Files
Abstract
The increased susceptibility of neonates to specific pathogens has previously been attributed to an underdeveloped immune system. More recent data suggest neonates have effective protection against most pathogens but are particularly susceptible to those that target immune functions specific to neonates. Bordetella pertussis (Bp), the causative agent of “whooping cough”, causes more serious disease in infants attributed to its production of pertussis toxin (PTx), although the neonate-specific immune functions it targets remain unknown. Problematically, the rapid development of adult immunity in mice has confounded our ability to study interactions of the neonatal immune system. Here, we define a period from five- to eight-days-old during which mice are much more susceptible to Bp than mice even a couple days older. These more narrowly defined “neonatal” mice effectively respond to and control Bp∆ptx, more rapidly even than adult mice. This clearance correlates with the early accumulation of neutrophils and T cells and suggests a role for PTx in disrupting their accumulation. Upon further examination, we observed that depleting neutrophils inhibited pups’ ability to rapidly clear Bp∆ptx, revealing a critical role for neutrophils. Pups deficient in complement (C3-/-) failed to recruit neutrophils and did not efficiently clear Bp∆ptx but recovered these abilities upon treatment with C3a. Additionally, one of the most important aspects of this susceptibility is the transition from neonatal to perinatal immune responses. This process is primarily driven by thymus development and the T cells generated; however, the true importance of these stages in disease response is poorly understood. Here, we utilize two complementary models of disrupted thymic development to assess the effects of different thymic development stages on responses to Bp. Utilizing a genetic model of disrupted thymic development, we show that post-birth thymus development is required to respond to and control Bp. With a complementary surgical model, mice thymectomized at P0 and P7 had substantially different T cell responses to Bp, with the later demonstrating an early CD8 response associated with more rapid control. These results suggest the NIS can be effective at particular stages, but these responses are severely disrupted by PTx.