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L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo.

ABSTRACT: 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.

SUBMITTER: Pan Q

PROVIDER: S-EPMC6741490 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo.

Pan Qin Q Chen Haidan H Wang Feng F Jeza Victor Tunje VT Hou Wei W Zhao Yinglan Y Xiang Tian T Zhu Ying Y Endo Yuchi Y Fujita Teizo T Zhang Xiao-Lian XL

Journal of innate immunity 20120302 3

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 - ...[more]

PMID: 22399010

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Project description:Influenza virus hemagglutinin (HA) N-glycans play important regulatory roles in the control of virus virulence, antigenicity, receptor-binding specificity, and viral escape from the immune response. Considered essential for controlling innate and adaptive immune responses against influenza virus infections, dendritic cells (DCs) trigger proinflammatory and adaptive immune responses in hosts. In this study, we engineered Chinese hamster ovary (CHO) cell lines expressing recombinant HA from pandemic H1, H5, and H7 influenza viruses. rH1HA, rH5HA, and rH7HA were obtained as wild-type proteins or in the presence of kifunensine (KIF) or further with endo-?-N-acetylglucosaminidase-treated KIF (KIF+E) to generate single-N-acetylglucosamine (GlcNAc) N-glycans consisting of (i) terminally sialylated complex-type N-glycans, (ii) high-mannose-type N-glycans, and (iii) single-GlcNAc-type N-glycans. Our results show that high-mannose-type and single-GlcNAc-type N-glycans, but not complex-type N-glycans, are capable of inducing more active hIL12 p40, hIL12 p70, and hIL-10 production in human DCs. Significantly higher HLA-DR, CD40, CD83, and CD86 expression levels, as well reduced endocytotic capacity in human DCs, were noted in the high-mannose-type rH1HA and single-GlcNAc-type rH1HA groups than in the complex-type N-glycan rH1HA group. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). The high-mannose-type or single-GlcNAc-type N-glycans of both avian and human HA types are more stimulatory than the complex-type N-glycans. HA-stimulated DC activation was accomplished partially through a mannose receptor(s). These results provide more understanding of the contribution of glycosylation of viral proteins to the immune responses and may have implications for vaccine development.Influenza viruses trigger seasonal epidemics or pandemics with mild-to-severe consequences for human and poultry populations. DCs are the most potent professional antigen-presenting cells, which play a crucial role in the link between innate and adaptive immunity. In this study, we obtained stable-expression CHO cells to produce rH1HA, rH5HA, and rH7HA proteins containing distinct N-glycan patterns. These rHA proteins, each with a distinct N-glycan pattern, were used to investigate interactions with mouse and human DCs. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). High-mannose-type and single-GlcNAc-type N-glycans were more effective than complex-type N-glycans in triggering mouse and human DC activation and maturation. We believe these results provide some useful information for influenza vaccine development regarding how influenza virus HA proteins with different types of N-glycans activate DCs.

Project description:UNLABELLED:Paramyxoviruses, enveloped RNA viruses that include human parainfluenza virus type 3 (HPIV3), cause the majority of childhood viral pneumonia. HPIV3 infection starts when the viral receptor-binding protein engages sialic acid receptors in the lung and the viral envelope fuses with the target cell membrane. Fusion/entry requires interaction between two viral surface glycoproteins: tetrameric hemagglutinin-neuraminidase (HN) and fusion protein (F). In this report, we define structural correlates of the HN features that permit infection in vivo. We have shown that viruses with an HN-F that promotes growth in cultured immortalized cells are impaired in differentiated human airway epithelial cell cultures (HAE) and in vivo and evolve in HAE into viable viruses with less fusogenic HN-F. In this report, we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion triggering and directly impact infection. Crystal structures of HN, which promotes viral growth in vivo, show a diminished interface in the HN dimer compared to the reference strain's HN, consistent with biochemical and biological data indicating decreased dimerization and decreased interaction with F protein. The crystallographic data suggest a structural explanation for the HN's altered ability to activate F and reveal properties that are critical for infection in vivo. IMPORTANCE:Human parainfluenza viruses cause the majority of childhood cases of croup, bronchiolitis, and pneumonia worldwide. Enveloped viruses must fuse their membranes with the target cell membranes in order to initiate infection. Parainfluenza fusion proceeds via a multistep reaction orchestrated by the two glycoproteins that make up its fusion machine. In vivo, viruses adapt for survival by evolving to acquire a set of fusion machinery features that provide key clues about requirements for infection in human beings. Infection of the lung by parainfluenzavirus is determined by specific interactions between the receptor binding molecule (hemagglutinin-neuraminidase [HN]) and the fusion protein (F). Here we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion and directly impact infection. The crystallographic and biochemical data point to a structural explanation for the HN's altered ability to activate F for fusion and reveal properties that are critical for infection by this important lung virus in vivo.

Dataset Information

L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo.

Publications

L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo.

Similar Datasets

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