Mentor: Nicholas Lukacs, PhD
Respiratory syncytial virus (RSV) is a ubiquitous human pathogen that produces severe lower respiratory disease in vulnerable individuals, characterized by lung infiltration of innate immune cells and a Th2-skewed adaptive immune response leading to excessive mucus production. RSV-associated bronchiolitis remains the leading cause of hospitalization among infants in the United States, and is responsible for considerable morbidity among patients who are elderly, immune compromised, and those with underlying chronic pulmonary illness. Pulmonary dendritic cells (DCs) direct innate and adaptive immune responses to viral pathogens through secretion of pro-inflammatory cytokines and type I interferon (IFN), as well as through migration and antigen presentation to T cells in lung-draining lymph nodes. In agreement with other studies of virally-infected DCs, work conducted by our laboratory has shown that macroautophagy (autophagy) facilitates TLR-dependent maturation and antigen-presenting cell (APC) function by RSV-infected DCs. The autophagic pathway and its constituent proteins are conversely known to antagonize other pattern recognition receptor (PRR) pathways such as RIG-like receptors (RLRs) and the NLRP3 inflammasome, suggesting a dual role as a negative regulator of inflammatory signaling. Through the use of Beclin-1 haploinsufficient mice and Map1-LC3b-deficient mice, which harbor defects in autophagosome formation, we intend to establish that autophagy within RSV-infected DCs promotes antiviral adaptive immune responses in vivo by driving TLR-mediated production of critical pro-inflammatory cytokines. Additionally, we are examining the antagonistic role of DC-associated autophagy on RLR and inflammasome signaling during RSV infection, and the impact this has on the development of lung pathology in response to RSV.
Bush SE, Kim D, Reed M, Clayton DH. Evolution of cryptic coloration in ectoparasites. Am Nat. 2010 Oct;176(4):529-35.
Gahring LC, Osborne AV, Reed M, Rogers SW. Neuronal nicotinic alpha7 receptors modulate early neutrophil infiltration to sites of skin inflammation.
Reed M, Morris S, Lukacs NW. Autophagy in dendritic cells modulates CD4+ T cell cytokine production during RSV infection. Oral and Poster presentation, American Association of Immunologists Immunology 2012. Boston MA, May 2012
8th Annual Int'l Respiratory Syncytial Virus Symposium Travel Grant, 2013