The Hospital for Sick Children Brampton, Ontario, Canada
Background: Recurrent and severe acute infections in severe malnutrition (SM) are associated with high morbidity and mortality in children under 5 in resource-poor settings. Impairments in innate immunological and metabolic processes underlies these adverse outcomes. Neutrophils, found to be increased in the circulation of children with SM, are first responder cells of the innate immune system that influence and regulate the inflammatory response for pathogen clearance through their large repertoire of effector functions. A plethora of metabolic processes mediates their diverse biological roles. However, little is known about their biology in malnourished conditions and the mechanism that can be exploited for immune-directed therapeutics requires further research. Objective: To investigate changes in neutrophil functions and determine the molecular mechanism underlying perturbed neutrophil responses in a mouse model of severe malnutrition. Design/Methods: Through various functional and molecular approaches in a lipopolysaccharide (LPS)- challenged low protein diet (LPD) mouse model, we investigated the impact of SM and acute inflammation on neutrophil biology. Results: Malnutrition disrupted neutrophil mitochondrial metabolism (p < 0.05) and total ATP generation (p < 0.05) that was associated with an impairment in the neutrophil differentiation cascade. This was assessed through gene expression of transcriptional factors (such as Cebpa, and Cebpe) mediating the neutrophil-specific developmental process. In turn, there was an accumulation of atypical immature neutrophils (p < 0.05) that were incapable of optimal antimicrobial functions, such as NADPH-oxidase ROS production and bacterial killing in the LPS-challenged malnourished host. In addition, these mice had exacerbated systemic pathogen spread, and permeability of the alveolocapillary membrane with resultant lung damage. This perturbed response may contribute to increased mortality risk in malnutrition.
Conclusion(s): This study points to a potential novel mechanism that could be targeted to boost neutrophil-mediated immunity and improve outcomes in childhood malnutrition.
