The aim of this proposal is to develop a novel immunotherapeutic that will prevent and treat potentially life- threatening infection with influenza virus. The proposal is based on the fact that mannose-binding lectin (MBL) is a broad-spectrum molecule of innate immunity. This serum protein recognizes a wide range of pathogens including viruses. Preliminary data indicate that 1) recombinant human MBL (rhMBL) neutralizes influenza virus, and 2) There is increased susceptibility to virus infection in mice lacking MBL. These observations support MBL as a strong candidate as an immunotherapeutic agent to treat influenza virus infection. A key goal of this project is first to evaluate clinical grade rhMBL that has been used in Phase I clinical studies, and second generation derivatives incorporating a part of L-ficolin, another lectin-like serum protein, that may have increased activity and increased pharmacologic properties. Preliminary studies demonstrate that these novel chimeric lectins bind mannan, the same carbohydrate that is expressed on influenza viruses and activate the lectin complement pathway. This grant proposal will leverage the infrastructure of the Program of Developmental Immunology at Massachusetts General Hospital, the extensive scientific experience of the investigators in the field of innate immunity and lung inflammation, the specialized resources and extensive scientific knowledge of the investigators in the field of influenza virus infection at the Department of Medicine at Boston University School of Medicine and the Department of Paediatrics &Adolescent Medicine and Microbiology at The University of Hong Kong and The Department of Medicine at Beth Israel Deaconess Medical Center and the product development expertise of Enzon, a US biotechnology company that acquired rights to produce recombinant lectin chimeras. We will evaluate the efficacy of rhMBL and lectin chimeras to activate the lectin complement pathway and to modulate phagocytic functions in vitro. We will also investigate the therapeutic potential of these lectins in mice genetically deficient for the MBL, complement component 3, ficolin-A (equivalent to human L-ficolin) or combinations these materials to elucidate the relative roles of each innate immune molecule in influenza virus infection. The goal is to develop a formulation of rhMBL or a derivative that could be used as prophylactic and/or therapeutic agetns against influenza virus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI074503-05
Application #
8133714
Study Section
Special Emphasis Panel (ZAI1-CCH-M (M2))
Program Officer
Krafft, Amy
Project Start
2007-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$929,766
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia et al. (2013) Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study. Virus Res 178:495-501
Ling, Man To; Tu, Wenwei; Han, Yan et al. (2012) Mannose-binding lectin contributes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection. J Infect Dis 205:44-53
Larvie, Mykol; Shoup, Timothy; Chang, Wei-Chuan et al. (2012) Mannose-binding lectin binds to amyloid ? protein and modulates inflammation. J Biomed Biotechnol 2012:929803
Takahashi, Kazue; Saha, Dalia; Shattino, Ivany et al. (2011) Complement 3 is involved with ventilator-induced lung injury. Int Immunopharmacol 11:2138-43
Michelow, Ian C; Lear, Calli; Scully, Corinne et al. (2011) High-dose mannose-binding lectin therapy for Ebola virus infection. J Infect Dis 203:175-9
Takahashi, Kazue; Chang, Wei-Chuan; Takahashi, Minoru et al. (2011) Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation. Immunobiology 216:96-102
Chang, Wei-Chuan; Hartshorn, Kevan L; White, Mitchell R et al. (2011) Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin. Biochem Pharmacol 81:388-95
Rohrer, Barbel; Coughlin, Beth; Kunchithapautham, Kannan et al. (2011) The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization. Mol Immunol 48:e1-8
Sebastian, Becky M; Roychowdhury, Sanjoy; Tang, Hui et al. (2011) Identification of a cytochrome P4502E1/Bid/C1q-dependent axis mediating inflammation in adipose tissue after chronic ethanol feeding to mice. J Biol Chem 286:35989-97
Takahashi, Kazue (2011) Mannose-binding lectin and the balance between immune protection and complication. Expert Rev Anti Infect Ther 9:1179-90

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