Biology subjects

Lederer, J.

Publications and source records attributed to Lederer, J..

4 recordsLinked to original sources

bioRxiv2026

Preclinical evaluation of Brincidofovir in glioblastoma demonstrates improved long term-survival and cytomegalovirus-dependent and independent effects

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM) progression. Ongoing clinical trials are assessing therapeutic approaches targeting CMV in GBM but to date no new therapy has been approved outside the standard of care. Previous preclinical studies have highlighted the potential of the antiviral drug Cidofovir (CDV) in GBM; however, its clinical use is limited by dose-dependent nephrotoxicity and poor cellular uptake, necessitating high intravenous doses to achieve therapeutic activity. Brincidofovir (BCV), a lipid conjugate of CDV has been developed, which does not induce nephrotoxicity and has significantly greater cellular bioavailability. Here we examined the effects of BCV in a newly established CMV-driven GBM model (SB28) and in patient-derived tumor neurospheres. We show that BCV prolongs survival in vivo and exerts both CMV-dependent and independent antitumor effects. Mechanistically, BCV induces DNA damage and cell cycle dysregulation in GBM cells and inhibits proliferation of patient-derived neurospheres in a dose-dependent manner. These data identify BCV as a dual-action therapeutic that suppresses viral oncomodulation while directly targeting tumor cell viability.

cancer biology↗

bioRxiv2025

Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state

Type I and III interferons (IFNs) are among the first lines of defense against viral infection, yet they are generally only produced by a tiny fraction of infected cells. Here, we show that cellular heterogeneity in IFN induction potential upon treatment with immunostimulatory RNA is not due to variability in sensing of stimuli but instead is shaped by heterogeneity in tonic cell signaling state. Using complementary single-cell approaches, we found that baseline variation in the c-Jun N-terminal kinase (JNK) and activator protein (AP)-1 transcription factor families correlated with IFNL1 expression predisposition. We further show that drug-based inhibition of JNK signaling virtually eliminates the innate antiviral response to immunostimulatory RNA. Finally, we show that single cell heterogeneity in IFN induction potential is heritable and stably maintained over numerous generations. Together, our study emphasizes the influence of intrinsic variability in cell state on innate immune regulation and IFN induction heterogeneity.

systems biology↗

bioRxiv2025

A Multigenerational ''Dirty'' Mouse Model for Studying Trauma-Induced Immune Dysregulation and Infection Susceptibility

Trauma induces immune dysregulation in both humans and mice, increasing infection susceptibility. Mouse models are critical in research but have been criticized for lacking translational relevance. This study tested whether multigenerational "natural immune" (NI) mice - generated by co-housing C57BL/6 mice with "dirty" pet shop mice and breeding through multiple generations - would develop a more human-like immune response to trauma and infection than "clean" specific pathogen-free (SPF) C57BL/6 mice whose immune systems developed without normal flora. To address this gap, SPF and NI mice underwent burn trauma followed by Pseudomonas aeruginosa lung infection. Peripheral blood and bone marrow immune cells were characterized by flow cytometry and mass cytometry (CyTOF). Blood samples from trauma patients were analyzed for comparison. At baseline, NI mice exhibited more neutrophils compared to SPF mice, closer resembling human peripheral immune composition. Following injury, SPF mice demonstrated increased blood neutrophils and monocytes with reduced B and T cells, whereas NI mice exhibited a muted blood immune cell response. In contrast, NI mice showed a robust emergency granulopoiesis response and preserved hematopoietic stem cells (HSCs) following secondary infection, whereas HSCs decreased in SPF mice. Time-matched blood samples from human trauma patients revealed alterations more closely resembling those observed in NI mice. These findings support the hypothesis that NI mice develop a more human-like immune response to trauma and infection than SPF mice. This suggests that NI mice may provide a more translationally relevant platform for studying trauma-induced immune dysfunction and infection susceptibility mechanisms. Summary SentenceMultigenerational natural immune mice exhibit more human-like immune responses to trauma and infection that offer a model with significant translatable advantages for studying post-injury immune dysfunction in patients.

immunology↗

bioRxiv2025

Intrinsic OASL expression licenses interferon induction during influenza A virus infection

Effective control of viral infection requires rapid induction of the innate immune response, especially the type I and type III interferon (IFN) systems. Despite the critical role of IFN induction in host defense, numerous studies have established that most cells fail to produce IFNs in response to viral stimuli. The specific factors that govern cellular heterogeneity in IFN induction potential during infection are not understood. To identify specific host factors that license some cells but not others to mount an IFN response to viral infection, we developed an approach for analyzing temporal scRNA-seq data of influenza A virus (IAV)-infected cells. This approach identified the expression of several interferon stimulated genes (ISGs) within pre-infection cells as correlates of IFN induction potential of those cells, post-infection. Validation experiments confirmed that intrinsic expression of the ISG OASL is essential for robust IFNL induction during IAV infection. Altogether, our findings reveal an important role for IFN-independent, intrinsic expression of ISGs in promoting IFN induction and provide new insights into the mechanisms that regulate cell-to-cell heterogeneity in innate immune activation.

immunology↗