Interleukin-27 Inhibits Vaccine-Enhanced Pulmonary Disease following Respiratory Syncytial Virus Infection by Regulating Cellular Memory Responses

Abstract

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in infants and young children, accounting for approximately 5% of hospitalizations due to lower respiratory tract infections (15). Premature infants, immunocompromised individuals, and the elderly are the populations at the greatest risk to develop life-threatening RSV infections (10, 29). Moreover, reinfections occur frequently during life due to incomplete immunity after RSV infection. A number of clinical epidemiology studies have identified that there is a strong association between RSV bronchiolitis in infancy and the development of wheezing and asthma in later childhood (31,36,37). The World Health Organization has established a high priority for the development of an RSV vaccine. However, efforts to develop a safe and effective vaccine have been unsuccessful. In the 1960s, a formalininactivated RSV (FI-RSV) vaccine was used to immunize infants; these infants developed a more severe disease upon natural RSV infection; 80% of them but only 5% of infants that received a control vaccine required hospitalization, and two died (21). Histology performed on the lungs of the deceased revealed extensive neutrophils, mononuclear cells, and lymphocytes and increased numbers of eosinophils infiltrating the lungs (33).Although the vaccine-enhanced disease (VED) is a major concern in the development of a safe and effective RSV vaccine, its immunological mechanisms are unclear. Many pieces of evidence showed that VED was associated with an exaggerated Th2-type response. Depletion of Th2 cytokine interlukin-4 (IL-4) or IL-13 of mice immunized with FI-RSV inhibited the development of pulmonary disease after RSV challenge (18). The Th2 polarization may have been related to the absence of a Th1-promoting RSVspecific cytotoxic T lymphocyte (CTL) response after immunization with FI-RSV (29). RSV challenge of FI-RSV-immunized mice elicited a robust memory CD4 ϩ T cell response in the absence of a detectable memory CD8 ϩ T cell response, pulmonary eosinophilia, and VED (29). Immunization of BALB/c mice with a recombinant vaccinia virus (vacv) that expresses the RSV M2 protein (vacvM2) elicited an RSV-specific memory CD8 ϩ T cell response. Mice coimmunized with FI-RSV and vacvM2 after RSV challenge did not develop pulmonary eosinophilia, along with downregulation of pulmonary Th2 cytokines and upregulation of Th1 cytokines (41). Despite the beneficial role, Th1-biased or CD8 ϩ T-biased cellular memory may also be detrimental to the host. RSV challenge of mice previously immunized with vacv expressing the RSV F protein (vacvF) exhibited a memory Th1 response in the absence of a detectable memory Th2 response and developed lung inflammation characterized by mononuclear cell infiltration (5,17,28). In the mice immunized with vacvM2 or vacvF, systemic disease, including weight loss, occurs after RSV challenge, although no eosinophilia was detectable (5,17,28). These data clearly suggested that both a Th2 memory response and a Th1 or CD8 ϩ...

Altered regulatory cytokine profiles in cases of pediatric respiratory syncytial virus infection

“…Induced IL-10 and IL-35 expression could benefit the host response to limit the exaggerated inflammatory response to RSV infection, such as Th1/Th2 cytokine responses. Although TGF-β1 possesses anti-inflammatory properties with the potential of inhibiting both Th1 and Th2 responses elicited in response to bacterial and viral infection [29][30][31], we did not find that TGF-β1 expression profiles differed between RSV-infected patients and healthy controls. IL-10 is a multifunctional cytokine.…”

Regulatory cytokine function in the respiratory tract

“…143 Similarly, in a model of vaccine-exacerbated RSV infection, where prior vaccination results in Th2 and Th17-dominated immunopathology upon subsequent natural infection, coadministration of plasmids driving IL-27 overexpression dampened the memory Th2 and Th17 responses to RSV, without impairing or enhancing the protective Th1 response, altogether resulting in substantially reduced pathology upon subsequent infection. 144 These studies suggest that IL-27 can control the balance of protective and pathogenic T helper cell subsets during RSV infection. Using a different approach, Pyle and colleagues have demonstrated a role for IL-27, induced by early IL-6 signaling, in promoting maturation and suppressive capacity of FoxP3 + Tregs during primary RSV infection, independently of IL-10 145 (Fig.…”

The Immunobiology of Interleukin-27

“…Thus, MRL/lpr mice that lack IL-27Rα have increased numbers of dermal mast cells (147), and in a model of passive cutaneous anaphylaxis, or when challenged with a helminth, Il-27rα −/− mice have elevated circulating levels of mast cell protease (12). Enhanced neutrophil activity has been a common characteristic of the absence of IL-27 in multiple experimental systems, including models of peritoneal sepsis (148) and infection with respiratory syncytial virus (RSV) (149,150); however, administering IL-27 to mice acutely infected with influenza reduced neutrophil accumulation and was associated with impaired viral clearance (20). Indeed, in mice infected with LCMV, the absence of IL-27Rα results in increased early viremia that may be due to a role of innate cells, but whether this is related to the situation seen with influenza is unclear (132).…”