Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin

Chang, Wei‐Chuan; Hartshorn, Kevan L.; White, Mitchell R.; Moyo, Patience; Michelow, Ian C.; Koziel, Henry; Kinane, Bernard; Schmidt, Emmett V.; Fujita, Teizo; Takahashi, Kazue

doi:10.1016/j.bcp.2010.10.012

Cited by 32 publications

(42 citation statements)

References 51 publications

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“…Chang et al [38] showed that recombinant chimeric lectins, consisting of an L-ficolin collagen domain and an MBL carbohydrate recognition domain, triggered a dose-dependent activation of the lectin complement pathway in the presence of influenza A virus, an observation that is consistent with our results.…”

Section: Discussionsupporting

confidence: 82%

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

Pan¹,

Chen²,

Wang³

et al. 2012

J Innate Immun

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L-ficolin, one of the complement lectins found in human serum, is a novel pattern recognition molecule that can specifically bind to microbial carbohydrates, thereby activating the lectin complement pathway and mounting a protective innate immune response. However, little is known about the role of L-ficolin during viral infections in vivo. In the present study, we used a mouse model of influenza A virus infection to demonstrate that the administration of exogenous L-ficolin or ficolin A (FCNA – an L-ficolin-like molecule in the mouse) is protective against the virus. Furthermore, FCNA-null mice have a greatly increased susceptibility to infection with the influenza A virus. Moreover, we found recombinant human L-ficolin inhibited influenza A virus entry into Madin-Darby canine kidney cells. More importantly, L-ficolin can recognize and bind hemagglutinin (HA) and neuraminidase (NA) glycoproteins and different subtypes of influenza A virus, and these interactions can be competitively inhibited by N-acetyl-D-glucosamine. In addition, the binding of L-ficolin and FCNA may lead to the activation of the lectin complement pathway. To our knowledge, this is the first report demonstrating that L-ficolin can block influenza virus infections both in vitro and in vivo using FCNA-knockout mice, possibly by interacting with the carbohydrates of HA and NA. Therefore, these data may provide new immunotherapeutic strategies based on the innate immune molecule L-ficolin against the influenza A virus.

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Section: Discussionsupporting

confidence: 82%

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

Pan¹,

Chen²,

Wang³

et al. 2012

J Innate Immun

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“…Three ficolins have been identified in human serum and have been quantified to be present at levels of about 5 g/ml (ficolin-2 or L-ficolin), 18 g/ml (ficolin-3 or H-ficolin), and 1 g/ml (ficolin-1 or M-ficolin), with the last value being close to that of circulating MBL (1.2 g/ml) (37)(38)(39)(40). There are few reports concerning virus recognition by ficolins, apart from the interaction of L-ficolin with hepatitis C and influenza A virus surface glycoproteins (41)(42)(43)(44).…”

Section: Importancementioning

confidence: 99%

Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein

Favier¹,

Gout

Reynard

et al. 2016

J Virol

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Ebola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system. E bola virus (EBOV), a member of the Filoviridae family, can cause a severe, often fatal, hemorrhagic fever (HF) in humans and nonhuman primates (1). The first Ebolavirus species was discovered in 1976 in the Democratic Republic of Congo (previously called Zaire), near the Ebola River (2). Subsequently, 28 outbreaks appeared sporadically until March 2014, when the most devastating outbreak occurred in western Africa, including the countries of Guinea, Liberia, and Sierra Leone (3-6). Most outbreaks are caused by the Zaire Ebola virus subspecies (7), which is the most pathogenic (case fatality rate, up to 90%). EBOV is classified in the category A agents of the Centers for Disease Control and Prevention (CDC) because it represents a substantial threat to public health, and consequently, its handling requires a biosafety level 4 (BSL-4) laboratory. The development of effective therapies against EBOV became an urgent priority during the spread of the most recent epidemics throughout Africa, which, in addition to causing the loss of thousands of human lives, caused economic and social instability (8).The trimeric transmembrane glycoprotein (GP) of EBOV plays a crucial role in EBOV infection by mediating its cellular attachment and entry into host cells (9, 1...

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“…In an attempt to reduce complications with the coagulation system, MBL derivatives have been produced. One such agent is recombinant chimeric lectin 4 (RCL4), a derivative of MBL in which the collagen-like domain of MBL is replaced with that of L-ficolin [7,140]. RCL4 is at least tenfold more efficient in activating the lectin complement pathway while it is significantly weaker in promoting thrombin-like activity [7].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

“…One such agent is recombinant chimeric lectin 4 (RCL4), a derivative of MBL in which the collagen-like domain of MBL is replaced with that of L-ficolin [7,140]. RCL4 is at least tenfold more efficient in activating the lectin complement pathway while it is significantly weaker in promoting thrombin-like activity [7]. Recent investigations in our laboratory demonstrate that RCL4 is more efficient than MBL in reducing infection with viruses, including influenza A, Ebola and Nipah [7,140].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

“…RCL4 is at least tenfold more efficient in activating the lectin complement pathway while it is significantly weaker in promoting thrombin-like activity [7]. Recent investigations in our laboratory demonstrate that RCL4 is more efficient than MBL in reducing infection with viruses, including influenza A, Ebola and Nipah [7,140]. Further research in this direction will improve our understanding of the interaction and coordination of the complement and coagulation systems and may yield agents that could have roles in protection from infection and possibly in correction of coagulopathy.…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

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Mannose-binding lectin and the balance between immune protection and complication

Takahashi¹

2011

Expert Review of Anti-infective Therapy

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The innate immune system is evolutionarily ancient and biologically primitive. Historically, it was first identified as an element of the immune system that provides the first-line response to pathogens, and increasingly it is recognized for its central housekeeping role and its essential functions in tissue homeostasis, including coagulation and inflammation, among others. A pivotal link between the innate immune system and other functions is mannose-binding lectin (MBL), a pattern recognition molecule. Multiple studies have demonstrated that MBL deficiency increases susceptibility to infection, and the mechanisms associated with this susceptibility to infection include reduced opsonophagocytic killing and reduced activation of the lectin complement pathway. Results from our laboratory have demonstrated that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3-deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus-infected MBL null mice developed disseminated intravascular coagulation, which was associated with elevated blood IL-6 levels (but not TNF-α) and systemic inflammatory responses. Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection. Beginning from these observations, this review focuses on the interaction of innate immunity and other homeostatic systems, the derangement of which may lead to complications in infection and other inflammatory states.

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Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin

Cited by 32 publications

References 51 publications

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

L-Ficolin Binds to the Glycoproteins Hemagglutinin and Neuraminidase and Inhibits Influenza A Virus Infection Both in vitro and in vivo

Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein

Mannose-binding lectin and the balance between immune protection and complication

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