From mice and toddlers: a critical role for IL-17 & neutrophils in the RSV vaccine enhanced disease

ACOSTA PL; HIJANO DR; LAWRENCE A; CABALLERO M; NEWCOMB D; PEEBLES RS; POLACK FP

Austin

Conferencia; The 4th ISIRV-AVG Conference - Novel Antiviral Therapies for Influenza and Other Respiratory Viruses: Bench to Bedside; 2015

International Society for Influenza and other Respiratory Virus Diseases

Background: Approximately 50% of infants are infected by respiratory syncytial virus (RSV)during their first year of life. There is still no vaccine licensed against the virus. A major obstacle to vaccine development has been the enhanced respiratory disease (ERD) that affected children immunized with a formalin inactivated vaccine against RSV (FIRSV) in the 1960s. Pathogenesis of ERD was associated with a polarization Th-2 of the immune response. Our data suggest that ERD was due to a polarization to Th-17 instead of Th-2. Objective: Determine the role of IL-17 & neutrophils in the enhanced disease (ERD) caused by respiratory syncytial virus (RSV) in toddlers immunized with an inactivated RSV vaccine (FIRSV). Study Design: Mice: 4-6 week old female BALB/c, C57BL/6, CXCR2-/- and foxp47-/- mice. Immunization: FIRSV 1x105 pfu, RSV 1x105 pfu, PBS (placebo) administered in footpad. Challenge: 60 days post-immunization, mice were challenged with RSV A2 106 pfu intranasally. Histopathology: Lung sections were stained with H&E and PAS. Cytokine responses and Th transcription factors were assayed in bronchoalveolar lavage fluids and regional lymph nodes by immunoasssay and real time RT-PCR. Lung sections from toddlers who died of ERD in 1967 were stained by immunohistochemistry. Results:  Inactivated RSV vaccine enhances IL-17 production in regional lymph nodes after immunization compared to the response elicited by RSV or placebo.  Th17 inmune response is enhanced in the lungs of mice with ERD and Th1 is suppressed.  ROR-γt (Th-17 master trancription factor) levels are increased in the lungs of mice with ERD.  AHR and bronchipneumonia are decreased in mice treated with anti-neutrophils antibody.  AHR and bronchipneumonia are significantly decreased in mice treated with anti-IL-17 antibody.  Decreased AHR, pneumonia and mucus production was observed in cxcr2-/- mice compared to control BALB/c mice with ERD.  AHR, and pneumonia are decreased in p47phox-/- compared to wt mice.  IL-17 positive cells are abundant in the lungs of toddlers killed by ERD in 1967.  Exuberant neutrophilic infiltrate in the lungs of toddlers with RSV were found. Conclusions:  Th-17 immune response and neutrophils play a key role in enhanced RSV disease.