title: Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors.
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.
authors.affiliation: Programs of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brudner
authors.forename: Marshall
authors.initials: M
authors.lastname: Karpel
authors.forename: Calli
authors.initials: C
authors.lastname: Lear
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: L Michael
authors.initials: LM
authors.lastname: Yantosca
authors.forename: Corinne
authors.initials: C
authors.lastname: Scully
authors.forename: Ashish
authors.initials: A
authors.lastname: Sarraju
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolovska
authors.forename: M Reza
authors.initials: MR
authors.lastname: Zariffard
authors.forename: Damon P
authors.initials: DP
authors.lastname: Eisen
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Mungall
authors.forename: Darrell N
authors.initials: DN
authors.lastname: Kotton
authors.forename: Amel
authors.initials: A
authors.lastname: Omari
authors.forename: I-Chueh
authors.initials: IC
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.forename: Lynda
authors.initials: L
authors.lastname: Stuart
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.forename: Alan B
authors.initials: AB
authors.lastname: Ezekowitz
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Spear
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.forename: Emmett V
authors.initials: EV
authors.lastname: Schmidt
authors.forename: Ian C
authors.initials: IC
authors.lastname: Michelow
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003165:Complement System Proteins / Q000378:metabolism; D029043:Ebolavirus / Q000502:physiology*; D018702:Filoviridae Infections / Q000378:metabolism*; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D037601:Mannose-Binding Lectin / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D010873:Pinocytosis; D011975:Receptors, Mitogen / Q000378:metabolism*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D037601:Mannose-Binding Lectin; D008562:Membrane Glycoproteins; D011975:Receptors, Mitogen; D014759:Viral Envelope Proteins; D003165:Complement System Proteins