Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.
Highlights d Some mouse colonies developed spontaneous resistance to rotavirus (RV) infection d Fecal microbial transplantation transfers RV resistance d Protection against RV was mediated by segmented filamentous bacteria (SFB) d SFB impeded RV by increasing epithelial cell turnover
BACKGROUND AND PURPOSERosiglitazone is an anti-diabetic drug acting as an insulin sensitizer. We recently found that rosiglitazone also inhibits the vascular isoform of ATP-sensitive K + channels and compromises vasodilatory effects of b-adrenoceptor activation and pinacidil. As its potency for the channel inhibition is in the micromolar range, rosiglitazone may be used as an effective KATP channel inhibitor for research and therapeutic purposes. Therefore, we performed experiments to determine whether other isoforms of KATP channels are also sensitive to rosiglitazone and what their sensitivities are. EXPERIMENTAL APPROACHKIR6.1/SUR2B, KIR6.2/SUR1, KIR6.2/SUR2A, KIR6.2/SUR2B and KIR6.2DC36 channels were expressed in HEK293 cells and were studied using patch-clamp techniques. KEY RESULTSRosiglitazone inhibited all isoforms of KATP channels in excised patches and in the whole-cell configuration. Its IC50 was 10 mmol·L -1 for the KIR6.1/SUR2B channel and~45 mmol·L -1 for KIR6.2/SURx channels. Rosiglitazone also inhibited KIR6.2DC36 channels in the absence of the sulphonylurea receptor (SUR) subunit, with potency (IC50 = 45 mmol·L -1 ) almost identical to that for KIR6.2/SURx channels. Single-channel kinetic analysis showed that the channel inhibition was mediated by augmentation of the long-lasting closures without affecting the channel open state and unitary conductance. In contrast, rosiglitazone had no effect on KIR1.1, KIR2.1 and KIR4.1 channels, suggesting that the channel inhibitory effect is selective for KIR6.x channels. CONCLUSIONS AND IMPLICATIONSThese results suggest a novel KATP channel inhibitor that acts on the pore-forming KIR6.x subunit, affecting the channel gating. LINKED ARTICLEThis article is commented on by Dart, pp. 23-25 of this issue. To view this commentary visit http://dx
Gut microbiota play an important role in the development of type 1 diabetes. We show herein that fermentable fiber inulin modulates gut microbiota to prevent and treat STZinduced diabetes and to delay diabetes development in non-obese diabetes (NOD) mouse models.
Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other’s expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.
Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies demonstrate the microbiota plays an important role in mediating host–viral interactions and determining the outcomes of these encounters. This review outlines recently described examples of how bacteria and viruses impact each other particularly during infectious processes. Mechanistically, these effects can be broadly categorized as reflecting direct bacterial–viral interactions and/or involving microbial impacts upon innate and/or adaptive immunity.
Key points• K + channels are the primary regulators of membrane potentials and cellular excitability, dysfunction of which may occur under several pathophysiological conditions affecting cellular function and stress responses, such as oxidative stress known to play an important role in the inflammation state.• In the study, we find evidence for the modulation of a K + channel by several oxidants. The underlying mechanism for the oxidant-mediated channel modulation appears to be mediated by S-glutathionylation, a newly recognized protein modification process.• A cysteine residue in the second transmembrane domain of the channel protein seems to be the target of S-glutathionylation.Abstract The Kir4.1 channel is expressed in the brainstem, retina and kidney where it acts on K + transportation and pH-dependent membrane potential regulation. Its heteromerization with Kir5.1 leads to K + currents with distinct properties such as single-channel conductance, rectification, pH sensitivity and phosphorylation modulation. Here we show that Kir5.1 also enables S-glutathionylation to the heteromeric channel. Expressed in HEK cells, an exposure to the oxidant H 2 O 2 or diamide produced concentration-dependent inhibitions of the whole-cell Kir4.1-Kir5.1 currents. In inside-out patches, currents were inhibited strongly by a combination of diamide/GSH or H 2 O 2 /GSH but not by either alone. The currents were also suppressed by GSSG and the thiol oxidants pyridine disulfides (PDSs), suggesting S-glutathionylation. In contrast, none of the exposures had significant effects on the homomeric Kir4
Background Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other’s function. Aim/methods To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background. Results Mice lacking TLR5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking TLR5, NLRC4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T-cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to WT mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes. Conclusions These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.
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