The Age-Driven Decline in Neutrophil Function Contributes to the Reduced Efficacy of the Pneumococcal Conjugate Vaccine in Old Hosts

Abstract

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.

Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling

“…To determine if mitochondrial ROS were important for the antimicrobial function of PMNs, we treated PMNs with MitoTEMPO and measured the ability of PMNs to kill S . pneumoniae TIGR4 strain using an established opsonophagocytic (OPH) killing assay [ 2 , 12 , 32 – 34 , 49 ]. We found that treatment with MitoTEMPO lead to a complete abrogation of bacterial killing by PMNs ( Fig 4A ).…”

“…On the other hand, infection of macrophages with S. aureus results in mitochondrial-derived vesicles containing anti-bacterial hydrogen peroxide that localize with bacterial containing phagosomes [16]. S. pneumoniae are extracellular bacteria that are killed very efficiently once engulfed by PMNs [34,49]. However, the dynamics of MitROS production by PMNs and their compartmentalization with the cell remain open questions and will be the focus of future studies in our laboratory.…”

Mitochondrial ROS production by neutrophils is required for host antimicrobial function againstStreptococcus pneumoniaeand is controlled by A2B adenosine receptor signaling

“…We previously found that scavenging/ detoxifying ROS completely abrogates the ability of PMNs to kill S. pneumoniae [12]. To determine if mitochondrial ROS were important for the antimicrobial function of PMNs, we treated PMNs with MitoTEMPO and measured the ability of PMNs to kill S. pneumoniae TIGR4 strain using an established opsonophagocytic (OPH) killing assay [2, 12, 32–34, 49]. We found that treatment with MitoTEMPO lead to a complete abrogation of bacterial killing by PMNs (Fig.…”

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

“…A recent study conducted in animal models has shown that the aging process impairs vaccine-mediated protection against S. pneumoniae due to the impaired ability of neutrophils to kill the bacteria, even when they were opsonized with immune sera from young controls [ 31 ]. In the increased incidence/development of cancer in older people, neutrophils appear to play an immunosuppressive role, interfering with the normal process of immune surveillance against cancer-associated antigens [ 32 ].…”