7t17
Zika Virus asymmetric unit bound with IgM antibody DH1017 Fab fragment
Structural highlights
FunctionIGG1_HUMAN Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).[1] [2] [3] Publication Abstract from PubMedCongenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy. A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization.,Singh T, Hwang KK, Miller AS, Jones RL, Lopez CA, Dulson SJ, Giuberti C, Gladden MA, Miller I, Webster HS, Eudailey JA, Luo K, Von Holle T, Edwards RJ, Valencia S, Burgomaster KE, Zhang S, Mangold JF, Tu JJ, Dennis M, Alam SM, Premkumar L, Dietze R, Pierson TC, Ooi EE, Lazear HM, Kuhn RJ, Permar SR, Bonsignori M Cell. 2022 Dec 8;185(25):4826-4840.e17. doi: 10.1016/j.cell.2022.10.023. Epub , 2022 Nov 18. PMID:36402135[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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