Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways

Abstract

In infants, can cause severe disease, manifested as pronounced leukocytosis, pulmonary hypertension, and even death. The exact cause of death remains unknown, and no effective therapies for treating fulminant pertussis exist. In this study, a neonatal mouse model of critical pertussis is characterized, and a central role for pertussis toxin (PT) is described. PT promoted colonization, leukocytosis, T cell phenotypic changes, systemic pathology, and death in neonatal but not adult mice. Surprisingly, PT inhibited lung inflammatory pathology in neonates, a result which contrasts dramatically with observed PT-promoted pathology in adult mice. Infection with a PT-deficient strain induced severe pulmonary inflammation but not mortality in neonatal mice, suggesting that death in these mice was not associated with impaired lung function. Dissemination of infection beyond the lungs was also detected in neonatal mice, which may contribute to the observed systemic effects of PT. We propose that it is the systemic activity of pertussis toxin and not pulmonary pathology that promotes mortality in critical pertussis. In addition, we observed transmission of infection between neonatal mice, the first report of transmission in mice. This model will be a valuable tool to investigate causes of pertussis pathogenesis and identify potential therapies for critical pertussis.

Neutralization of pertussis toxin by a single antibody prevents clinical pertussis in neonatal baboons

“…B. pertussis is a respiratory infection and while PTx exerts systemic effects (27), it is expected that anti-PTx antibodies are also needed at the mucosal surface to protect neutrophils mediating bacterial clearance. Thus, anti-PTx antibodies may indirectly support bacterial clearance, as reduced B. pertussis lung colonization was observed in prior mouse and adolescent baboon studies with hu1B7 (20).…”

Discovery of compounds inhibiting the ADP-ribosyltransferase activity of pertussis toxin

“…ADP-ribosyltransferase activity of pertussis toxin is important for the pathological effects of pertussis toxin. Seven-day-old neonatal mice infected with a B. pertussis strain expressing a mutant of PtxS1 lacking the ART-activity fully survived a challenge, which caused 100% mortality with the parental strain of B. pertussis 11 . Purified AB 5 holotoxin containing the same PtxS1 mutant was incapable of inducing leukocytosis in mice in doses that were 100-fold more than the median lethal dose of wild-type AB 5 holotoxin 24 .…”

“…Rats experimentally infected with B. pertussis developed prolonged paroxysmal coughing, but an isogenic pertussis toxin-deficient strain did not cause such pathology 9, 10 . Seven-day-old neonatal mice infected with a pertussis toxin-deficient strain of B. pertussis survived a challenge, which caused 100% mortality with the parental strain 11 . Therefore, targeting of pertussis toxin might prove beneficial in the treatment of whooping cough, especially in young children who still lack the vaccine-induced protection.…”

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

“…Finally, effects of CsA and its non-immunosuppressive derivative NIM811 were investigated in an infant mouse model of pertussis. This model has recently been established and recapitulates several hallmarks of severe disease observed in humans such as leukocytosis and death, which are both PTdependent 8 . Here, 7-day old mice were infected with a PT-producing wild type strain of B. pertussis via aerosol and then treated intranasally with either CsA or NIM811 or vehicle.…”

“…In mouse models, PT causes exacerbated and prolonged airway inflammation 7 . Mutant strains of B. pertussis that do not express PT, do not cause severe symptoms such as leukocytosis or death in animal models 8 . This observation clearly indicates that PT promotes disease severity and represents an attractive drug target 7,9,10 .…”