Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors

Brudner, Matthew, Karpel, Marshall, Lear, Calli M, Chen, Li, Yantosca, Louis M, Scully, Corinne, Sarraju, Ashish, Sokolovska, Anna, Zariffard, M. Reza, Eisen, Damon, Mungall, Bruce A., Kotton, Darrell N., Omari, Amel, Huang, I-Chueh, Farzan, Michael, Takahashi, Kazue, Stuart, Lynda, Stahl, Gregory L., Ezekowitz, Alan B., Spear, Gregory T., Olinger, Gene G., Schmidt, Emmett V., and Michelow, Ian C. (2013) Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors. PLoS ONE, 8 (4). e60838.

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Abstract

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.

Item ID: 51431
Item Type: Article (Research - C1)
ISSN: 1932-6203
Additional Information:

2013 Brudner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funders: National Institute of Health (NIH), USA, Department of Defence (DoD), USA
Projects and Grants: NIH Grant U01 AI070330, DoD Grants 4.10006, DoD Grants 4.10007
Date Deposited: 05 Nov 2017 23:53
FoR Codes: 06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110309 Infectious Diseases @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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