Biology subjects

Forst, C. V.

Publications and source records attributed to Forst, C. V..

5 recordsLinked to original sources

bioRxiv2025

Single-Cell Network Analysis Identifies CLEC4E as a Key Mediator of Proinflammatory mDC Responses in Influenza Infection

The severity of influenza is often driven by an excessive host immune response rather than the virus itself, yet the key molecular drivers within specific immune cells remain poorly understood. While recent single-cell RNA sequencing studies have successfully identified immune populations involved, they have largely not identified the upstream drivers modulating their pro-inflammatory functions. Here we employed an integrated single-cell co-expression network to address this gap. Our analysis identified myeloid dendritic cells (mDCs) as central to pro-inflammatory response during infection. Through a multi-layered key driver analysis, we pinpointed C-type lectin, CLEC4E as a top candidate modulating this pathological inflammatory response. The role of CLEC4E was confirmed in an independent single-cell dataset from influenza-infected patients and further validated in vivo. Pharmacological inhibition of CLEC4E in a murine influenza model significantly reduced disease severity and lower viral titers in the lungs. This study not only clarifies that CLEC4E overexpression in mDCs contributes to pro-inflammatory signaling pathways influencing influenza severity but also shows the power of single-cell network approaches to uncover novel and robust therapeutic targets hidden within complex immune responses.

systems biology↗

bioRxiv2021

Tissue Specific Age Dependence of the Cell Receptors Involved in the SARS-CoV-2 Infection

The coronavirus disease 2019 (COVID-19) pandemic has affected tens of millions of individuals and caused hundreds of thousands of deaths worldwide. Due to its rapid surge, there is a shortage of information on viral behavior and host response after SARS-CoV-2 infection. Here we present a comprehensive, multiscale network analysis of the transcriptional response to the virus. We particularly focus on key-regulators, cell-receptors, and host-processes that are hijacked by the virus for its advantage. ACE2-controlled processes involve a key-regulator CD300e (a TYROBP receptor) and the activation of IL-2 pro-inflammatory cytokine signaling. We further investigate the age-dependency of such receptors and identify the adipose and the brain as potentially contributing tissues for the diseases severity in old patients. In contrast, several other tissues in the young population are more susceptible to SARS-CoV-2 infection. In summary, this present study provides novel insights into the gene regulatory organization during the SARS-CoV-2 infection and the tissue-specific age dependence of the cell receptors involved in COVID-19.

systems biology↗

bioRxiv2021

Sex disparities in influenza: a multiscale network analysis

Sex differences in the pathogenesis of infectious diseases due to differential immune responses between females and males have been well documented for multiple pathogens. However, the molecular mechanism underlying the observed sex differences in influenza virus infection remains poorly understood. In this study, we used a network-based approach to characterize the blood transcriptome collected over the course of infection with influenza A virus from female and male ferrets to dissect sex-biased gene expression. We identified significant differences in the temporal dynamics and regulation of immune responses between females and males. Our results elucidate sex-differentiated pathways involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory responses, including a female-biased IRE1/XBP1 activation and male-biased crosstalk between metabolic reprogramming and IL-1 and AP-1 pathways. Overall, our study provides molecular insights into sex differences in transcriptional regulation of immune responses and contributes to a better understanding of sex bias in influenza pathogenesis.

systems biology↗

bioRxiv2018

Transcriptional Circuit Fragility Influences HIV Proviral Fate

Transcriptional circuit architectures can be evolutionarily selected to precisely dictate a given response. Unlike these cellular systems, HIV is regulated through a complex circuit composed of two successive phases (host and viral), which create a positive feedback loop facilitating viral replication. However, it has long remained unclear whether both phases operate identically and to what extent the host phase influences the entire circuit. Here we report that while the host phase is regulated by a checkpoint whereby KAP1 mediates transcription activation, the virus evolved a minimalist system bypassing KAP1. Given the complex circuits architecture, cell-to-cell KAP1 fluctuations impart heterogeneity in the host transcriptional responses thus affecting the feedback loop. Mathematical modeling of a complete circuit reveals how these oscillations ultimately influence homogeneous reactivation potential of a latent virus. Thus, while HIV drives molecular innovation to fuel robust gene activation, it experiences transcriptional fragility thereby influencing viral fate and cure efforts.\n\nIn BriefHIV evolved a minimalist but robust transcriptional circuit bypassing host regulatory checkpoints; however, the fragility of the circuit in the host phase (which primes HIV for activation) largely affects proviral transcription and fate.\n\nHighlightsO_LIThe host and viral phases of the HIV transcriptional circuit have different functional requirements\nC_LIO_LIHIV evolved a minimalist program to robustly bypass host cell regulatory checkpoints\nC_LIO_LIA mathematical model reveals that the host phase is subject to transcriptional circuit fragility\nC_LIO_LIHost transcriptional circuit fragility influences the viral feedback and latency reversal potential\nC_LI

molecular biology↗

bioRxiv2018

Cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection

Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single cell level and how it impacts virus-host interactions at a systems level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability of viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show a correlation between DVGs and viral-induced variation of the host transcriptional program and an association between differential induction of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single cell level improve our understanding of the complex virus-host interplay during influenza infection.\n\nIMPORTANCEDefective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate disease severity and pathogenicity of the influenza infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single cell transcriptional profiling. Here we characterized virus and host transcriptomes in individual influenza-infected cells, including that of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective virus genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.

microbiology↗