Abstract
BackgroundIndividuals with impaired immunity are more susceptible to infections than immunocompetent subjects. No vaccines are currently available to induce protection against E. coli meningoencephalitis. This study evaluated the potential of poly(I:C) pre-treatment to induce trained immunity. Poly(I:C) was administered as a non-specific stimulus of innate immune responses to protect immunocompetent and neutropenic wild-type mice from a subsequent challenge by the intracranial injection of E. coli K1.MethodsThree days prior to infection, mice received an intraperitoneal injection of poly(I:C) or vehicle. Kaplan-Meier survival curves were analyzed. In short-term experiments, bacterial titers and the inflammatory response were characterized in the blood, cerebellum, and spleen homogenates. NK cell subpopulations in the brain and spleen were analyzed by flow cytometry. Numbers of microglia and activation scores were evaluated by histopathology.ResultsPre-treatment with 200 μg poly(I:C) increased survival time, reduced mortality, and enhanced bacterial clearance in the blood, cerebellum, and spleen at early infection in neutropenic mice. Poly(I:C)-mediated protection correlated with an augmented number of NK cells (CD45+NK1.1+CD3−) and Iba-1+ microglial cells and a higher production of IFN-γ in the brain. In the spleen, levels of CCL5/RANTES and IFN-γ were increased and sustained in surviving poly(I:C)-treated animals for 14 days after infection. In immunocompetent animals, survival time was not significantly prolonged in poly(I:C)-treated animals although poly(I:C) priming reduced brain bacterial concentrations compared with vehicle-injected animals at early infection.ConclusionsPre-treatment with the viral TLR3 agonist poly(I:C) modulated innate immune responses and strengthened the resistance of neutropenic mice against E. coli K1 meningoencephalitis.
Highlights
Individuals with impaired immunity are more susceptible to infections than immunocompetent subjects
We have shown that CD11b+Ly-6G+Ly-6Cint granulocytes are critical elements in the early host defense against E. coli meningitis [18]
Previous work suggested that the protective effect of Toll-like receptors (TLR) stimulation was stronger in neutropenic than in wt mice [10]
Summary
Individuals with impaired immunity are more susceptible to infections than immunocompetent subjects. Prevention of infections in immunocompromised as well as in aged persons has proven difficult, because responses to vaccines begin to decline in healthy adults beyond 40–50 years of age [7]. To overcome this problem, vaccines incorporate adjuvants to increase seroconversion rates in populations with reduced responsiveness [8]. Natural ligands or synthetic agonists of Tolllike receptors (TLRs) are being investigated as potential adjuvants for human vaccines [8,9,10]. Poly(I:C) through TLR3 recognition promotes Th1 cellular immune responses via the TLR/IL-1 receptor (TIR)-domain-containing adaptor protein-inducing IFN-β (TRIF). Poly(I:C) strongly elicited humoral and cellular immunity as part of anti-viral vaccines [12] and enhanced the immunogenicity of the vaccine Bacille Calmette-Guérin against tuberculosis in mouse and non-human primates [13,14,15]
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