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Influenza A whole virion vaccine induces a rapid reduction of peripheral blood leukocytes via interferon-α-dependent apoptosis
Manabu Atoa, Corresponding author contact information, E-mail the corresponding author,
Yoshimasa Takahashia, E-mail the corresponding author,
Hideki Fujiia, 1, E-mail the corresponding author,
Shu-ichi Hashimotoa, 2, E-mail the corresponding author,
Tomohiro Kajia, b, E-mail the corresponding author,
Shigeyuki Itamurac, E-mail the corresponding author,
Yoshinobu Horiuchid, e, E-mail the corresponding author,
Yoshichika Arakawad, 3, E-mail the corresponding author,
Masato Tashiroc, E-mail the corresponding author,
Toshitada Takemoria, b, E-mail the corresponding author
a Department of Immunology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
b Laboratory for Immunological Memory, Riken Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
c Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
d Department of Bacteriology II, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
e Division of Quality Assurance, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
http://dx.doi.org/10.1016/j.vaccine.2013.02.016
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 s 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.
Highlights
► Whole virion but not HA split influenza vaccines induce a decrease of PBL in an IFNα-dependent manner. ► TLR-7 and MyD-88 signaling is responsible for the loss of PBL. ► The loss of PBL is independent of redistribution, but is caused by apoptosis. ► The role of IFNα/βR signaling in IgG induction is possibly limited to within a short time after vaccination.
http://www.sciencedirect.com/science/article/pii/S0264410X13001795
Manabu Atoa, Corresponding author contact information, E-mail the corresponding author,
Yoshimasa Takahashia, E-mail the corresponding author,
Hideki Fujiia, 1, E-mail the corresponding author,
Shu-ichi Hashimotoa, 2, E-mail the corresponding author,
Tomohiro Kajia, b, E-mail the corresponding author,
Shigeyuki Itamurac, E-mail the corresponding author,
Yoshinobu Horiuchid, e, E-mail the corresponding author,
Yoshichika Arakawad, 3, E-mail the corresponding author,
Masato Tashiroc, E-mail the corresponding author,
Toshitada Takemoria, b, E-mail the corresponding author
a Department of Immunology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
b Laboratory for Immunological Memory, Riken Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
c Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
d Department of Bacteriology II, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
e Division of Quality Assurance, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan
http://dx.doi.org/10.1016/j.vaccine.2013.02.016
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 s 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.
Highlights
► Whole virion but not HA split influenza vaccines induce a decrease of PBL in an IFNα-dependent manner. ► TLR-7 and MyD-88 signaling is responsible for the loss of PBL. ► The loss of PBL is independent of redistribution, but is caused by apoptosis. ► The role of IFNα/βR signaling in IgG induction is possibly limited to within a short time after vaccination.
http://www.sciencedirect.com/science/article/pii/S0264410X13001795