoculation, a result which may have undesirable adverse effects. The cellular mechanisms for this response have not been elucidated so far. Here we report that formalin-inactivated influenza A whole virus vaccine (whole virion) induces a significant decrease in PBL in mice 5-16 h after administration, whereas an ether-split vaccine (HA split) made from the same influenza virus strain does not induce a similar loss of PBL. Concordant with this reduction in the number of PBL, a rapidly induced and massive production of interferon (IFN)-α is observed when mice are injected with whole virion, but not with HA split vaccines. The role of Toll-like receptors (TLR), which are involved in signal transduction of influenza virus, and the subsequent induction of IFNα were confirmed using mice lacking TLR7, MyD-88, or IFNα/β receptor. We further demonstrated that the observed PBL loss is caused by apoptosis in an IFNα-dependent manner, and not by leukocyte redistribution due to chemokine signaling failure. These findings indicate that RNA-encapsulated whole virion vaccines can rapidly induce a loss of leukocytes from peripheral blood by apoptosis, which may modulate the subsequent immune response.
authors: Department of Immunology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. ato@nih.go.jp
authors: Manabu
authors: M
authors: Ato
authors: Yoshimasa
authors: Y
authors: Takahashi
authors: Hideki
authors: H
authors: Fujii
authors: Shu-ichi
authors: S
authors: Hashimoto
authors: Tomohiro
authors: T
authors: Kaji
authors: Shigeyuki
authors: S
authors: Itamura
authors: Yoshinobu
authors: Y
authors: Horiuchi
authors: Yoshichika
authors: Y
authors: Arakawa
authors: Masato
authors: M
authors: Tashiro
authors: Toshitada
authors: T
authors: Takemori
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014771:Virion / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D015164:Vaccines, Inactivated; D053633:Receptor, Interferon alpha-beta