Biology subjects

Mandelboim, O.

Publications and source records attributed to Mandelboim, O..

6 recordsLinked to original sources

bioRxiv2025

RadD from Fusobacterium nucleatum Engages NKp46 to Promote Antitumor Cytotoxicity

Fusobacterium nucleatum, a Gram-negative bacterium implicated in periodontal disease, has emerged as a contributor to tumor progression in various cancers. Whether the presence of Fusobacterium nucleatum inhibits tumor progression is largely unknown. Here, we identify a subspecies-specific interaction between F. nucleatum and the natural killer (NK) cell receptor NKp46. Analysis of TCGA datasets revealed that the co-occurrence of F. nucleatum and high NKp46 expression correlates with improved survival in head and neck cancers but not in colorectal cancers. Using binding assays, we demonstrate that both human NKp46 and its murine ortholog, Ncr1, directly recognize the fusobacterial adhesin RadD. Genetic deletion of radD or blockade of NKp46 significantly impaired NK cell-mediated cytotoxicity in vitro and promoted tumor growth. In vivo infection with F. nucleatum accelerated tumor progression, with an exacerbated effect observed in the absence of RadD or NKp46. These findings highlight RadD as a critical ligand for NKp46 and establish the NKp46-RadD axis as a key interface in host-microbe-tumor interactions, offering a novel target for immunotherapeutic intervention in cancer influenced by microbial factors.

immunology↗

bioRxiv2025

NKp46 Recognizes the Hyphal Form of Candida albicans and Mediates Protective Antifungal Immunity

Candida albicans is an opportunistic fungal pathogen capable of transitioning between yeast and hyphal forms, a morphological plasticity critical for its pathogenicity. Natural killer (NK) cells play a crucial role in antifungal immunity, yet the molecular basis of their interaction with C. albicans remains incompletely understood. Here, we identify NKp46 (NCR1 in mice), an activating receptor on NK cells, as a functional receptor for the hyphal--but not yeast--form of C. albicans. Using image flow cytometry and binding assays with NKp46-Ig and NCR1-Ig fusion proteins, we demonstrate that NKp46 selectively binds to hyphae. This interaction is mediated by the D2 domain of NKp46 and is sialic acid independent. Blocking NKp46 impairs NK cell degranulation and fungal killing in vitro. In vivo, mice deficient in NCR1 exhibit increased susceptibility to systemic C. albicans infection. Our findings establish NKp46 as a key sensor of invasive fungal morphology and underscore its role in early antifungal immunity.

immunology↗

bioRxiv2024

Natural killer cell function is regulated by TGF-β signaling in pregnancy and tumor progression

The immune compartment of the maternal-fetal interface must balance between supporting maternal-fetal interactions and maintaining maternal tolerance. Despite recent advances, the cellular and molecular regulators that drive maternal immune cell remodeling remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively characterized the immune compartment dynamics in the maternal-fetal interface of both human and mouse and charted the markers and functional pathways associated with these cells. Comparing immune signatures in decidua and tumors of human and mice, we identify conserved gene modules that are activated in natural killer (NK) cells of both compartments, including TFG-{beta} signaling. Genetic ablation and antibody blockade of the TGF-{beta} pathway in NK cells resulted in enhanced anti-tumor immunity.

immunology↗

bioRxiv2021

SARS-CoV-2 receptor binding domain fusion protein efficiently neutralizes virus infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic, causing health and economic problems. Currently, as dangerous mutations emerge there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus membrane binds to the angiotensin converting enzyme 2 (ACE2) receptor on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in vitro and in vivo SARS-CoV-2 infection, better than ACE2-Ig. Mechanistically we show that anti-spike antibodies generation, ACE2 enzymatic activity and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus concentration infection. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients. Author SummarySARS-CoV-2 infection caused serious socio-economic and health problems around the globe. As dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. SARS-CoV-2 infection starts via binding of SARS-CoV-2 spike protein receptor binding domain (RBD) to its receptor, ACE2, on host cells. To intercept this binding, we generated Ig-fusion proteins. ACE2-Ig was generated to possibly block RBD by binding to it and RBD-Ig to block ACE2. We indeed showed that the fusion proteins bind to their respective target. We found that it is more efficient to inhibit SARS-CoV-2 infection by blocking ACE2 receptor with RBD-Ig. We also showed that RBD-Ig does not interfere with ACE2 activity or surface expression. Importantly, as our treatment does not target the virus directly, it may be efficient against any emerging variant. We propose here that RBD-Ig physically blocks virus infection by binding to ACE2 and thus it may be used for the treatment of SARS-CoV-2-infected patients.

immunology↗

bioRxiv2020

The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. NK cell activity is regulated by signals received from activating and inhibitory receptors. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically targets MICA*008 to proteasomal degradation, thus hindering the elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines. Author SummaryHuman cytomegalovirus (HCMV) is a common pathogen that usually causes asymptomatic infection in the immunocompetent population, but the immunosuppressed and fetuses infected in utero suffer mortality and disability due to HCMV disease. Current HCMV treatments are limited and no vaccine has been approved, despite significant efforts. HCMV encodes many genes of unknown function, and virus-host interactions are only partially understood. Here, we discovered that a hitherto uncharacterized HCMV protein, UL147A, downregulates the expression of an activating immune ligand allele named MICA*008, thus hindering the elimination of HCMV-infected cells. Elucidating HCMV immune evasion mechanisms could aid in the development of novel HCMV treatments and vaccines. Furthermore, MICA*008 is a highly prevalent allele implicated in cancer immune evasion, autoimmunity and graft rejection. In this work we have shown that UL147A interferes with MICA*008s poorly understood, nonstandard maturation pathway. Study of UL147A may enable manipulation of its expression as a therapeutic measure against HCMV.

immunology↗

bioRxiv2019

Comprehensive Annotations of Human Herpesvirus 6A and 6B Genomes Reveal Novel and Conserved Genomic Features

Human herpesvirus 6 (HHV-6) A and B are highly ubiquitous betaherpesviruses, infecting the majority of the human population. Like other herpesviruses, they encompass large genomes and our understanding of their protein coding potential is far from complete. Here we employ ribosome profiling and systematic transcript analysis to experimentally define the HHV-6 translation products and to follow their temporal expression. We identify hundreds of new open reading frames (ORFs), including many upstream ORFs (uORFs) and internal ORFs (iORFs), generating a complete unbiased atlas of HHV-6 proteome. Furthermore, by integrating systematic data from the prototypic betaherpesvirus, human cytomegalovirus, we uncover numerous uORFs and iORFs that are conserved across betaherpesviruses and we show that uORFs are specifically enriched in late viral genes. Using our transcriptome measurements, we identified three highly abundant HHV-6 encoded long non-coding RNAs (lncRNAs), one of which generates a non-polyadenylated stable intron that appears to be a conserved feature of betaherpesviruses. Overall, our work reveals the complexity of HHV-6 genomes and highlights novel features that are conserved between betaherpesviruses, providing a rich resource for future functional studies.

microbiology↗