Pertussis toxin suppresses dendritic cell-mediated delivery of B. pertussis into lung-draining lymph nodes

Author summaryOf the three classical Bordetella species causing respiratory infections in mammals, only the human-specialized whooping cough agent B. pertussis produces the pertussis toxin (PT) as its major virulence factor. Human pertussis is an acute respiratory illness and the pleiotropic activities of pertussis toxin account for the characteristic systemic manifestations of the disease, such as hyperleukocytosis, histamine sensitization, hyperinsulinemia, or inflammatory lung pathology. We found that PT activity inhibits the migration of infected dendritic cells from the lungs into the draining mediastinal lymph nodes (mLNs). This prevents mLN infection by bacteria evading from migratory cells and delivery of bacterial antigens into mLNs. As a result, the induction of adaptive serum antibody responses to infection is delayed. We thus propose that PT action serves to create a time window for proliferation of B. pertussis on airway mucosa to facilitate transmission of the pathogen among humans. The adenylate cyclase (ACT) and the pertussis (PT) toxins of Bordetella pertussis exert potent immunomodulatory activities that synergize to suppress host defense in the course of whooping cough pathogenesis. We compared the mouse lung infection capacities of B. pertussis (Bp) mutants (Bp AC(-) or Bp PT-) producing enzymatically inactive toxoids and confirm that ACT action is required for maximal bacterial proliferation in the first days of infection, whereas PT action is crucial for persistence of B. pertussis in mouse lungs. Despite accelerated and near complete clearance from the lungs by day 14 of infection, the PT- bacteria accumulated within the lymphoid tissue of lung-draining mediastinal lymph nodes (mLNs). In contrast, the wild type or AC(-) bacteria colonized the lungs but did not enter into mLNs. Lung infection by the PT- mutant triggered an early arrival of migratory conventional dendritic cells with associated bacteria into mLNs, where the PT- bacteria entered the T cell-rich paracortex of mLNs by day 5 and proliferated in clusters within the B-cell zone (cortex) of mLNs by day 14, being eventually phagocytosed by infiltrating neutrophils. Finally, only infection by the PT- bacteria triggered an early production of anti-B. pertussis serum IgG antibodies already within 14 days of infection. These results reveal that action of the pertussis toxin blocks DC-mediated delivery of B. pertussis bacteria into mLNs and prevents bacterial colonization of mLNs, thus hampering early adaptive immune response to B. pertussis infection.

Automated summary

The pertussis toxin PT inhibits migration of infected dendritic cells from the lungs to the draining lymph nodes, delaying the induction of adaptive serum antibody responses to infection. This suggests that PT action allows time for B. pertussis proliferation on the airway mucosa to facilitate transmission among humans.