Abstract
Severe Acute Respiratory Syndrome caused substantial morbidity and mortality during the 2002–2003 epidemic. Many of the features of the human disease are duplicated in BALB/c mice infected with a mouse-adapted version of the virus (MA15), which develop respiratory disease with high morbidity and mortality. Here, we show that severe disease is correlated with slow kinetics of virus clearance and delayed activation and transit of respiratory dendritic cells (rDC) to the draining lymph nodes (DLN) with a consequent deficient virus-specific T cell response. All of these defects are corrected when mice are treated with liposomes containing clodronate, which deplete alveolar macrophages (AM). Inhibitory AMs are believed to prevent the development of immune responses to environmental antigens and allergic responses by interacting with lung dendritic cells and T cells. The inhibitory effects of AM can also be nullified if mice or AMs are pretreated with poly I:C, which directly activate AMs and rDCs through toll-like receptors 3 (TLR3). Further, adoptive transfer of activated but not resting bone marrow–derived dendritic cells (BMDC) protect mice from lethal MA15 infection. These results may be relevant for SARS in humans, which is also characterized by prolonged virus persistence and delayed development of a SARS-CoV-specific immune response in individuals with severe disease.
Highlights
The lung is exposed to many challenges, both environmental and pathogenic
clodronate-filled liposomes (CL) are useful for depletion of Alveolar macrophages (AM), and to a lesser extent, alveolar/airway DCs [9], but intranasal administration does not affect the level of circulating macrophages
BALB/c mice were treated with 75 ml of CL or phosphate buffered saline (PBS) intranasally (i.n.) and total lung cells were harvested after enzymatic digestion
Summary
The lung is exposed to many challenges, both environmental and pathogenic Defense of this portal must be tightly regulated so that appropriate immune responses to pathogens are mounted but responses to innocuous antigens are minimized. Resident AMs are continuously encountering inhaled substances due to their exposed position in the alveolar lumen, but they are kept in a quiescent state. They function poorly as accessory cells for in vitro T cell activation [4,5] and in many situations actively suppress the induction of adaptive immunity through their effects on alveolar and interstitial DCs and T cells [6,7,8]. It has been estimated that the pool of murine alveolar macrophages can process up to 109 intratracheally injected bacteria before there is ‘‘spillover’’ of bacteria to DCs and before adaptive immunity is induced [10]
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