Biology subjects

Cassol, E.

Publications and source records attributed to Cassol, E..

4 recordsLinked to original sources

bioRxiv2025

Nucleic acid strand length governs mitochondrial reprogramming and mtROS-associated antiviral responses following TLR3 engagement

Mitochondria are important rheostats that regulate innate sensing processes by producing energy, biosynthetic precursors, and bioactive molecules that affect cellular signaling. When viral nucleic acids engage endosomal and cytosolic pattern recognition receptors (PRR), antiviral immune responses are supported by mitochondrial remodeling but the role of mitochondria in fine tuning ligand-specific responses remains incompletely understood. For example, endosomal TLR3 can detect various lengths of dsRNA (0.4-8 kb) ranging from viral segmented genomes or endogenous nucleic acids have been shown to induce distinct cytokine profiles. However, it is unclear if these differences are associated with differential mitochondrial remodeling. Here, we report that TLR3 engagement with both high (HMW; 1.5-8 kb) or low molecular weight (LMW; 0.2-1 kb) Polyinosinic:polycytidylic acid (Poly(I:C)) is associated with reduced but sustained oxidative phosphorylation (OXPHOS) activity and increased mitochondrial reactive oxygen species (mtROS) production/accumulation to support antiviral responses in bone marrow-derived macrophages (BMDM). They differed in the amount of mtROS production, their spare respiratory capacity (SRC) and their mitochondrial membrane potential (MMP). Interestingly, while uncoupling protein 2 (UCP2) was found required for antiviral cytokine production, it did not contribute to ligand specific responses. Dynamic modulation of complex I of the electron transport chain (ETC), however resulted in the differential accumulation of mtROS (HMW>LMW). Further, selectively targeting the mtROS derived from Complex I leads to augmented type I IFN production. Overall, these findings highlight that targeting specific sources of mtROS without affecting electron flow may be a potential avenue for specific augmentation of antiviral responses during viral infections.

immunology↗

bioRxiv2019

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production. We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose conditions, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine-tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral versus inflammatory immune responses.

immunology↗

bioRxiv2019

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naive and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNF and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

immunology↗

bioRxiv2017

Designing Anti-Zika Virus Peptides Derived from Predicted Human-Zika Virus Protein-Protein Interactions

The production of anti-Zika virus (ZIKV) therapeutics has become increasingly important as the propagation of the devastating virus continues largely unchecked. Notably, a causal relationship between ZIKV infection and neurodevelopmental abnormalities has been widely reported, yet a specific mechanism underlying impaired neurological development has not been identified. Here, we report on the design of several synthetic competitive inhibitory peptides against key pathogenic ZIKV proteins through the prediction of protein-protein interactions (PPIs). Often, PPIs between host and viral proteins are crucial for infection and pathogenesis, making them attractive targets for therapeutics. Using two complementary sequence-based PPI prediction tools, we first produced a comprehensive map of predicted human-ZIKV PPIs (involving 209 human protein candidates). We then designed several peptides intended to disrupt the corresponding host-pathogen interactions thereby acting as anti-ZIKV therapeutics. The data generated in this study constitute a foundational resource to aid in the multi-disciplinary effort to combat ZIKV infection, including the design of additional synthetic proteins.

synthetic biology↗