The central theme of the Program Project is to understand the innate host defense mechanisms against inhaled pathogens by the two pulmonary collectins, surfactant proteins A and D (SP-A, SP-D). This understanding is important not only in the context of prevalent respiratory infections but also those associated with serious global biothreats ? the emergence of antibiotic-resistant organisms;evolution and rapid spread of more lethal respiratory viruses;and potential use of inhaled pathogens in acts of bioterrorism. Effective pulmonary host defense requires early recognition of microorganisms. Following deposition of an organism into the respiratory tract, there is a critical window of opportunity for pathogen clearance;delayed response favors infection. The pulmonary collectins play a front-line role in the innate defense against many gram-negative and positive bacteria and their endotoxins, mycobacteria, pathogenic fungi, and obligate intracellular pathogens including influenza A (lAV) and other potentially lethal viruses. The innate defense properties of pulmonary collectins depend upon their rapid recognition and, in some cases, neutralization of inhaled microorganisms based on pattern recognition of highly-conserved microbial surface components such as N-linked high-mannose glycans on lAV and gram-negative lipolysaccharide (endotoxin). Other studies show that animals deficient in lung collectins show significantly increased susceptibility to microbiological challenges. Studies of recombinant truncated SP-A and SP-D in murine models of allergy and infection have offered the possibility that aerosolized forms of these proteins delivered by inhalation may have therapeutic potential in controlling respiratory infection, inflammation, and allergy in humans. In this program project, a highly collaborative and focused group of projects using complementary approaches, including x-ray crystallography, mutagenesis, spectroscopy, in vitro and in vivo analyses using animal models, aim specifically at innate responses of collectins, and proteins such as KGF that modulate their activity, to lAV and gram-negative bacteria both to gain mechanistic understanding and assist design of potential collectin-based therapeutics with increased antimicrobial activities. .

Public Health Relevance

The pulmonary collectins are at the front line of defense in protective mechanisms against inhaled pathogens such as influenza virus A (lAV) and gram-negative bacteria. As important innate host defense molecules, they provide a rapid and broad-spectrum immunological response that can be used against inhaled bioterror agents, highly virulent new or emerging microbial strains, and antibiotic resistant pathogens. Mechanistic information can be used in designing novel therapeutics based on aerosolized foms of these proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083222-02
Application #
7924146
Study Section
Special Emphasis Panel (ZAI1-EC-I (M2))
Program Officer
Leitner, Wolfgang W
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$1,938,284
Indirect Cost
Name
Boston University
Department
Physiology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
van Eijk, Martin; Rynkiewicz, Michael J; Khatri, Kshitij et al. (2018) Lectin-mediated binding and sialoglycans of porcine surfactant protein D synergistically neutralize influenza A virus. J Biol Chem 293:10646-10662
Rynkiewicz, Michael J; Wu, Huixing; Cafarella, Tanya R et al. (2017) Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop. Biochemistry 56:4095-4105
Nikolaidis, Nikolaos M; Noel, John G; Pitstick, Lori B et al. (2017) Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection. Proc Natl Acad Sci U S A 114:E6613-E6622
Goh, Boon Chong; Wu, Huixing; Rynkiewicz, Michael J et al. (2016) Elucidation of Lipid Binding Sites on Lung Surfactant Protein A Using X-ray Crystallography, Mutagenesis, and Molecular Dynamics Simulations. Biochemistry 55:3692-701
Tripathi, Shweta; White, Mitchell R; Hartshorn, Kevan L (2015) The amazing innate immune response to influenza A virus infection. Innate Immun 21:73-98
Tripathi, Shweta; Wang, Guangshun; White, Mitchell et al. (2015) Antiviral Activity of the Human Cathelicidin, LL-37, and Derived Peptides on Seasonal and Pandemic Influenza A Viruses. PLoS One 10:e0124706
White, Mitchell R; Kandel, Ruth; Tripathi, Shweta et al. (2014) Alzheimer's associated ?-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 9:e101364
Tripathi, Shweta; Verma, Anamika; Kim, Eun-Jeong et al. (2014) LL-37 modulates human neutrophil responses to influenza A virus. J Leukoc Biol 96:931-8
Nikolaidis, Nikolaos M; White, Mitchell R; Allen, Kimberly et al. (2014) Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses. Am J Physiol Lung Cell Mol Physiol 306:L1036-44
Tripathi, Shweta; Tecle, Tesfaldet; Verma, Anamika et al. (2013) The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol 94:40-9

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