Age-Associated Changes in the Respiratory Epithelial Response to Influenza Infection

Abstract

Older adults suffer a disproportionate burden of influenza-related morbidity and mortality typically attributed to defects in the aging immune system collectively known as immunosenescence. While the age-related decline in the adaptive immune system has been well characterized, little is known about how aging affects the principal site of influenza infection-the nasal epithelium. In human nasal epithelial cell cultures (hNECs) from older adults, we found similar or increased levels of cytokines during influenza infection compared with hNECs from younger individuals. However, hNECs from older individuals demonstrated decreased mRNA expression for several key proteins that affect clearance of infected cells, including MHC-I and transporter associated with antigen presentation (TAP). These findings were confirmed at the level of protein expression. In vivo studies corroborated the in vitro differences in MHC-I and TAP gene expression and also revealed important decreases in the expression of key influenza-specific antiviral mediators MX1 and IFITM1. Furthermore, epithelial cell-cytotoxic T lymphocyte co-cultures demonstrate that CTL cytotoxic activity is dose-dependent on MHC-I antigen presentation. Taken together, these results indicate that aging is associated with important changes in the nasal epithelium, including antigen presentation and antiviral pathways, which may contribute to increased severity of disease in older adults through impaired clearance of infected cells.

Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives

“…How this vaccine performs in older adults has not been tested yet. These results will be interesting since in aged individuals the response to influenza in respiratory epithelial cells is lower with respect to antigen processing and presentation (187).…”

New Approach Methods to Evaluate Health Risks of Air Pollutants: Critical Design Considerations for In Vitro Exposure Testing

“…Advantages of using cells collected from humans include the ability to perform analyses on a specific subpopulation of interest. For example, our research group has evaluated primary differentiated human nasal epithelial cells obtained from volunteers, selecting according to different age groups (i.e., between the ages of 20-27 and 55+) [67]. These data provide insight for important age-associated differences between epithelial responses to air pollutants [67].…”

“…For example, our research group has evaluated primary differentiated human nasal epithelial cells obtained from volunteers, selecting according to different age groups (i.e., between the ages of 20-27 and 55+) [67]. These data provide insight for important age-associated differences between epithelial responses to air pollutants [67]. Obtaining cells from human donors also allows for the identification of toxicity responses and trends in disease susceptibility that may be dependent upon sex (i.e., sexually dimorphic).…”

“…For instance, increased expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been found in nasal epithelial cells derived from males exposed to ozone, while this trend was not apparent in females [68]. A potential limitation surrounding the use of cells from human donors includes the identification of study participants that meet specific study inclusion criteria at high enough enrollment rates, ensuring study feasibility [67]. Cells from donors can also exhibit limited life spans in comparison to cell lines [49].…”

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

“…These deposits also increase the prevalence of atherosclerosis and coronary artery disease in the elderly, severely affecting the cardiovascular system (Hansson, 2005). Alongside the respiratory and genito-urinary systems show reduced function with age as well as decreased immune function, leading to increased infection rates in the elderly (Kline and Bowdish, 2016; Nicolle, 2016; Chason et al, 2018). This suggests that several compartments of the immune system, including mucosal immunity, are altered in old age (Sala-Rabanal et al, 2015; Martelli et al, 2016).…”