5 research outputs found
FimH Adhesin of Type 1 Fimbriae Is a Potent Inducer of Innate Antimicrobial Responses Which Requires TLR4 and Type 1 Interferon Signalling
Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-Ξ² production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88β/β, Trifβ/β, IFNβΞ±/Ξ²Rβ/β or IRF3β/β mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88β/β, IFN-Ξ±/Ξ²Rβ/β, IRF3β/β or TLR4β/β mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-Ξ², but not IFN-Ξ± or IFN-Ξ³. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC) and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6) mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4β/β mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens
Bioluminescent Imaging Reveals Divergent Viral Pathogenesis in Two Strains of Stat1-Deficient Mice, and in Ξ±ΓΞ³ Interferon Receptor-Deficient Mice
Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1β/β and IFNΞ±ΓΞ³Rβ/β mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1β/β mice and in IFNΞ±ΓΞ³Rβ/β mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1β/β (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNΞ±ΓΞ³Rβ/β mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1β/β and IFNΞ±ΓΞ³Rβ/β mice, we infected an additional Stat1β/β strain deleted in the DNA-binding domain (129Stat1β/β (DBD)). These 129Stat1β/β (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNΞ±ΓΞ³Rβ/β mice. This lethal pattern was also observed when 129Stat1β/β (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1β/β (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1β/β mouse strains. The data are consistent with the hypothesis that Stat1β/β (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection