Abstract
Human ficolin-2 (ficolin-2/P35) is a lectin complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during Mycobacterium tuberculosis (Mtb) infection. Here, we describe our novel findings that the ficolin-2 serum levels of 107 pulmonary tuberculosis (TB) patients were much lower compared with 107 healthy controls. In vitro analysis showed that ficolin-2 bound to the virulent Mtb H37Rv strain much more strongly than to the non-virulent M. bovis BCG and M. smegmatis. Ficolin-2 bound to the surface glycolipid portion of H37Rv and blocked H37Rv infection in human lung A549 cells. Opsonophagocytosis was also promoted by ficolin-2. Importantly, we found that administration of exogenous ficolin-2 had a remarkable protective effect against virulent Mtb H37Rv infection in both C57BL/6J and BALB/c mice. Ficolin-A (a ficolin-2-like molecule in mouse) knockout mice exhibited increased susceptibility to H37Rv infection. We further demonstrated that ficolin-2 could defend against virulent Mtb H37Rv infection at least partially by activating JNK phosphorylation and stimulating the secretion of interferon (IFN)-γ, interleukin (IL)-17, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide (NO) production by macrophages. Our data provide a new immunotherapeutic strategy against TB based on the innate immune molecule ficolin-2 and indicate that ficolin-2 insufficiency is associated with higher susceptibility to infection in humans.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Alveolar Epithelial Cells / drug effects
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Alveolar Epithelial Cells / metabolism
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Alveolar Epithelial Cells / microbiology
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Animals
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Case-Control Studies
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Cytokines / biosynthesis
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Disease Models, Animal
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Female
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Ficolins
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Genetic Predisposition to Disease
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Glycolipids / metabolism
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Humans
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Inflammation Mediators / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lectins / blood
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Lectins / genetics
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Lectins / metabolism*
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Lectins / pharmacology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / microbiology
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Male
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Membrane Lipids / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Middle Aged
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / metabolism
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Mycobacterium tuberculosis / pathogenicity*
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Nitric Oxide / biosynthesis
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Phosphorylation
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Protein Binding
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Tuberculosis / genetics
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Tuberculosis / metabolism*
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Tuberculosis / microbiology
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Tuberculosis / mortality
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Virulence
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Young Adult
Substances
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Cytokines
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Glycolipids
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Inflammation Mediators
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Lectins
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Membrane Lipids
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Nitric Oxide
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JNK Mitogen-Activated Protein Kinases
Grants and funding
This work was supported by grants from the National Special Fund of China for the Important Infectious Diseases (2012ZX10003002-015), the 973 Program of China (2009CB522507, 2012CB720604), National Natural Science Foundation of China (30921001, 30800038) and National Outstanding Youth Foundation of China (81025008, 81000714), the Program for Changjiang Scholars and Innovative Research Team in University, the 211 program (303-581045), the Science and Technology Program of Wuhan (201150530141) and 3551 plan, and SFB/Transregio TRR60. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.