Biology subjects

Slein, M. D.

Publications and source records attributed to Slein, M. D..

4 recordsLinked to original sources

bioRxiv2025

Antibodies targeting HSV glycoprotein B require effector functions to protect neonatal mice

Glycoprotein B (gB) serves as the viral fusion protein for herpes simplex virus (HSV), mediating fusion between viral and host membranes resulting in infection. As such, gB represents a potentially critical target for the host immune system with high potential relevance for vaccine design. Here we investigated the mechanisms of protection for a panel of gB-specific monoclonal antibodies (mAb) in a mouse model of neonatal HSV (nHSV) infection. Viral neutralization contributed, but Fc effector functions were critical for mAb-mediated protection against nHSV mortality, depending on dose. Moreover, AAV-mediated in vivo expression of a gB-specific mAb in mice provided transgenerational protection against HSV-1 and HSV-2 mortality in their offspring. These findings demonstrate that antibodies targeting gB can serve as potent therapeutics and that they require diverse functional profiles to afford optimal protection, informing vaccine design.

immunology↗

bioRxiv2024

Improving antibody-mediated protection against HSV infection by eliminating interactions with the viral Fc receptor gE/gI

Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules, allowing the virus to escape immune clearance. In addition to their role in neuropathogenesis and cell-cell spread, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG and promote evasion of humoral immune responses. While monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of the vFcR on mAb-mediated protection by binding to IgG is unknown. Using HSV-1 with intact and ablated gE-mediated IgG Fc binding, and Fc-engineered antibodies with modified ability to interact with gE/gI, we investigated the role of the vFcR in viral pathogenesis and mAb-mediated protection from nHSV. The gD-specific human mAb HSV8 modified to lack binding to gE exhibited enhanced neutralization and in vivo protection compared to its native IgG1 form. This improved protection by the engineered mAbs was dependent on the presence of the vFcR. Human IgG3 allotypes lacking vFcR binding also exhibited enhanced antiviral activity in vivo, suggesting that vaccines that robustly induce IgG3 responses could show enhanced protection. suggesting the value of vaccination strategies that robustly induce this subclass. Lastly, analysis of longitudinal responses to acute primary genital infection in humans raised the possibility that unlike most viruses, HSV may exhibited slow induction of IgG3. In summary, this study demonstrates that mAbs lacking the ability to interact with the vFcR can exhibit improved protection from HSV--offering new prospects for antibody-based interventions. One Sentence Summary: The herpes simplex virus neutralizing antibody HSV8 demonstrates improved activity in vitro and in vivo when its IgG Fc domain lacks the ability to bind the viral Fc receptor glycoprotein E/I complex through either Fc engineering or natural human IgG3 allotypes.

immunology↗

bioRxiv2024

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death by an infectious disease globally, with no efficacious vaccine. Antibodies are implicated in Mtb control, but the mechanisms of antibody action remain poorly understood. We assembled a library of TB monoclonal antibodies (mAb) and screened for the ability to restrict Mtb in mice, identifying protective antibodies targeting known and novel antigens. To dissect the mechanism of mAb-mediated Mtb restriction, we optimized a protective lipoarabinomannan-specific mAb through Fc-swapping. In vivo analysis of these Fc-variants revealed a critical role for Fc-effector function in Mtb restriction. Restrictive Fc-variants altered distribution of Mtb across innate immune cells. Single-cell transcriptomics highlighted distinctly activated molecular circuitry within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediated Mtb restriction. Therefore, improved antibody-mediated restriction of Mtb is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.

immunology↗

bioRxiv2023

Antibody effector functions are required for broad and potent protection of neonates from herpes simplex virus infection

The failure of multiple herpes simplex virus (HSV) vaccine candidates that induce neutralizing antibody responses raises the hypothesis that other activities, such as Fc domain-dependent effector functions, may be critical for protection. While neonatal HSV (nHSV) infection result in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, suggesting the potential efficacy of antibody-based therapeutics to protect neonates. We therefore investigated the mechanisms of monoclonal antibody (mAb)-mediated protection in a mouse model of nHSV infection. Both neutralization and effector functions contributed to robust protection against nHSV-1. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types that is consistent with vaccine trial results. Together, these results emphasize that effector functions are crucial for optimal mAb-mediated protection, informing effective Ab and vaccine design, and demonstrating the potential of polyfunctional Abs as potent therapeutics for nHSV infections. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/555423v1_figa1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1045d4corg.highwire.dtl.DTLVardef@18946d9org.highwire.dtl.DTLVardef@18a5eaeorg.highwire.dtl.DTLVardef@14e1b54_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Mechanistic dissection of antibody-mediated protection from HSV.Monoclonal antibodies (mAbs) with varying neutralizing potencies and Fc modifications that impact effector function were evaluated in wildtype (WT) and Fc{gamma}R-/- mice to define mechanisms of antibody-mediated protection from HSV infection. To model human vulnerability to HSV disease during the neonatal period, neonatal mice were challenged with HSV, treated with mAb, and then assessed for morbidity and mortality. We observed that polyfunctional mAbs provide broader and more potent protection than antibodies with either low neutralization or low effector function. Moreover, while sufficient for protection against HSV-1, neutralization activity alone was unable to protect from HSV-2 infection. C_FIG

immunology↗