2008 AFAR Research Grant: Age-Dependent Toll-Like Receptor Dysfunction Increases Susceptibility to Pneumonia

Please give a brief summary of your AFAR research project.
Toll-like receptors (TLRs) are proteins on the cell surface that recognize microorganisms during an infection and initiate cell-signaling cascades that activate the innate immune system. Aging is associated with increased susceptibility to pneumonia; clinical observations suggest that the immune system of the elderly fails to respond during an infection. We hypothesize that age-dependent TLR dysfunction occurs in the lungs and contributes towards the susceptibility of the elderly to pneumonia. We will determine if TLR dysfunction occurs in the lungs of young, mature and aged mice.

What problems are you addressing and what specific questions will your research seek to answer?
Pneumonia in the elderly is characterized by its rapid onset, fulminate course, and high mortality rate. Despite access to antimicrobials and supportive critical care, the case-fatality rate for individuals >65 years of age is 15-25%. At this time, little information is known regarding how advanced age affects the ability of a person to detect an infection. This is despite the abundance of clinical evidence that suggests that this process is dysfunctional. We will determine the effects of aging on TLR and TLR associated cell signaling protein levels in the lungs. We will determine the ability of these proteins to transmit intracellular signals that lead to cell activation during pneumonia.

What aspects of your project are most interesting from a scientific point of view?
An age-dependent decline in the immune response has been reported in the literature since 400 BC. Hippocrates, in his 'Aphorisms', noted that "the fevers of old men are less acute than others, for the body is cold". Since Hippocrates, many other investigators have confirmed that the elderly do respond with a vigorous immune response during infection and have begun to examine the molecular mechanisms that are responsible for this age-associated lapse. It is now evident that aging is associated with TLR dysfunction. Age-related changes in TLR expression, TLR signaling, and TLR dependent induction of pro-inflammatory cytokines has been reported by several investigators. Importantly, the impact of age-dependent TLR dysfunction in the lungs is unknown. ADTD in the lungs may help explain: 1) why the elderly have a greater incidence of pneumonia; 2) why pneumonia is more severe in the elderly and is associated with a high case-fatality rate; 3) why 10% of the elderly with pneumonia show no overt clinical signs of infection such as fever, cough and dyspnea, all symptoms of lung inflammation; and, 4) why lack of fever in the elderly with pneumonia is a prognostic indicator of a poor clinical outcome. This proposal will investigate ADTD and determine its impact in the lungs during pneumonia.

What are the implications of your research for age-related diseases and disorders?
In the United States 35 million people are >65 years of age and are susceptible to pneumonia. Completion of this proposal will expand our understanding of TLR dysfunction to include the respiratory tract, alveolar macrophages, mucosal epithelial cells, and infection with S. pneumoniae, the leading cause of CAP. Findings identified by this study may serve as the basis for preventive medicine and/or improved pharmacological intervention. This project will examine the effects of age-related changes on functional disease outcomes.

Return to 2008 AFAR Grantees