Antigen-specific Memory Th17 Cells Promote Cross-Protection Against Nontypeable Haemophilus Influenzae after Mild Influenza A Virus Infection

Secondary bacterial pneumonia after influenza A virus (IAV) infection is the leading cause of hospitalization and death associated with IAV infection worldwide. Nontypeable Haemophilus influenzae (NTHi) is one of the most common causes of secondary bacterial pneumonia. Current efforts to develop vaccines against NTHi infection focus on inducing antibodies but are hindered by antigenic diversity among NTHi strains. Therefore, we investigated the contribution of the memory T helper type 17 (Th17) response in protective immunity against IAV/NTHi coinfection. We observed that even a mild IAV infection impaired the NTHi-specific Th17 response and increased morbidity and mortality compared with NTHi monoinfected mice. However, pre-existing memory NTHi-specific Th17 cells induced by a previous NTHi infection overcame IAV-driven Th17 inhibition and were cross-protective against different NTHi strains. Last, mice immunized with a NTHi protein that induced a strong Th17 memory response were broadly protected against diverse NTHi strains after challenge with coinfection. These results indicate that vaccination that limits IAV infection to mild disease may be insufficient to eliminate the risk of a lethal secondary bacterial pneumonia. However, NTHi-specific memory Th17 cells provide serotype-independent protection despite an ongoing IAV infection and demonstrate the advantage of developing broadly protective Th17-inducing vaccines against secondary bacterial pneumonia.