Orally administered live attenuated <i>Salmonella</i> Typhimurium protects mice against lethal infection with H1N1 influenza virus

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Pre-stimulation of toll-like receptors (TLRs) by agonists has been shown to increase protection against influenza virus infection. In this study, we evaluated the protective response generated against influenza A/Puerto Rico/8/1934 (PR8; H1N1) virus by oral and nasal administration of live attenuated <I>Salmonella enterica</I> serovar Typhimurium, JOL911 strain, in mice. Oral and nasal inoculation of JOL911 significantly increased the mRNA copy number of TLR-2, TLR4 and TLR5, and downstream type I interferon (IFN) molecules, IFN-α and IFN-β, both in peripheral blood mononuclear cells (PBMCs) and in lung tissue. Similarly, the mRNA copy number of interferon-inducible genes (ISGs), Mx and ISG15, were significantly increased in both the orally and the nasally inoculated mice. Post PR8 virus lethal challenge, the nasal JOL911 and the PBS control group mice showed significant loss of body weight with 70% and 100% mortality, respectively, compared to only 30% mortality in the oral JOL911 group mice. Post sub-lethal challenge, the significant reduction in PR8 virus copy number in lung tissue was observed in oral [on day 4 and 6 post-challenge (dpc)] and nasal (on 4dpc) than the PBS control group mice. The lethal and sub-lethal challenge showed that the generated stimulated innate resistance (StIR) in JOL911 inoculated mice conferred resistance to acute and initial influenza infection but might not be sufficient to prevent the PR8 virus invasion and replication in the lung. Overall, the present study indicates that oral administration of attenuated <I>S.</I> Typhimurium can pre-stimulate multiple TLR pathways in mice to provide immediate early StIR against a lethal H1N1 virus challenge.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pre-stimulation of TLR pathways provides stimulated innate resistance (StIR) against influenza virus. </LI> <LI> <I>S.</I> Typhimurium activates multiple TLR pathways, downstream interferons and effector interferon stimulated genes in PBMCs and in lung tissues. </LI> <LI> Oral administration of attenuated <I>S.</I> Typhimurium elicit StIR against PR8 influenza virus. </LI> <LI> The StIR generated in response to <I>S.</I> Typhimurium can protect mice against lethal challenge of PR8 influenza virus. </LI> </UL> </P>