Biology subjects

Lambrecht, B.

Publications and source records attributed to Lambrecht, B..

6 recordsLinked to original sources

bioRxiv2025

The cellular Activating Protein 1 cFos regulates Influenza A virus replication

Previous research has demonstrated that Influenza A virus (IAV) infection activates AP-1 transcription factors as part of the antiviral response. In this study, we identified cFos as the most upregulated AP-1 transcription factor during IAV infection in A549 human lung cells. Surprisingly, the knockdown of cFos resulted in impaired IAV replication. Fluorescence microscopy and functional analyses indicated that cFos is implicated in IAV infection through its nuclear function, rather than its cytoplasmic role as an activator of lipid synthesis. The investigation into the role of cFos in IAV infection revealed increased apoptosis and elevated interferon-{beta} mRNA levels in cFos-knockdown A549 cells during IAV infection. This suggests that cFos may enhance cell survival and reduce interferon-{beta} expression during infection, thereby facilitating IAV proliferation. Furthermore, the levels of viral NA mRNA and the expression of late viral proteins NA and M2 decreased upon cFos knockdown. Overall, this study identifies cFos as a proviral factor for IAV, through the modulation of innate immunity and apoptosis during infection, and potentially by supporting the viral transcription. Author SummaryInfluenza A viruses pose a significant threat to global public health. Understanding the interaction between the virus and host is essential for the development of antiviral therapies. We identified cFos, a cellular Activating Protein-1, as a pro-viral factor for influenza A viruses. cFos was found to enhance cell survival and regulate the expression of certain cytokines during viral infection. Our findings also suggested a potential role for cFos in the viral transcription, especially of the viral proteins expressed late in the viral cycle.

microbiology↗

bioRxiv2024

CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs. First it downregulates Foxp3 expression, however in cooperation with CREM, CREB expression in Tregs alters chromatin accessibility to the ST-2 region and thereby influences T cell specific immune responses mediated by IL-10. Brief summary: Mice with a Foxp3-specific knockout of CREB display enhanced expression of IL-13, IL-10, ST-2 and CREM, which prevents gut inflammation GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/601312v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a2d341org.highwire.dtl.DTLVardef@1db6852org.highwire.dtl.DTLVardef@19e024borg.highwire.dtl.DTLVardef@a8c84d_HPS_FORMAT_FIGEXP M_FIG C_FIG Created by Biorender

immunology↗

bioRxiv2023

Ym1 protein crystals promote type 2 immunity

Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 (Gal10) protein, an abundant protein in eosinophils. Whereas mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by Chil3 and Chil4 and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs.

immunology↗

bioRxiv2020

ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation.

Loss-of-function of ADAR1 causes the severe autoinflammatory disease Aicardi-Goutieres Syndrome (AGS). ADAR1 converts adenosines into inosines within double-stranded (ds) RNA. This process called A-to-I editing masks self-dsRNA from detection by the antiviral dsRNA sensor MDA5. ADAR1 binds to dsRNA in both the canonical A-form and in the poorly defined Z-conformation (Z-RNA). Mutations in the Z-RNA binding Z-domain of ADAR1 are common in AGS patients. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. Using ADAR1 Z-domain mutant human cells and knock-in mice, we demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by pairing of inversely oriented SINEs. As a result, ADAR1 Z-domain mutant human cells and transgenic mice develop a spontaneous MDA5-dependent immune response. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.

immunology↗

bioRxiv2020

Structural and functional impact of the H5 hemagglutinin expression into a NDV vector vaccine backbone

Recombinant Newcastle disease viruses (rNDV) have been used as bivalent vectors for vaccination against multiple economically important avian pathogens. NDV-vectored vaccines expressing the immunogenic H5 hemagglutinin (rNDV-H5) are considered attractive candidates to protect poultry from both highly pathogenic avian influenza (HPAI) and Newcastle disease (ND). However, the impact of the insertion of a recombinant protein, such as H5, on the biological characteristics of the parental NDV strain has been little investigated to date. The present study compared a rNDV-H5 vaccine and its parental NDV LaSota strain in terms of their structural and functional characteristics, as well as their recognition by the innate immune sensors. Structural analysis of the rNDV-H5 demonstrated a decreased number of fusion (F) and a higher number of hemagglutinin-neuraminidase (HN) glycoproteins compared to NDV LaSota. These structural differences were accompanied by increased hemagglutinating and neuraminidase activities of rNDV-H5. During in vitro rNDV-H5 infection, increased mRNA expression of TLR3, TLR7, MDA5, and LGP2 was observed, suggesting that the recombinant virus is recognized differently by sensors of innate immunity when compared with the parental NDV LaSota. Given the growing interest in using NDV as a vector against human and animal diseases, these data highlight the importance to thoroughly understand the recombinant vaccines structural organization, functional characteristics, and the immune responses elicited.

microbiology↗

bioRxiv2019

Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive, for reasons that remain unclear. Here we show that linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of Th17 effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromises the integrity of the electron transport chain (ETC). Ultimately, this leads to loss of mitochondrial metabolism and cytokine production in differentiating Th cells. In accordance, mice lacking Gfm1 in T cells are protected from EAE, demonstrating that this pathway plays a key role in maintaining T cell function and pathogenicity.

immunology↗