Pertussis, caused by Bordetella pertussis, is a reemerging disease of major public health concern. Pertussis severity is age-related, with B. pertussis causing severe manifestations that are unique to young infants and not observed at an older age. These infants are at increased risk of cardiopulmonary failure and death from B. pertussis-induced pulmonary hypertension (PH). Age-related differences in disease severity indicate that host responses to B. pertussis differ with age. The causal mechanism for PH in severe pertussis is unknown and there are currently no effective therapeutic interventions for the treatment of pertussis-associated PH or death. The study proposed here aims to address this critical gap in knowledge, providing mechanistic information and validating the use of potentially novel therapeutics for pertussis. PH-associated cardiac dysfunction is initiated by remodeling of pulmonary arteries, but how does B. pertussis cause this remodeling? And, why is this function age-related? In unpublished and preliminary studies, B. pertussis was found to induce activation of the renin-angiotensin system (RAS) in the lungs of infant mice but not adult mice and pertussis toxin (PT) expression was required for B. pertussis-induced PH in infant mice. The RAS is one of the most important and best-studies systems in the pathogenesis of hypertension but has not been linked to infection-induced PH. The proposed experiments will test the hypothesis that high RAS activity in the infant lung and PT-mediated inhibition of a protective component of this system cause pathogenic RAS signaling and initiates pathologies that drive the onset of PH. Critical points of regulation in the RAS include the formation and degradation of angiotensin II (ANGII) by angiotensin-converting enzyme (ACE) and ACE2 respectively and ANGII signaling via AT1 and AT2 receptors to mediate opposing actions that may be pathogenic (AT1, vasoconstriction and proliferation) or protective (AT2, vasodilation and anti-proliferative) in our system. Preliminary data also shows that 1) basal pulmonary ANGII levels are higher in infants than adults, 2) B. pertussis downregulates expression of the angiotensin precursor gene Agt in adult lungs but increases expression in infant lungs, 3) B. pertussis downregulates ACE in adult lungs but not infant lungs and 4) basal expression of AT2 is significantly greater in infant lungs than adult lungs. These data indicate that, in infants, high AT2 levels are required to limit the effect of excessive ANGII signaling through AT1. However, AT2, but not AT1, is susceptible to PT-mediated inhibition, hence PT produced during infection would have a greater impact on ANGII signaling in infants than it would in adults.
In aim 1, the age-related effect of B. pertussis on ANGII peptide accumulation and ACE and ACE2 activity will be examined. Age-related expression of AT2 will also be determined and the effect of infection of AT2 activity will be tested.
In aim 2, the contribution of the RAS and PT-mediated inhibition of AT2 on B. pertussis-induced PH and death will be resolved. If our hypothesis is correct, RAS-targeting therapeutics may save the lives of young infants with severe pertussis.
Bordetella pertussis kills more than 160 000 children each year, with fatal outcomes associated with young age and the manifestation of pulmonary hypertension. We have identified age-related differences in the renin-angiotensin system that may potentiate B. pertussis-induced pulmonary hypertension. This research will provide new fundamental knowledge on age-related regulation of the renin-angiotensin system, in addition to furthering our understanding of the mechanism of B. pertussis-induced pulmonary hypertension and identifying novel therapeutics that could improve the health and survival of B. pertussis-infected infants.