Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Abstract

Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after singlestranded RNA (ssRNA) stimulation of the TLR-7-MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF) - IntroductionThere are numerous studies addressing the contribution of eosinophilic leukocytes to immune mechanisms regulating allergic diseases and granulomatous and fibrotic disorders, and eosinophil recruitment in response to helminthic parasite infection has been well documented. 1 In contrast, there is only limited information on the role of eosinophils in immunity against infectious pathogens. Eosinophil recruitment was observed in response to acute severe respiratory syncytial virus (RSV) infection in human infants, 2-4 and infection of airway epithelial cells results in the expression of several eosinophil chemoattractants. 5,6 However, it is not at all clear whether eosinophils contribute to host defense or to the immunopathology observed in response to RSV infection. RSV infection is the most commonly identified cause of lower respiratory tract infections in infants, and severe disease has been associated with progression to childhood asthma, a disease state characterized by a mild to moderate eosinophilia. 7,8 In addition, exacerbations of established asthma are most frequently caused by viral infections, of which RSV has been implicated. 9 Recently, transcripts encoding Toll-like receptor (TLR)-1, TLR-4, TLR-7, TLR-9, and TLR-10, all of which coordinate innate and acquired immune responses, were shown to be expressed constitutively by eosinophils. 10 Recognition of viral nucleic acids, including double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and dsDNA, occurs via activation of TLR-3, TLR-7, and TLR-9, respectively, and results in the production of type I IFNs and the initiation of the antiviral host response. 11-15 RSV is a negative ssRNA virus that generates dsRNA during its replication cycle. Although TLR-3 and TLR-7 both recognize viral RNA, TLR-3 uses toll-interleukin receptor domain-containing adaptorinducing IFN-␤ (TRIF) and does not require MyD88, while TLR-7 signaling is MyD88 dependent. 12 These differences in adaptor usage, along with the activation of different IFN regulatory factors (IRFs), are proposed to provi...

Pneumonia virus of mice: severe respiratory infection in a natural host

“…Taken together, these results suggest that TLR4 actually does not have a crucial, indispensable function in promoting host defense against a natural respiratory virus infection. However, other pattern recognition receptors (e.g., TLR3 [36], TLR7 [37]) have been explored vis à vis their role in promoting host defense against respiratory syncytial virus challenge, and might be intriguing subjects for future study with the natural PVM pathogen model.…”

Overcoming T-Cell-Mediated Immunopathology to Achieve Safe Respiratory Syncytial Virus Vaccination

“…In mice undergoing a primary RSV infection, it has been found that eosinophils contribute to viral clearance [61]. This has not been directly tested in mice undergoing a memory response to RSV, however, work from vacvF-immunized mice and IL-13-deficient vacvG-immunized mice, neither of which develop pulmonary eosinophilia, demonstrate that viral clearance is not significantly altered in the absence of eosinophils [44,52].…”

L’éosinophile : nouvel acteur de la réponse immunitaire innée ?

“…[19,20]. Chez la souris, il n'existe qu'une seule étude publiée sur l'expression des TLR sur les éosinophiles murins ; elle a mis en évidence la présence des TLR 3, 4, 5 et 7 [21]. L'expression par les éosinophiles de ces différents récepteurs de l'immunité innée, et la reconnaissance de l'appartenance de …”

“…In vitro, le même phénomène est observé après infection par le RSV (respiratory syncytial virus). Phipps et ses collaborateurs ont montré de manière indirecte que les éosinophiles améliorent l'élimination du virus via un processus dépendant de TLR7 et MyD88 [21]. Lors d'une infection par le virus de l'immunodéficience humaine (VIH), l'éosinophile peut constituer à la fois un réservoir de virus, puisque cette cellule est infectable via l'antigène CD4 qu'elle exprime, mais elle peut aussi participer à l'activité antivirale via la libération d'EPO et d'H2O2, ce qui illustre parfaitement le concept de dualité fonctionnelle de l'éo-sinophile [25].…”