Recognition of conserved antigens by Th17 cells provides broad protection against pulmonaryHaemophilus influenzaeinfection

Abstract

Nontypeable (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.

The persistence of NontypeableHaemophilus influenzaefuels airway inflammation

“…In the present study, we were able to evaluate the pro-inflammatory burden caused by NTHi persistence, associated with constitutive recruitment of neutrophils, as well as with increased levels of both γ δ + and CD4 + T cell subsets in the late phase of bacterial persistence. Previous studies identified a protective role of type 17 immunity (intended as IL-17 secreting cells) during transient and acute NTHi infection in mice [29] [33]. Here, we found that chronic inflammation due to NTHi persistence is associated with CD3 + CD4 + IL-17 + cells.…”

“…To date, animal models have been developed to mimic the acute phase of NTHi infection rather than the chronic phase, limiting steps forward in the field. Airway persistence of NTHi is common in CF disease but also in other lung diseases with different aetiology, including COPD or lung cancer [29][30][31]. In this context, Croasdell A. et al exploited an acute infection model in which different amounts of NTHi were inoculated by oropharyngeal aspiration in C57BL/6J mice (up to 10 8 CFU) and 24 hours post-infection they found >90% of bacteria had been cleared, independently from the inoculum dose [32].…”

The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae

“…This may potentially prone the T cell-mediated immunity to a Th2/Tc2 response in COPD patients treated with corticosteroids ( 277 ). Interestingly, antigen-specific Th17 cells from NTHi-immunized non-COPD mice model recognize both homologous and heterologous strains of NTHi, and are able to confer protection upon adoptive transfer ( 278 ). However, it is unclear whether the Th17 cell which is prone to the inflammatory response could be “trained” to counteract the NTHi infection in COPD patients, particularly during exacerbations.…”

Updates on T helper type 17 immunity in respiratory disease

“…Elicitation of lung memory Th17 cells to (S. pneumoniae) or K. pneumoniae can provide T cells that can provide serotype‐independent immunity to a pulmonary challenge with those pathogens . This approach has also shown pre‐clinical success with Haemophilus influenzae , an important pathogen in COPD . Based on this work, there is the possibility to take advantage of this immunology to prevent invasive bacterial and fungal infection in the lung.…”