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Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.

Fusco ML, Hashiguchi T, Cassan R, Biggins JE, Murin CD, Warfield KL, Li S, Holtsberg FW, Shulenin S, Vu H, Olinger GG, Kim do H, Whaley KJ, Zeitlin L, Ward AB, Nykiforuk C, Aman MJ, Berry JD, Berry J, Saphire EO - PLoS Pathog. (2015)

Bottom Line: Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific.Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves.The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV.

No MeSH data available.


Related in: MedlinePlus

Filovirus GP cross-reactivity of 40G1 and 2D8.(A) Reactivity of 40G1 and 2D8 mAbs to GP antigens determined by ELISA at 5μg/ml. SUDV, Sudan virus; BDBV, Bundibugyo virus; RESTV, Reston virus. (B) Binding curves determined by ELISA with mAb serial dilutions starting at 20μg/ml. Note that MARV GPΔmuc, MARV GPcl, and EBOV GPcl curves overlay in both graphs.
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ppat.1005016.g005: Filovirus GP cross-reactivity of 40G1 and 2D8.(A) Reactivity of 40G1 and 2D8 mAbs to GP antigens determined by ELISA at 5μg/ml. SUDV, Sudan virus; BDBV, Bundibugyo virus; RESTV, Reston virus. (B) Binding curves determined by ELISA with mAb serial dilutions starting at 20μg/ml. Note that MARV GPΔmuc, MARV GPcl, and EBOV GPcl curves overlay in both graphs.

Mentions: Two of the highly cross-reactive MARV antibodies, mAbs 40G1 and 2D8, also exhibit binding to Ebola, Sudan, Bundibugyo and Reston virus mucin-deleted GPs by ELISA (Fig 5A). Binding curves show that the affinity of 40G1 and 2D8 for mucin-containing EBOV GP is weak, affinity for GPΔmuc is stronger, and binding to EBOV GPcl (the receptor-binding competent core) is strongest and equal to that of MARV GPcl (Fig 5B). Hence, the 40G1 and 2D8 epitopes are conserved across the filovirus family, exposed on all versions of Marburg virus GP, but masked on ebolavirus GP by the mucin-like domain and the glycan cap.


Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.

Fusco ML, Hashiguchi T, Cassan R, Biggins JE, Murin CD, Warfield KL, Li S, Holtsberg FW, Shulenin S, Vu H, Olinger GG, Kim do H, Whaley KJ, Zeitlin L, Ward AB, Nykiforuk C, Aman MJ, Berry JD, Berry J, Saphire EO - PLoS Pathog. (2015)

Filovirus GP cross-reactivity of 40G1 and 2D8.(A) Reactivity of 40G1 and 2D8 mAbs to GP antigens determined by ELISA at 5μg/ml. SUDV, Sudan virus; BDBV, Bundibugyo virus; RESTV, Reston virus. (B) Binding curves determined by ELISA with mAb serial dilutions starting at 20μg/ml. Note that MARV GPΔmuc, MARV GPcl, and EBOV GPcl curves overlay in both graphs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4482612&req=5

ppat.1005016.g005: Filovirus GP cross-reactivity of 40G1 and 2D8.(A) Reactivity of 40G1 and 2D8 mAbs to GP antigens determined by ELISA at 5μg/ml. SUDV, Sudan virus; BDBV, Bundibugyo virus; RESTV, Reston virus. (B) Binding curves determined by ELISA with mAb serial dilutions starting at 20μg/ml. Note that MARV GPΔmuc, MARV GPcl, and EBOV GPcl curves overlay in both graphs.
Mentions: Two of the highly cross-reactive MARV antibodies, mAbs 40G1 and 2D8, also exhibit binding to Ebola, Sudan, Bundibugyo and Reston virus mucin-deleted GPs by ELISA (Fig 5A). Binding curves show that the affinity of 40G1 and 2D8 for mucin-containing EBOV GP is weak, affinity for GPΔmuc is stronger, and binding to EBOV GPcl (the receptor-binding competent core) is strongest and equal to that of MARV GPcl (Fig 5B). Hence, the 40G1 and 2D8 epitopes are conserved across the filovirus family, exposed on all versions of Marburg virus GP, but masked on ebolavirus GP by the mucin-like domain and the glycan cap.

Bottom Line: Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific.Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves.The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV.

No MeSH data available.


Related in: MedlinePlus