Pertussis Toxin Inhibits Early Chemokine Production To Delay Neutrophil Recruitment in Response toBordetella pertussisRespiratory Tract Infection in Mice

Abstract

Pertussis is an acute respiratory disease of humans caused by the bacterium Bordetella pertussis. Pertussis toxin (PT) plays a major role in the virulence of this pathogen, including important effects that it has soon after inoculation. Studies in our laboratory and other laboratories have indicated that PT inhibits early neutrophil influx to the lungs and airways in response to B. pertussis respiratory tract infection in mice. Previous in vitro and in vivo studies have shown that PT can affect neutrophils directly by ADP ribosylating G i proteins associated with surface chemokine receptors, thereby inhibiting neutrophil migration in response to chemokines. However, in this study, by comparing responses to wild-type (WT) and PT-deficient strains, we found that PT has an indirect inhibitory effect on neutrophil recruitment to the airways in response to infection. Analysis of lung chemokine expression indicated that PT suppresses early neutrophil recruitment by inhibiting chemokine upregulation in alveolar macrophages and other lung cells in response to B. pertussis infection. Enhancement of early neutrophil recruitment to the airways in response to WT infection by addition of exogenous keratinocyte-derived chemokine, one of the dominant neutrophil-attracting chemokines in mice, further revealed an indirect effect of PT on neutrophil chemotaxis. Additionally, we showed that intranasal administration of PT inhibits lipopolysaccharide-induced chemokine gene expression and neutrophil recruitment to the airways, presumably by modulation of signaling through Toll-like receptor 4. Collectively, these results demonstrate how PT inhibits early inflammatory responses in the respiratory tract, which reduces neutrophil influx in response to B. pertussis infection, potentially providing an advantage to the pathogen in this interaction.

Attenuated Bordetella pertussis Vaccine Candidate BPZE1 Promotes Human Dendritic Cell CCL21-Induced Migration and Drives a Th1/Th17 Response

“…These results imply that PT, in addition to its role in bacterial colonization (32) and inhibition of an early inflammatory response (33), mediates an immune evasion mechanism that strongly interferes with DC functions. More importantly, these findings highlight a crucial difference between BPZE1 and BPSM and suggest that one of the main advantages that the vaccine strain may have in vivo is its capacity to rapidly and efficiently activate the acquired immune response by allowing the migration of DCs to lymph nodes.…”

Polymicrobial Interactions: Impact on Pathogenesis and Human Disease

“…One example of virulence factor sharing has been observed for Bordetella pertussis, the causative agent of whooping cough. B. pertussis encodes the 105-kDa A-B-type pertussis toxin, which it utilizes to deplete impending host innate immune responses encountered in the human respiratory tract (5). Bacterial superinfection with S. aureus, H. influenzae, or S. pneumoniae is quite common during and after infection with B. pertussis (188).…”

Coqueluche grave: Estado del arte

“…Asimismo la TP juega un rol importante en la promoción de infección en las vías respiratorias por la supresión y modulación de la respuesta inmune e inflamatoria del hospedero 44 . Se ha descrito que la TP retrasa el reclutamiento temprano de neutrófilos y su influjo a la vía aérea por inhibición de la up regulation de los genes que expresan citoquinas (KC, MIP-2 y LIX) 45 , inhibe la producción de anticuerpos séricos y a su vez reduce la capacidad de éstos para controlar la infección 46,47 y suprime la respuesta inmune adaptativa por efecto sobre diferentes células (monocitos, células dendríticas) 48,49 . Otros de los efectos de esta toxina es el bloqueo de los receptores α-2 adrenérgicos y los receptores dopaminérgicos (D2), responsable en parte de la resistencia a catecolaminas observada en los casos graves 50,51 .…”