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Cell Zika virus-specific IgM induced during pregnancy instead of IgG showed a strong neutralizing effect

 Last Update: 2022-12-30
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Written by | Qi

Up to 14% of pregnant women infected with Zika virus (ZIKV) have babies born with neurodevelopmental deficits
.
Neutralizing antibodies (nAbs) have been shown to exert protective effects
against ZIKV and other flaviviruses.
To date, research on nAbs has focused on IgG antibodies, but flavivirus infection is characterized by virus-specific and prolonged IgM responses [1-3].

In order to verify the contribution of IgM to neutralizing ZIKV in pregnant women, the team of Mattia Bonsignori from NIH recently co-published an article A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent in the journal Cell neutralization, they demonstrated that plasma IgM contributes to ZIKV immunity during pregnancy, mediating neutralization
within 3 months of symptom onset.
From a pregnant woman infected with ZIKV, they isolated a pentameric ZIKV-specific IgM (DH1017.
IgM), which exhibits a super-ZIKV neutralizing effect that relies on the IgM isotype
.
DH1017.
IgM is more effective than when expressed as IgG in protecting mice from viremia
during attack by lethal ZIKV.
This study identifies the role of DH1017.
IgM in the prevention of ZIKV as a safe and effective candidate immunotherapy agent
during pregnancy.

The researchers first identified specific IgM neutralizing antibodies in the plasma of all 10 pregnant subjects infected with ZIKV, using fluorescent ZIKV virus as bait to enrich ZIKV-responsive B cells, generating a total of 49 ZIKV-responsive Ig secretion culture supernatants, from which 9 B-LCLs
were established.
One of them produced an IgM antibody – DH1017.
IgM, which does not cross-react with other flaviviruses, shows a superior ZIKV neutralizing effect
.
Subsequently, the authors generated DH1017 Fab and IgG isoforms through recombination, and evaluated their ability to bind to ZIKV virions, and DH1017.
Fab and DH1017.
IgG showed weaker binding ability compared with DH1017.
IgM, with a difference of 10,000-fold and >-40-fold
neutralization efficacy, respectively.
To further characterize the safety of the three, the authors measured the binding of nine autoantigens associated with autoimmune diseases, and all isoforms were negative for reactivity to all autoantigens
.

The authors sought to evaluate whether DH1017.
IgM could protect mice from ZIKV infection
.
DH1017.
IgM was more effective in protecting mice from viremia, compared to all fractions of the control IgM group who died from infection
.
At half dose, although DH1017.
IgM still prevents lethality, protection against viremia is incomplete
.
In addition, DH1017.
IgG also prevented infection from causing death, but all mice exhibited high viral loads in their blood and required higher than 5 times the dose of IgM to control viremia, indicating that DH1017.
IgM isotype confers more effective virus control
in mice.

Next, the authors used cryo-EM and single-particle reconstruction to characterize the DH1017 epitope
.
The Cα backbone of the extracellular domain of ZIKV's asymmetric E glycoprotein consists of 3 E monomers, and the DH1017 variable domain mainly interacts
with domain II (DII) of all three E monomers.
Computational models show that the arms of DH1017.
IgM pentamers can be bent towards the virus surface, and each arm can contact adjacent asymmetric epitopes (q2f and i2f), so that the pentamer can be exposed to up to five epitope pairs, i.
e.
, polyvalent antigen recognition patterns
.
It should be noted that DH1017.
The in vitro and in vivo activity of IgM superior to DH1017.
IgG demonstrates the functional advantages conferred by IgM isoforms, thanks to its polymer structure and ability to
bind virions at high prices.
In addition to the effects of polyvalent binding, the large molecular size of IgM may interfere with virions attaching to cell membranes more effectively than IgG, and may prevent cell entry
by making the particles stiffer.
This can spatially impede interaction with the cell surface to prevent binding or fusion with host cells, and a 5-fold excess dose of DH1017.
IgG achieves a biological effect comparable to DH1017.
IgM, further verifying that the main determinant of DH1017.
IgM's superpotency is its polyvalent isotype
.

In conclusion, this work highlights the importance of IgM for ZIKV neutralization in early pregnancy, providing a proof of concept for the development of engineered multimer antibody formulations as a potential prevention and treatment strategy.
However, further studies are needed to evaluate whether DH1017.
IgM can prevent fetal infection in animal models of pregnancy and reduce fetal damage
by rapidly reducing maternal viremia.

Original link: https://doi.
org/10.
1016/j.
cell.
2022.
10.
023

Platemaker: Eleven

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