Biology subjects

Maurer, L.

Publications and source records attributed to Maurer, L..

5 recordsLinked to original sources

bioRxiv2023

Efficient formation and maintenance of humoral and CD4 T cell immunity targeting the viral capsid in acute-resolving hepatitis E infection

Background and aimsCD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open-reading-frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells and neutralizing antibodies that target either nHEV or eHEV particles in immunocompetent individuals with acute and resolved HEV infection. MethodsHEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multi-parametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined. ResultsHEV-specific CD4 T cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells primarily target the ORF2-derived capsid, which correlates with the presence of nAbs targeting nHEV. In contrast, ORF3-specific CD4 T cells are hardly detectable and eHEV is less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time. ConclusionThe viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction for several years after infection. Impact and implicationsThe interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target the viral capsid, leading to efficient neutralization of the naked virus (nHEV) while the quasi-envelope (eHEV) particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of HEV-specific CD4 T cell and antibody immunity.

immunology↗

bioRxiv2023

Human pluripotent stem cell-derived hepatocyte-like cells for hepatitis D virus studies

Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co- infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively secrete infectious progeny virions. We also show that HLCs expressing HBsAg support extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV/HBV co-entry factor, which was rate-limiting HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions. TeaserA human stem cell-derived hepatocyte culture model for hepatitis D virus studies

microbiology↗

bioRxiv2022

Gasdermin D is the only Gasdermin that provides non-redundant protection against acute Salmonella gut infection

Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1{beta} (IL1{beta}) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute Salmonella Typhimurium (S.Tm) gut infection. However, to date, we lack a comprehensive functional assessment of the different Gasdermins (GSDMA-E) during S.Tm infection in vivo. Here, we have performed littermate-controlled oral S.Tm infections to investigate the impact of all murine Gasdermins. While GSDMA, -C and -E appear dispensable, we show that GSDMD (i) restricts S.Tm loads in the gut tissue and systemic organs, (ii) controls gut inflammation kinetics, and (iii) prevents epithelium disruption by 72h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs). In vivo experiments, 3D- and 2D-enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding cells and affects extrusion kinetics. As such, this work identifies a non-redundant multipronged role of GSDMD in mucosal tissue defence against a common enteric pathogen. HIGHLIGHTSO_LIGasdermin D restricts Salmonella Typhimurium (S.Tm) translocation across the gut tissue, controls gut inflammation kinetics, and prevents epithelium disruption by 72h of the infection. C_LIO_LIGasdermins A, C and E appear dispensable for protection against acute S.Tm gut infection. C_LIO_LIGasdermin D in bone-marrow-derived lamina propria cells and intestinal epithelial cells complement each other to suppress gut tissue S.Tm loads. C_LIO_LIGasdermin D is not required for extrusion of infected intestinal epithelial cells but drives their permeabilization and affects qualitative features of the extrusion process. C_LI

immunology↗

bioRxiv2022

Hindlimb Muscle Representations in Mouse Motor Cortex Defined by Viral Tracing

Descending pathways from the cortex to the spinal cord are involved in the control of natural movement. Although mice are widely used in the study of the neurobiology of movement and as models of neurodegenerative disease, an understanding of motor cortical organization is lacking, particularly for hindlimb muscles. In this study, we used the retrograde transneuronal transport of rabies virus to compare the organization of descending cortical projections to fast- and slow-twitch hindlimb muscles surrounding the ankle joint in mice. Although the initial stage of virus transport from the soleus muscle (predominantly slow-twitch) appeared to be more rapid than that associated with the tibialis anterior muscle (predominantly fast-twitch), the rate of further transport of the virus to cortical projection neurons in layer V was equivalent for the two injected muscles. After appropriate survival times, dense concentrations of layer V projection neurons were identified in three cortical areas: the primary motor cortex (M1), secondary motor cortex (M2), and primary somatosensory cortex (S1). The origin of the cortical projections to each of the two injected muscles overlapped almost entirely within these cortical areas. This organization suggests that cortical projection neurons maintain a high degree of specificity, even when they are involved in controlling muscles with different functional roles (fast-versus slow-twitch, extensor versus flexor). Our results represent an important addition to the understanding of the mouse motor system and lay the foundation for future studies investigating the mechanisms underlying motor system dysfunction and degeneration in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy.

neuroscience↗

bioRxiv2021

High Mobility Group Box 1 enhances ADP-mediated platelet activation by increasing platelet surface P2Y12 localization

Thrombosis and inflammation are intimately linked and synergistically contribute to the pathogenesis of a number of vascular diseases. On a cellular level, while the platelet is central to thrombus formation as well as an active mediator of inflammation, the molecular mechanisms of cross-talk between thrombosis and inflammation remain elusive. High-Mobility Group Box 1 protein (HMGB1) is an inflammatory regulator that also stimulates platelet activation through its interaction with toll-like receptor 4 (TLR4). However, it remains unclear whether cross-talk between HMGB1 and traditional thrombotic agonists exists to modulate platelet activation. Using isolated human platelets, we tested whether HMGB1 treatment affects platelet activation mediated by traditional agonists. We found that HMGB1 enhances ADP-mediated platelet activation, but not platelet activation stimulated by thrombin or collagen. Further, inhibition of the canonical ADP purinergic P2Y12 receptor attenuates HMGB1-dependent platelet activation. Mechanistically, we discovered that HMGB1 activates platelet surface TLR4 to release ADP from the platelet and concomitantly increase the localization of P2Y12 on the platelet membrane. These data demonstrate that ADP-dependent P2Y12 activation contributes to HMGB1 mediated platelet activation, while HMGB1 primes platelets for an enhanced activation response to ADP. These novel findings further our understanding of thrombo-inflammatory signaling and provide new insight for therapeutic P2Y12 inhibition. Key PointsO_LIHMGB1 enhances ADP-mediated platelet activation but not platelet activation stimulated by collagen or thrombin. C_LIO_LIHMGB1 stimulates platelet ADP release and increases platelet surface localization of P2y12 receptors via TLR4-dependent mechanism(s). C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/436776v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@17a31c0org.highwire.dtl.DTLVardef@158391corg.highwire.dtl.DTLVardef@10d78a0org.highwire.dtl.DTLVardef@16a6a8f_HPS_FORMAT_FIGEXP M_FIG Caption: HMGB1 activates TLR4 to activate platelets, release platelet ADP, and upregulate P2Y12 at the platelet surface. C_FIG

cell biology↗