Insights Into the Effects of Mucosal Epithelial and Innate Immune Dysfunction in Older People on Host Interactions With Streptococcus pneumoniae

Abstract

In humans, nasopharyngeal carriage of Streptococcus pneumoniae is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together, these kill over 500,000 people over the age of 70 years worldwide every year. Pneumococcal conjugate vaccines have been largely successful in reducing IPD in young children and have had considerable indirect impact in protection of older people in industrialized country settings (herd immunity). However, serotype replacement continues to threaten vulnerable populations, particularly older people in whom direct vaccine efficacy is reduced. The early control of pneumococcal colonization at the mucosal surface is mediated through a complex array of epithelial and innate immune cell interactions. Older people often display a state of chronic inflammation, which is associated with an increased mortality risk and has been termed 'Inflammageing'. In this review, we discuss the contribution of an altered microbiome, the impact of inflammageing on human epithelial and innate immunity to S. pneumoniae, and how the resulting dysregulation may affect the outcome of pneumococcal infection in older individuals. We describe the impact of the pneumococcal vaccine and highlight potential research approaches which may improve our understanding of respiratory mucosal immunity during pneumococcal colonization in older individuals.

Keywords: epithelium; inflammageing; innate immunity; older individuals; pneumococcus (Streptococcus pneumoniae).

Figure 1

The impact of pneumococcal infection on mucosal immunity in older individuals. The human respiratory epithelium includes many cell types all of which contribute to the development of innate immunity through a physical barrier held together by junctional proteins, and a chemical barrier via secretions of mucus, cytokines, chemokines, antimicrobial peptides, vitamin D and retinoic acid. Innate immune cells such as monocytes, neutrophils and MAIT cells are also present in the mucosa. In older individuals, there is a loss of physical movement both at a mechanical elasticity level and a lack of cilia beating which impacts on mucus clearance. This contributes towards increased prevalence of luminal factors such as cell debris, secreted factors, microbiota and pathogens such as S. pneumoniae which trigger already elevated baseline levels of cytokines such as IL-6, IL-8 and TNFα. In younger adults, epithelial-derived secretion of anti-microbial peptides such as cathelicidin and NFκB activation, leads to autophagy. Impaired autophagy and type 1 interferon responses in older individuals may lead to suppressed IFNβ levels, increasing pneumococcal load. Increased expression of epithelial senescence markers and pneumococcal ligands such as PAFr in older people enhances pneumococcal colonization, influencing adhesion, micro-invasion and transmigration potential. Vitamin D deficiency in older people may affect epithelial barrier integrity. In younger adults, disruption to barrier function after pneumococcal infection affected the expression of junctional proteins such as Claudins. In older adults, dysregulation of barrier may enhance rates of pneumococcal transmigration, infiltration of innate immune cells and inflammation. Although MAIT cells are rare in the airway of older individuals, neutrophil prevalence is enhanced, which elevates degranulation and reactive oxygen species levels following pneumococcal infection. However, neutrophil ability for opsonophagocytosis and chemotaxis is impaired in older individuals. Monocyte function may also be impaired in signal transduction and secrete less IL-6, IL-8 and TNFα during infection, in comparison to younger adults. PNE cell, pulmonary neuroendocrine cell; AMP, anti-microbial peptides. Created with Biorender.com.