Abstract
Many studies have linked severe RSV infection during early-life with an enhanced likelihood of developing childhood asthma, showing a greater susceptibility in boys. Our studies show that early-life RSV infection leads to differential long-term effects based upon the sex of the neonate; leaving male mice prone to exacerbation upon secondary allergen exposure while overall protecting female mice. During initial viral infection, we observed better viral control in the female mice with correlative expression of interferon-β that was not observed in male mice. Additionally, we observed persistent immune alterations in male mice at 4 weeks post infection. These alterations include Th2 and Th17-skewing, innate cytokine expression (Tslp and Il33), and infiltration of innate immune cells (DC and ILC2). Upon exposure to allergen, beginning at 4 weeks following early-life RSV-infection, male mice show severe allergic exacerbation while female mice appear to be protected. Due to persistent expression of TSLP following early-life RSV infection in male mice, genetically modified TSLPR−/− mice were evaluated and demonstrated an abrogation of allergen exacerbation in male mice. These data indicate that TSLP is involved in the altered immune environment following neonatal RSV-infection that leads to more severe responses in males during allergy exposure, later in life. Thus, TSLP may be a clinically relevant therapeutic target early in life.
Highlights
An increase in viral gene expression was observed in male compared to female mice on day 4 of infection (Fig. 2c) with female but not male mice having an increase in interferon-β gene expression (Fig. 2d), a critical cytokine required for viral clearance.[38]
Clinically, data suggest that severe Respiratory syncytial virus (RSV) infection during early-life enhances the likelihood of developing childhood asthma by 3–5 fold.[1,45]
Clinical data show that boys are more susceptible to RSV, hospitalized at a 2:1 ratio compared to girls, and are more than twice as likely to develop childhood asthma.[2,21,46]
Summary
Respiratory syncytial virus (RSV) is often the first clinically relevant pathogen encountered, with most children infected during the first 2 years of life.[1,2] This viral infection is the leading cause of childhood hospitalization and increases the risk for developing childhood asthma and recurrent wheezing.[1,3] The health burden costs of RSV infection account for over 3 million hospitalizations and ~100,000 deaths per year in children under 5, worldwide.[4,5]Recent pre-clinical and clinical data, including data from our laboratory, suggest that severe RSV disease is associated with an altered innate and adaptive immune response, characterized by excessive Th2 and Th17 immune responses.[4,6,7,8,9,10,11] Numerous studies have shown that RSV plays a role in reducing innate cytokine production that is necessary for appropriate anti-viral responses.[4,10,12,13] Both viral replication as well as immunopathology can lead to RSV disease symptoms and probing these and potentially other underlying disease mechanisms that are supported by clinical data will be important for therapeutically targeting the immune environment.
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