MEMORY TH17 CELLS IN THE LUNG DURING SECONDARY BACTERIAL PNEUMONIA FOLLOWING INFLUENZA A VIRUS INFECTION

Secondary bacterial infection is the primary cause of morbidity and mortality associated with influenza A virus (IAV) infection. Specifically, nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Sp) are the most common cause of lethal secondary bacterial pneumonia in IAV infected individuals. Current vaccines used to protect against bacterial infection are very limited because the antibodies generated are specific to the bacterial strain used in immunization. T-helper type 17 (Th17) cells are increasingly recognized as the key mediators of serotype-independent protection against respiratory bacterial infections. During virus/bacteria co-infection, however, the protective anti-bacterial Th17 responses are inhibited by viral infection, resulting in persistent bacterial colonization in the lung. It is unknown whether the memory Th17 cells from bacterial immunization can restore the Th17 response lost during virus/bacterial co-infection and whether this is sufficient to protect against lethal co-infection. In this study, we first established a mouse model that was highly susceptible to secondary bacterial infection following a mild IAV infection. Immunization against the bacteria conferred complete protection against co-infection in a bacterial serotype-independent manner by mounting rapid recall Th17 responses. Furthermore, we found that an FDA approved histone deacetylase inhibitor (HDACi), Romidepsin (RMD), acts as a novel adjuvant to augment antigen-specific Th17 responses in the lung and improve immunization-induced protection against co-infection. Animals immunized with vaccine adjuvanted with RMD display increased survival, body weight recovery, bacterial clearance, and antigen-specific recall Th17 responses. Together, these results provide a strategy to develop universal vaccines against co-infection by inducing protective Th17 responses and suggest that RMD could augment vaccine efficacy as a mucosal adjuvant.

Author dc:creator

• Yang, Ying

Advisor dc:contributor.advisor

• Abt, Michael, C

• Immunology and Infectious Disease
• Microbiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/59169

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/59169