Abstract
In a mouse model of respiratory tract infection by Bordetella pertussis, bacteria multiply in the airways over the first week and are then cleared over the next 3–4 weeks by the host immune response. Pertussis toxin (PT), a virulence factor secreted exclusively by B. pertussis, promotes bacterial growth in the airways by suppression and modulation of host immune responses. By comparison of wild type and PT-deficient strains, we examined the role of PT in modulating airway cytokine and chemokine responses affecting neutrophil recruitment during B. pertussis infection in mice. We found that, despite early inhibition of neutrophil recruitment by PT, high numbers of neutrophils were recruited to the airways by 4 days post-infection with the wild type strain, but not with the PT-deficient strain, and that this correlated with upregulation of neutrophil-attracting chemokine gene expression. In addition, there was similar upregulation of genes expressing the cytokines IL-17A (IL-17), TNF-α and IFN-γ, indicating a mixed Th1/Th17 response. Expression of IL-6, a cytokine involved in Th17 induction, was upregulated earlier than the IL-17 response. We showed that PT, rather than bacterial numbers, was important for induction of these responses. Flow cytometric analysis revealed that the IL-17-producing cells were macrophages and neutrophils as well as T cells, and were present predominantly in the airways rather than the lung tissue. Antibody neutralization of IL-17 significantly reduced chemokine gene expression and neutrophil recruitment to the airways, but only modestly increased peak bacterial loads. These data indicate that PT stimulates inflammatory responses by induction of Th1- and Th17-associated cytokines, including IL-17, during B. pertussis infection in mice, but a role for IL-17 in protection against the infection remains to be established.
Highlights
Bordetella pertussis is a Gram-negative bacterial pathogen that infects the human respiratory tract and causes an acute disease known as pertussis or whooping cough
We reported that Pertussis toxin (PT) inhibits early neutrophil influx to the airways in response to B. pertussis infection in Balb/c mice [5,7,30], through a mechanism involving inhibition of neutrophil-attracting chemokine gene expression [7]
In this report we showed that subsequent to this early inhibitory phase, a second wave of neutrophil recruitment in response to WT B. pertussis infection occurs, starting before the peak of infection and remaining until at least 14 days post-infection, when only low bacterial loads are seen in the airways
Summary
Bordetella pertussis is a Gram-negative bacterial pathogen that infects the human respiratory tract and causes an acute disease known as pertussis or whooping cough. Symptomatic disease (cough) and transmission are not observed in the mouse model, several characteristics of the human disease are present, such as bacterial multiplication and clearance, limitation of the infection to the respiratory tract, and increased severity of infection in infant mice [2,3]. Systemic effects of the disease observed in humans, such as leukocytosis and hypoglycemia, can be detected in infected mice [3]. These characteristics, as well as the availability of inbred mice and genetically altered immunodeficient strains, make the mouse model useful for the study of host immune responses to B. pertussis infection
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