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Elderly individuals are at increased risk of life-threatening pulmonary infections. Neutrophils are a key determinant of the disease course of pathogen-induced pneumonia. Optimal host defense balances initial robust pulmonary neutrophil responses to control pathogen numbers, ultimately followed by the resolution of inflammation to prevent pulmonary damage. Recent evidence suggests that phenotypic and functional heterogeneity in neutrophils impacts host resistance to pulmonary pathogens. Apart from their apparent role in innate immunity, neutrophils also orchestrate subsequent adaptive immune responses during infection. Thus, the outcome of pulmonary infections can be shaped by neutrophils. This review summarizes the age-driven impairment of neutrophil responses and the contribution of these cells to the susceptibility of the elderly to pneumonia. We describe how aging is accompanied by changes in neutrophil recruitment, resolution, and function. We discuss how systemic and local changes alter the neutrophil phenotype in aged hosts. We highlight the gap in knowledge of whether these changes in neutrophils also contribute to the decline in adaptive immunity seen with age. We further detail the factors that drive dysregulated neutrophil responses in the elderly and the pathways that may be targeted to rebalance neutrophil activity and boost host resistance to pulmonary infections.
24The elderly are susceptible to serious infections by Streptococcus pneumoniae 25 (pneumococcus), which calls for a better understanding of the pathways driving the 26 decline in host defense in aging. We previously found that extracellular adenosine (EAD) 27shaped polymorphonuclear cell (PMN) responses, which are crucial for controlling 28 infection. EAD is produced by CD39 and CD73, and signals via A1, A2A, A2B and A3 29 receptors. The objective of this study was to explore the age-driven changes in the EAD 30 pathway and its impact on PMN function. We found in comparison to young mice, PMNs 31 from old mice expressed significantly less CD73, but similar levels of CD39 and 32 adenosine receptors. PMNs from old mice failed to efficiently kill pneumococci ex vivo; 33 however, supplementation with adenosine rescued this defect. Importantly, transfer of 34 PMNs expressing CD73 from young mice reversed the susceptibility of old mice to 35 pneumococcal infection. To identify which adenosine receptor(s) is involved, we used 36 specific agonists and inhibitors. We found that A1 receptor signaling was crucial for 37 PMN function as inhibition or genetic ablation of A1 impaired the ability of PMNs from 38 young mice to kill pneumococci. Importantly, activation of A1 receptors rescued the age-39 associated defect in PMN function. In exploring mechanisms, we found that PMNs from 40 old mice failed to efficiently kill engulfed pneumococci and that A1 receptor controlled 41 intracellular killing. In summary, targeting the EAD pathway reverses the age-driven 42 decline in PMN antimicrobial function, which has serious implications in combating 43 infections. 44 45 46 47
Despite the availability of vaccines, Streptococcus pneumoniae (pneumococcus) remains a serious cause of infections in the elderly. The efficacy of anti-pneumococcal vaccines declines with age. While age-driven changes in antibody responses are well defined, less is known about the role of innate immune cells such as polymorphonuclear leukocytes (PMNs) in the reduced vaccine protection seen in aging. Here we explored the role of PMNs in protection against S. pneumoniae in vaccinated hosts. We found that depletion of PMNs in pneumococcal conjugate vaccine (PCV) treated young mice prior to pulmonary challenge with S. pneumoniae resulted in dramatic loss of host protection against infection. Immunization boosted the ability of PMNs to kill S. pneumoniae and this was dependent on bacterial opsonization by antibodies. Bacterial opsonization with immune sera increased several PMN anti-microbial activities including bacterial uptake, degranulation and ROS production. As expected, PCV failed to protect old mice against S. pneumoniae. In probing the role of PMNs in this impaired protection, we found that aging was accompanied by an intrinsic decline in PMN function. PMNs from old mice failed to effectively kill S. pneumoniae even when the bacteria were opsonized with immune sera from young controls. In exploring mechanisms, we found that PMNs from old mice produced less of the antimicrobial peptide CRAMP and failed to efficiently kill engulfed pneumococci. Importantly, adoptive transfer of PMNs from young mice reversed the susceptibility of vaccinated old mice to pneumococcal infection. Overall, this study demonstrates that the age-driven decline in PMN function impairs vaccine-mediated protection against Streptococcus pneumoniae.
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