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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Delayed IL-17RA signaling in early life promotes type I interferon/CXCL10-dependent inhibition of pneumococcal
Teniola Idowu1, Daniel P Fecko1, Hannes Eichner1
1Department of Microbiology, New York University School of Medicine, NY, New York, USA.
Insights
Infant immune responses to Streptococcus pneumoniae are delayed, prolonging bacterial colonization. This is due to a delayed IL-17A response that fails to restrain the type I interferon/CXCL10 axis, impairing bacterial clearance.
Area of Science:
- Immunology
- Microbiology
- Developmental Biology
Background:
- Infants are highly susceptible to respiratory infections like Streptococcus pneumoniae (Spn).
- The underlying immune mechanisms predisposing infants to prolonged Spn colonization are not well understood.
- Interleukin-17A (IL-17A) plays a role in host defense against bacterial pathogens.
Purpose of the Study:
- To investigate the age-dependent immune mechanisms governing Streptococcus pneumoniae colonization in early life.
- To elucidate the role of IL-17 receptor A (IL-17RA) signaling in infant immunity to Spn.
- To understand the interplay between IL-17RA, type I interferon (IFN), and CXCL10 in Spn upper respiratory tract (URT) colonization.
Main Methods:
- Utilized an infant mouse model of Streptococcus pneumoniae colonization.
- Employed IL-17RA-deficient and wild-type (WT) infant mice for comparative analysis.
- Conducted transcriptomic profiling of the URT.
- Investigated the roles of type I interferon receptor 1 (IFNAR1) and CXCL10 through genetic deletion.
Main Results:
- Infant mice exhibited a delay in IL-17A production, correlating with prolonged Spn colonization.
- IL-17RA-deficient infant mice showed persistent Spn colonization and altered URT gene expression, including increased CXCL10.
- WT infant mice showed increased CXCL10 expression dependent on IFNAR1 signaling and pneumolysin, with Ifnar1 or Cxcl10 deficiency accelerating bacterial clearance.
- Adult mice demonstrated earlier IL-17A induction, minimal CXCL10, and no altered clearance rates upon Ifnar1 or Cxcl10 deficiency.
Conclusions:
- A developmental window exists in early life characterized by delayed IL-17A production.
- This delay impairs IL-17RA-dependent restraint of the type I interferon/CXCL10 axis.
- Impaired myeloid cell-mediated clearance due to this axis imbalance prolongs Spn carriage in infants.
Abstract:
Early life is characterized by heightened susceptibility to respiratory pathogens, yet the immune mechanisms that predispose infants to infection remain poorly defined. Using an infant mouse model of Streptococcus pneumoniae (Spn) colonization, we identify an age-dependent delay in IL-17 A production that was associated with prolonged bacterial colonization in infant mice. Consistent with a critical role for this pathway, IL-17 receptor A (IL-17RA)-deficient infant mice exhibited persistent Spn colonization of the upper respiratory tract (URT). Transcriptomic profiling of the URT from Spn-colonized IL-17RA-deficient infant mice revealed an enrichment of antiviral responses compared to WT controls and included increased expression of the interferon-stimulated gene Cxcl10, a chemokine whose expression is positively associated with Spn carriage in humans. These results suggested that IL-17RA signaling constrains the interferon response during URT Spn colonization. WT infant mice exhibited progressively increased expression of Cxcl10 during Spn colonization and was dependent on type 1 interferon (IFNAR1) signaling and the pore forming bacterial toxin, pneumolysin. Genetic deletion of Ifnar1 or Cxcl10, including myeloid cell-specific deletion of Ifnar1, accelerated bacterial clearance in infant mice. In contrast, adult mice exhibited earlier induction of IL-17 A, minimal induction of Cxcl10 expression, and no alteration in bacterial clearance rates following Ifnar1 or Cxcl10 deficiency. Taken together, our results reveal a developmental window in which delayed IL-17 A production postpones the IL-17RA-dependent restraint of the type I interferon/CXCL10 axis, thereby prolonging pneumococcal carriage through impaired myeloid cell-mediated bacterial clearance.
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