Abstract
β-(1→3)-D-glucans with β-(1→6)-glycosidic linked branches produced by mushrooms, yeast and fungi are known to be an immune activation agent, and are used in anti-cancer drugs or health-promoting foods. In this report, we demonstrate that oral administration of Aureobasidium pullulans-cultured fluid (AP-CF) enriched with the β-(1→3),(1→6)-D-glucan exhibits efficacy to protect mice infected with a lethal titer of the A/Puerto Rico/8/34 (PR8; H1N1) strain of influenza virus. The survival rate of the mice significantly increased by AP-CF administration after sublethal infection of PR8 virus. The virus titer in the mouse lung homogenates was significantly decreased by AP-CF administration. No significant difference in the mRNA expression of inflammatory cytokines, and in the population of lymphocytes was observed in the lungs of mice administered with AP-CF. Interestingly, expression level for the mRNA of virus sensors, RIG-I (retinoic acid-inducible gene-I) and MDA5 (melanoma differentiation-associated protein 5) strongly increased at 5 hours after the stimulation of A. pullulans-produced purified β-(1→3),(1→6)-D-glucan (AP-BG) in murine macrophage-derived RAW264.7 cells. Furthermore, the replication of PR8 virus was significantly repressed by pre-treatment of AP-BG. These findings suggest the increased expression of virus sensors is effective for the prevention of influenza by the inhibition of viral replication with the administration of AP-CF.
Highlights
We focus on the immune stimulatory function of the A. pullulans-produced b-(1R3),(1R6)-D-glucan, and demonstrate that oral administration of A. pullulans-cultured fluid (AP-CF) enriched with the b-(1R3),(1R6)-D-glucan exhibits efficacy to increase the survival rate of mice infected with the A/Puerto Rico/ 8/34 (PR8; H1N1) strain of influenza virus
The results show that expression of RIG-I and MDA5 mRNAs increased with AP-BG stimulation, whereas IPS-1 mRNA was not (Figure 5A–C)
And 5E, mRNA expression of RIG-I and MDA5 increased after the stimulation of AP-BG in the phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. These results suggest that the AP-BG stimulation upregulates the expression of RIG-I and MDA5 in macrophages
Summary
Oral administration of A. pullulans-cultured fluid (AP-CF) increases the survival rate of mice after a lethal influenza A virus infection. The results show that in addition to the effect on the induction of pro-inflammatory cytokines, the population of lymphocytes in the lungs of AP-CF administered mice was not significantly changed in comparison with that of the control mice (Figure 3A–D). The population of dendritic cells in the lungs tended to slightly increase with administration of AP-CF on day 5 after influenza A virus infection (Figure 3A). The results demonstrate that the virus titers of influenza A virus in the cultured medium significantly decreased with the pre-treatment of AP-BG (Figure 5F) These observations suggest that increment of RIG-I expression with AP-BG stimulation may inhibit the influenza A virus replication through enhancement of the sensitivity to activate downstream signaling pathways of RIG-I
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