Many viral infections are more severe in aged compared to young populations. This was strikingly illustrated in the 2002-2003 outbreak of the Severe Acute Respiratory Syndrome (SARS), in which >50% of patients who were over 60 year old died while no deaths occurred in those under 24 years. A nearly identical steep age dependence in susceptibility is also observed in mice infected with mouse-adapted strains of SARS-coronavirus (SARS-CoV), making this a useful model for identifying defects in the host immune response in aged mice. Our preliminary results suggest that migration of respiratory dendritic cells (rDC) to draining lymph nodes (DLN) is defective in aged SARS-CoV-infected mice, resulting in a poor anti-virus T cell response, poor virus clearance and increased lung damage as well as increased mortality. Pre-treatment with poly I:C reverses the increased morbidity and mortality observed in these aged infected mice. The central hypothesis of this proposal is that age-dependent changes in rDC function and subsequent T cell responses are critical for the poor outcomes observed in aged populations with respiratory virus infections. This objective will be approached in the following specific aims.
Aim 1. To determine the extent to which the defective T cell response in SARS-CoV- infected 12-14m mice is T cell-intrinsic. Defects in rDC migration to the DLN inhibit the generation of a robust T cell response, but this observation does not preclude additional T cell- intrinsic defects contributing to severe disease. This possibility will be investigated.
Aim 2. To investigate the basis and time of onset of rDC dysfunction in old mice. The goals of this aim will be to determine if additional defects in rDC function exist in SARS-CoV-infected aged mice and determine the basis of these defects. The mechanism of action of poly I:C, which is protective, will be investigated. Finally, age-dependent changes in the function of specific lipid mediators such as prostaglandin E2, which are critical for efficient rDC migration to DLN, will be analyzed.
Aim 3. To determine whether defective rDC function is common in aged mice infected with respiratory pathogens. A key goal of the proposal is to examine the generality of our results by determining whether rDC function and consequent anti-virus T cell responses are compromised in mice infected with other respiratory viruses, such as influenza A virus, respiratory syncytial virus or MHV-1, a pneumotropic murine coronavirus. Identification of rDC defects as critical in the increased susceptibility to viral respiratory infections will provide a novel therapeutic target in infected patients.
Disease severity is often more severe in patients with acute respiratory viral infections, including the infection caused by the Severe Acute Respiratory Syndrome-coronavirus (SARS-CoV). This project is based on new information showing that dendritic cell and T cell function are defective in aged mice infected with the SARS-CoV and possibly other respiratory viruses. Understanding and correcting these defects in animals with acute viral infections provides the basis for enhancing the immune response in the elderly.
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