Abstract
Bordetella bronchiseptica and Bordetella pertussis are closely related respiratory pathogens that evolved from a common bacterial ancestor. While B. bronchiseptica has an environmental reservoir and mostly establishes chronic infections in a broad range of mammals, B. pertussis is a human-specific pathogen causing acute pulmonary pertussis in infants and whooping cough illness in older humans. Both species employ a type III secretion system (T3SS) to inject a cytotoxic BteA effector protein into host cells. However, compared to the high BteA-mediated cytotoxicity of B. bronchiseptica, the cytotoxicity induced by B. pertussis BteA (Bp BteA) appears to be quite low and this has been attributed to the reduced T3SS gene expression in B. pertussis. We show that the presence of an alanine residue inserted at position 503 (A503) of Bp BteA accounts for its strongly attenuated cytotoxic potency. The deletion of A503 from Bp BteA greatly enhanced the cytotoxic activity of B. pertussis B1917 on mammalian HeLa cells and expression of Bp BteAΔA503 was highly toxic to Saccharomyces cerevisiae cells. Vice versa, insertion of A503 into B. bronchiseptica BteA (Bb BteA) strongly decreased its cytotoxicity to yeast and HeLa cells. Moreover, the production of Bp BteAΔA503 increased virulence of B. pertussis B1917 in the mouse model of intranasal infection (reduced LD50) but yielded less inflammatory pathology in infected mouse lungs at sublethal infectious doses. This suggests that A503 insertion in the T3SS effector Bp BteA may represent an evolutionary adaptation that fine-tunes B. pertussis virulence and host immune response.
Highlights
The genus Bordetella embraces three closely related mammalian pathogens, the so-called classical bordetellae, B. pertussis, B. parapertussis, and B. bronchiseptica that cause respiratory infections of various symptoms, duration, and severity
We found that B. pertussis had the cytotoxic activity of its type III secretion system-delivered effector BteA strongly attenuated by insertion of an alanine residue at position 503 as compared to the BteA homologue of the animal
We report here that B. pertussis BteA (Bp BteA) possesses a much lower cytotoxic activity to yeast and human cells than bronchiseptica BteA (Bb BteA) and that this is due to the insertion of an additional alanine residue at position 503 (A503) of Bp BteA, which is conserved in different B. pertussis lineages
Summary
The genus Bordetella embraces three closely related mammalian pathogens, the so-called classical bordetellae, B. pertussis, B. parapertussis, and B. bronchiseptica that cause respiratory infections of various symptoms, duration, and severity. The B. parapertussis species consists of two distinct lineages, those that infect sheep and those that cause a whooping cough illness in humans [5,6,7]. The B. bronchiseptica species infects a broad range of mammals, including humans, and consists of 2 distinct subpopulations, designed as a complex I and complex IV [8]. These bacteria elicit pathologies ranging from typical chronic and often asymptomatic respiratory infections, up to acute illnesses, such as kennel cough in dogs, or bronchopneumonia, and atrophic rhinitis in piglets [3, 9]
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