Biology subjects

Rheaume, C.

Publications and source records attributed to Rheaume, C..

3 recordsLinked to original sources

bioRxiv2025

Influenza A Virus Interferes With Respiratory Syncytial Virus in Mice and Reconstituted Human Airway Epithelium

Epidemiological studies suggest that respiratory syncytial virus (RSV) and influenza A virus (IAV) might interfere with each other. Viral interference mainly relies on interferon production elicited by a first virus that reduces the replication of a second virus. In this paper, we first investigated the interactions between RSV-A2 and influenza A(H1N1)pdm09 in BALB/c mice infected with each single virus or both viruses simultaneously or sequentially before, at the peak of interferon elicited by each virus or after that peak. IAV reduced by almost 3.0 logs the replication of RSV administered at the peak of interferon induced by influenza, but the opposite was not true. However, IAV-infected mice challenged with RSV or the vehicle lost more weight and had a lower survival rate compared to single infections. Interferon expression, cytokine levels and pulmonary inflammation were almost similar between groups. Disease worsening was attributed to an aggravation of IAV-induced pulmonary congestion following intranasal instillation of fluid (with or without RSV). In human airway epithelia, IAV also interfered with RSV replication. Viral interference was dependent on the timing and sequence of infections, but not on differential interferon susceptibilities. Overall, our results help to understand the mechanisms of interaction between two major respiratory viruses. ImportanceRespiratory syncytial virus and influenza virus may interfere with each other based on epidemiological studies. It is suggested that a first virus may induce the production of interferon and interfere with the replication of a second unrelated virus. Our data showed that influenza A virus interferes with respiratory syncytial virus replication in mouse lungs, but the opposite was not observed. In reconstituted human airway epithelia, viral interference was dependent on the timing and sequence of infections, but not on differential interferon susceptibilities. Understanding the mechanisms of interaction between respiratory viruses may help the development of prophylactic or therapeutic modalities.

microbiology↗

bioRxiv2019

Characterization of clostridium botulinum neurotoxin serotype A (BoNT/A) and fibroblast growth factor receptor interactions using a novel receptor dimerization assay

Clostridium botulinum neurotoxin serotype A (BoNT/A) is a potent neurotoxin that also serves as an effective therapeutic for a variety of neuromuscular and glandular diseases and disorders. The observed pharmacological effect of BoNT/A is due to specific targeting and entry into motor nerve terminals within muscles followed by cleavage of the SNARE protein, SNAP-25, inducing a block in neurotransmission and temporary muscular paralysis. Specific binding and internalization of BoNT/A into neuronal cells are mediated by its binding domain (HC/A), which binds to GT1b ganglioside and protein cell surface receptors. Previously, fibroblast growth factor receptor 3 (FGFR3) was identified as a BoNT/A receptor, in addition to synaptic vesicle protein (SV2). To further study BoNT/A interactions with FGFRs, an FCS & TIRF receptor dimerization assay was developed to measure dimerization of FGFRs in live cells, as FGFR dimerization can be considered an indirect measure for receptor-ligand binding interaction and downstream signaling. The ability of HC/A to facilitate dimerization of three FGFR subtypes (FGFR1-3) was assessed. Recombinant HC/A (rHC/A) was shown to dimerize FGFR subtypes in the rank order FGFR3c > FGFR2b > FGFR1c. With potencies (EC50 values) defined as the concentration of ligand required to dimerize 50% of the receptors, wild type rHC/A dimerized FGFR3c with an EC50 of 24 nM, similar to FGF9, a native FGFR3c ligand, which had an EC50 of 15 nM, while FGFR1c and FGFR2b required higher rHC/A concentrations ([≥]100 nM and 68 nM, respectively). Furthermore, addition of the GT1b ganglioside to the culture media resulted in increased dimerization, whereas a ganglioside mutant variant of HC/A (rHC/A W1266L;Y1267S) showed decreased dimerization. Interestingly, reduced dimerization was also observed with an SV2 mutant variant of HC/A (rHC/A T1145A;T1146A). These results support a model wherein BoNT/A interacts with FGFRs, gangliosides, and SV2 on the cell surface to facilitate cell uptake.

cell biology↗

bioRxiv2018

Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures

BackgroundInfluenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials.\n\nMethodsWe exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo and ex vivo.\n\nResultsOur strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial.\n\nConclusionsThis original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed.

microbiology↗