Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis

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 and its components, such as virtual memory T cells which are prominent prior to the maturation of the thymus. Here, we examine the rapid change in susceptibility of young mice and 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 display significantly increased susceptibility to wild type Bp but very rapidly and effectively respond to and control Bp lacking PTx, more rapidly even than adult mice. Thus, PTx efficiently blocks some very effective form(s) of neonatal protective immunity, potentially providing a tool to better understand the neonatal immune system. The rapid clearance of the PTx mutant correlates with the early accumulation of neutrophils and T cells and suggests a role for PTx in disrupting their accumulation. These results demonstrate a striking age-dependent response to Bp, define an early age of extreme susceptibility to Bp, and demonstrate that the neonatal response can be more efficient than the adult response in eliminating bacteria from the lungs, but these neonatal functions are substantially blocked by PTx. This refined definition of “neonatal” mice may be useful in the study of other pathogens that primarily infect neonates, and PTx may prove a particularly valuable tool for probing the poorly understood neonatal immune system.

The Neonatal Immune System and Respiratory Pathogens

“…Additionally, they can be activated independently of antigens, instead rapidly expanding after cytokine signaling [ 21 , 69 ]. These are observed in highest amount at P8 and are greatly reduced by P10, suggesting they are a significant component of the neonatal immune system [ 70 ]. Neonatal mice also have populations of regulatory T cells (Tregs) which are primarily anti-inflammatory and produce TH2 cytokines and responses.…”

“…MDSCs (discussed above) have a primary role in T cell suppression [ 65 ]. Despite this, it was observed that P5 mice inoculated with a mutant of B. pertussis had an influx of neutrophils into the lungs, followed by T cells at 1 dpi (P6) [ 70 ]. However, it has also been observed that T cells are defective in migrating to neonatal alveolar spaces in lungs [ 28 ].…”

“…Some experiments have used neonatal mice to assess the specific response against B. pertussis [ 68 , 70 , 88 ]. These experiments suggest that, like human infants, neonatal mice are more susceptible to B. pertussis than adult mice are.…”

“…These experiments suggest that, like human infants, neonatal mice are more susceptible to B. pertussis than adult mice are. Neonatal mice and humans fail to control B. pertussis infection and suffer increased mortality and lung inflammation [ 68 , 70 ]. Neonatal mice also develop pulmonary hypertension, one of the primary causes of death of human infants with B. pertussis [ 108 , 109 ].…”

Making friends: active selection of symbionts and rejection of pathogens by the neonatal immune system

“…This apparent failure, and the later transition to a more adult-like immune system, support a common view that the neonatal immune system (NIS) is an incompletely developed version of the adult immune system. However, newer work suggests that rather than being simply deficient, the NIS has different, and in some cases more effective, responses than the adult immune system (AIS), with the potential for vigorous responses being more tightly controlled ( 1 , 2 ). These neonatal-specific responses, believed to prevent damaging inflammation, appear to contribute to the increased susceptibility of neonates to a subset of pathogens.…”