The detrimental impact of tobacco on human health is clearly recognized
and despite aggressive efforts to prevent smoking, close to one billion
individuals worldwide continue to smoke. People with chronic obstructive
pulmonary disease (COPD) are susceptible to recurrent respiratory infections
with pathogens, including non-typeable Haemophilus influenzae
(NTHI), yet the reasons for this increased susceptibility are poorly understood.
As mortality rapidly increases with multiple exacerbations, development of
protective immunity is critical to improving patient survival. Acute NTHI
infection has been studied in the context of cigarette smoke exposure, but this
is the first study to investigate chronic infection and the generation of
adaptive immune responses to NTHI following chronic smoke exposure. After
chronic NTHI infection, mice that had previously been exposed to cigarette smoke
developed increased lung inflammation and compromised adaptive immunity relative
to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to
cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells
produced reduced levels of antibodies against outer membrane lipoprotein P6,
with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17,
which is associated with neutrophilic inflammation, was enhanced. Interestingly,
cigarette smoke exposed mice exhibited a similar defect in the generation of
adaptive immunity following immunization with P6. Our study has conclusively
demonstrated that cigarette smoke exposure has a profound suppressive effect on
the generation of adaptive immune responses to NTHI and suggests the mechanism
by which prior cigarette smoke exposure predisposes COPD patients to recurrent
infections, leading to exacerbations and contributing to mortality.