Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection withChlamydiaSpecies

Abstract

The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Chlamydia trachomatis is an obligate intracellular gram-negative bacterium that primarily infects epithelial cells lining the ocular, respiratory, and urogenital tract surfaces and causes many human diseases including trachoma, pneumonia, and pelvic inflammatory disease (2). Although effective antibiotics are available, the incidence of C. trachomatis infections continues to increase worldwide (41). In the United States alone, it is estimated that there are approximately 2.8 million new cases of urogenital C. trachomatis infection each year (58). An effective and safe Chlamydia vaccine is needed to address the global C. trachomatis epidemic, and a comprehensive understanding of the means of protective immunity and immunopathology of C. trachomatis infection is essential for vaccine development.C. trachomatis infection results in a wide variety of clinical manifestations, ranging from asymptomatic to mild or severe symptoms, acute or chronic inflammatory responses, and a wide range of chronic complications (5,47,59). Host genetic factors appear to be important in determining the outcome of Chlamydia infections. It has been reported that the increased incidence of Chlamydia-induced chronic diseases, such as tubal infertility and scarring trachoma, is correlated with certain human leukocyte antigen (HLA) haplotypes and polymorphism of genes encoding interleukin-10 (IL-10), CD14, and tumor necrosis factor alpha (6,7,16,25,44,54). However, how these specific genes are involved in shaping the specific immune responses during Chlamydia infection in humans remains unclear. As in humans, inbred mouse strains, such as, and DBA/2J (H-2 d ) mice respond to respiratory (1,39,40,63), genital (9-12, 52), and intraperitoneal (i.p.) (36) Chlamydia infections differently. C57BL/6 mice are regarded as a resistant strain, whereas BALB/c, DBA/2, and C3H/HeN mice are reported as susceptible strains with higher mortality, more prolonged bacterial burden, more severe tissue inflammatory responses (such as neutrophil infiltration), and higher rates of infertility following Chlamydia infection. Thus, these inbred mouse strains have been used extensively for identification of specific host factors that regulate immune responses and immune mechanisms underlying the pathogenesis of Chlamydia infection.Based on animal models (5,8,38,50) and hum...

Chlamydial Respiratory Infection during Allergen Sensitization Drives Neutrophilic Allergic Airways Disease

“…This finding demonstrates that neither IFN-g nor IL-17 plays a critical mechanistic role during the challenge phase of Chlamydia-induced neutrophilic AAD. Depletion during sensitization and infection phases of the experimental models is not appropriate, as both IFN-g and IL-17 are induced by and are required for the clearance of chlamydial respiratory infection (10,11,70). Thus, the absence of these factors during infection would dramatically change the profile and magnitude of infection and subsequently the responses to OVA.…”

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

“…Numerous studies have indicated that Th17 cells and their signature cytokine IL-17A are critical to the airway's immune response against various infections, including intracellular bacteria [123,124] and fungi [125]. The innate IL-17A-producing cells, γδ T cells have been shown to act on nonimmune lung cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins and inflammatory chemokines as CCL28, in those cells, causing the migration of IgE-secreting B cells to the infected tissues [126] as well as the proliferation of human airway epithelial cells in vitro.…”

“…The bronchoalveolar lavage from lung transplant recipients showed detectable Candida spp., Aspergillus spp., or Cryptococcus spp. Because all of the transplant recipients had been treated with antibiotics and immunosuppressants, thus ablating host immune responses and the prokaryotic milieu of the lung microbiota, this first study supports the notion that host defense, and perhaps some sort of bacterial microbiota-mediated resistance mechanisms, play a major role in keeping fungal colonization extremely low in the lungs.Numerous studies have indicated that Th17 cells and their signature cytokine IL-17A are critical to the airway's immune response against various infections, including intracellular bacteria [123,124] and fungi [125]. The innate IL-17A-producing cells, γδ T cells have been shown to act on nonimmune lung cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins and inflammatory chemokines as CCL28, in those cells, causing the migration of IgE-secreting B cells to the infected tissues [126] as well as the proliferation of human airway epithelial cells in vitro.…”

Mus spretus SEG/Pas mice resist virulent Yersinia pestis, under multigenic control

“…There are six IL-17 family members and five receptors. Specifically, IL-17RA and IL-17RC subunits of IL-17 receptor, which map to the Yprl3 interval (Supplementary Table 1), interact with IL-17 and IL-17F to induce production of other proinflammatory cytokines, chemokines and growth factors, 31 leading to an accumulation of neutrophils at the sites of infection and inflammation. 32 In fact, several studies have reported that IL-17R deficiency results in significant delay in neutrophil recruitment and impaired host defense against bacteria including L. monocytogenes, 33 Bacillus subtilis 34 and Klebsiella pneumoniae.…”