Extracellular adenosine signaling reverses the age‐driven decline in the ability of neutrophils to kill <i>Streptococcus pneumoniae</i>

Bhalla, Manmeet; Simmons, Shaunna R.; Abamonte, Alexsandra; Herring, Sydney E.; Roggensack, Sara E.; Ghanem, Elsa N. Bou

doi:10.1111/acel.13218

Cited by 21 publications

(77 citation statements)

References 43 publications

(115 reference statements)

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“…It is well known that PMN antibacterial function declines with age (8,9). We previously found that this could be recapitulated in mouse models where we observed a significant decrease in opsonophagocytic killing of S. pneumoniae by PMNs isolated from old mice compared to young controls (10). Strikingly, adoptive transfer of PMNs from young mice reversed the susceptibility of aged mice to pneumococcal pneumonia (10).…”

Section: Introductionsupporting

confidence: 65%

Transcriptome profiling reveals CD73 and age-driven changes in neutrophil responses againstStreptococcus pneumoniae

Bhalla

Heinzinger

Morenikeji

et al. 2021

Preprint

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Neutrophils are required for host resistance against Streptococcus pneumoniae but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is down-regulated in neutrophils from aged mice. This study explored transcriptional changes in neutrophils induced by S. pneumoniae to identify pathways controlled by CD73 and dysregulated with age. Ultrapure bone marrow-derived neutrophils isolated from wild type (WT) young, old, and CD73KO young mice were mock-challenged or infected with S. pneumoniae ex vivo. RNA sequencing was performed to identify differentially expressed genes (DEGs). We found that infection triggered distinct global transcriptional changes across hosts, that were strongest in CD73KO neutrophils. Surprisingly, there were more down-regulated than up-regulated genes in all groups upon infection. Down-regulated DEGs indicated a dampening of immune responses in old and CD73KO hosts. Further analysis revealed that CD73KO neutrophils expressed higher numbers of long non-coding RNAs (lncRNAs) compared to WT controls. Predicted network analysis indicated that CD73KO specific lncRNAs control several signaling pathways. We found that genes in the JNK-MAPK-pathway were up-regulated upon infection in CD73KO and WT old but not in young mice. This corresponded to functional differences, as phosphorylation of the downstream AP-1 transcription factor component c-Jun was significantly higher in infected CD73KO and old mice neutrophils. Importantly, inhibiting JNK/AP-1 rescued the ability of these neutrophils to kill S. pneumoniae. Altogether, our findings revealed that neutrophils modify their gene expression to better adapt to bacterial infection and that this capacity declines with age and is regulated by CD73.

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Section: Introductionsupporting

confidence: 65%

Transcriptome profiling reveals CD73 and age-driven changes in neutrophil responses againstStreptococcus pneumoniae

Bhalla

Heinzinger

Morenikeji

et al. 2021

Preprint

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“…We then compared the opsonic activity of sera from old mice. As PMNs function is known to decline with age and can confound the interpretation of the data (35, 49), we first measured the ability of sera isolated from old mice to elicit opsonophagocytic bacterial killing by PMNs isolated from young mice. We found that while sera from PCV13 immunized old mice failed to significantly improve bacterial killing by PMNs relative to Sham controls (Fig 5B), sera from LEPS vaccinated old mice elicited significantly higher opsonophagocytic killing by PMNs than both controls as well as the PCV13 group (Fig 5B).…”

Section: Resultsmentioning

confidence: 99%

“…Mice were infected with S. pneumoniae , as previously described (32, 35). Briefly, mice were intratracheally (i.t) challenged with either the serotype 4 (5 × 10 5 CFU) or 19F (2 × 10 7 CFU) strain of S. pneumoniae .…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, mice were intratracheally (i.t) challenged with either the serotype 4 (5 × 10 5 CFU) or 19F (2 × 10 7 CFU) strain of S. pneumoniae . Following infection with the S. pneumoniae serotype 4 strain, mice were monitored daily over 2 weeks for survival and clinical signs of disease (weight loss, activity level, posture, and breathing, scored healthy [0] to severely sick [21], as previously described (32, 35)) while bacteremia was determined for up to 72 hr post infection. In case of infection with the S. pneumoniae serotype 19F strain, mice were scored for clinical signs of disease at twenty-four hours post infection and euthanized to assess bacterial burden in the lung.…”

Section: Methodsmentioning

confidence: 99%

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Liposomal encapsulation of polysaccharides (LEPS) as an effective vaccine strategy to protect aged hosts against S. pneumoniae infection

Bhalla

Nayerhoda

Tchalla

et al. 2021

Preprint

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Despite the availability of licensed vaccines, pneumococcal disease caused by the bacteria Streptococcus pneumoniae (pneumococcus), remains a serious infectious disease threat globally. Disease manifestations include pneumonia, bacteremia, and meningitis, resulting in over a million deaths annually. Pneumococcal disease disproportionally impacts elderly individuals ≥65 years old. Interventions are complicated through a combination of complex disease progression and 100 different bacterial capsular polysaccharide serotypes. This has made it challenging to develop a broad vaccine against S. pneumoniae, with current options utilizing capsular polysaccharides as the primary antigenic content. However, current vaccines are substantially less effective in protecting the elderly. We previously developed a Liposomal Encapsulation of Polysaccharides (LEPS) vaccine platform, designed around limitations of current pneumococcal vaccines, that allowed the non-covalent coupling of polysaccharide and protein antigen content and protected young hosts against pneumococcal infection in murine models. In this study, we modified the formulation to make it more economical and tested the novel LEPS vaccine in aged hosts. We found that in young mice (2-3 months), LEPS elicited comparable responses to the pneumococcal conjugate vaccine Prevnar-13. Further, LEPS immunization of old mice (20-22 months) induced comparable antibody levels and improved antibody function compared to Prevnar-13. Importantly, LEPS protected old mice against both invasive and lung localized pneumococcal infections. In summary, LEPS is an alternative and effective vaccine strategy that protects aged hosts against different manifestations of pneumococcal disease.

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“…Immunosenescence, the overall dysregulation in immunity that occurs with age, drives the increased susceptibility of the elderly to invasive pneumococcal diseases and the linked decline in vaccine efficacy [98][99][100]. Several aspects of the age-related decline in adaptive immunity have been characterized [97,101,102].…”

Section: Pneumococcal Disease and The Elderlymentioning

confidence: 99%

Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease

et al. 2021

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This mini-review will cover recent trends in intranasal (IN) vaccine delivery as it relates to applications for respiratory tract diseases. The logic and rationale for IN vaccine delivery will be compared to methods and applications accompanying this particular administration route. In addition, we will focus extended discussion on the potential role of IN vaccination in the context of respiratory tract diseases, with a special emphasis on pneumococcal disease. Here, elements of this disease, including its prevalence and impact upon the elderly population, will be viewed from the standpoint of improving health outcomes through vaccine design and delivery technology and how IN administration can play a role in such efforts.

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Extracellular adenosine signaling reverses the age‐driven decline in the ability of neutrophils to kill Streptococcus pneumoniae

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 21 publications

References 43 publications

Transcriptome profiling reveals CD73 and age-driven changes in neutrophil responses againstStreptococcus pneumoniae

Transcriptome profiling reveals CD73 and age-driven changes in neutrophil responses againstStreptococcus pneumoniae

Liposomal encapsulation of polysaccharides (LEPS) as an effective vaccine strategy to protect aged hosts against S. pneumoniae infection

Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease

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