Biology subjects

Cremers, N.

Publications and source records attributed to Cremers, N..

4 recordsLinked to original sources

bioRxiv2026

Rat hepatitis E virus infection has multiphasic viral replication kinetics in vivo

Background and AimsHepatitis E virus (HEV) infections are a growing threat to global public health. To obtain an in-depth understanding of HEV infections in untreated and ribavirin-treated rats, we characterized the early HEV viral kinetics using rat HEV (rHEV) as a surrogate model and using two routes of virus inoculation: intravenous (I.V.) or oral infection. Approach and ResultsWe frequently collected feces, serum, and tissue samples up to 60 days after infection in both infection models to characterize the rHEV viral kinetics. A ~2-week delay in quantifiable RNA levels in feces was observed in the oral versus the I.V. infection model. Early rHEV viral kinetics in feces were found to be multiphasic and showed good concordance with those in the various tissue compartments studied. Comparison of the viral kinetics in these samples also revealed that the liver may serve as the initial site of rHEV replication, followed by replication in the intestine and spleen. While a dosage of 60 mg/kg/day ribavirin was found optimal to maintain rHEV RNA levels at (nearly) undetectable in feces, levels were detectable in the liver and increased both in feces and liver after treatment discontinuation. ConclusionsWe found that the two rHEV infection models share similar multiphasic viral kinetics with the liver as the main site of viral replication. Additionally, the rHEV RNA load in feces could be used as a reliable proxy for that in the liver, spleen, and intestine. We also show that ribavirin at 60 mg/kg/day was partially effective in preventing viral rebound. These findings may aid in exploring the correlation between the infection phases and antiviral efficacy, ultimately guiding therapeutic decisions.

microbiology↗

bioRxiv2025

Oropouche virus results in severe congenital disease in embryonic mice

The recent outbreak of Oropouche virus (OROV) in Latin-America with unprecedented reports of vertical transmission resulting in congenital malformations and fetal death, redefines the threat posed by this arbovirus. We here explore the teratogenic potential of an epidemic strain of the virus in a mouse model, whereby a low inoculum of OROV is injected into the placenta. The virus replicates efficiently in multiple embryonic organs, with high titers in the brain, and causes intrauterine growth restriction. Infected embryos display multi-organ pathology, including pneumonitis, myocarditis, steatohepatitis and severe neuropathology. Embryonic brains exhibit microcephaly, ventriculomegaly and extensive neural loss, mirroring findings in human fetal cases. A dramatic alteration of the neural cell population correlates with massive cell death, demonstrating the extreme cytotoxicity of OROV for the developing brain. The infection also triggers neuroinflammation characterized by cytokine upregulation, microglial activation and neutrophil infiltration. Altogether, our findings establish a link between congenital OROV infection and neurodevelopmental disease, highlighting its teratogenic potential.

microbiology↗

bioRxiv2025

Oral 4-fluorouridine completely suppresses epidemic Oropouche virus replication in mice and confers protection against virus-induced disease.

Oropouche virus (OROV) is an orthobunyavirus that causes increasingly frequent and severe outbreaks in Central and South America. We report that 4'-fluorouridine (4'-FlU) inhibits the in vitro replication of epidemic and pre-epidemic OROV strains in multiple cell lines. In vitro polymerase assays demonstrate that 4'-FlU (as its triphosphate) targets the Peribunyaviridae L protein, is incorporated during RNA synthesis and causes premature chain termination. Following 69 consecutive days of in vitro passages of OROV in the presence of suboptimal concentrations of 4'-FlU, no drug-resistant variants were identified in the viral polymerase. In stringent mouse (AG129) or Syrian hamster OROV-infection models, oral administration of 4'-FlU completely blocked viral replication and virus-induced disease, even when administration was delayed until 72 hours after infection. Our findings support exploring the potential of 4'-FlU for the management of OROV infections in humans.

microbiology↗

bioRxiv2021

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

Predicting when future events will occur and adjusting behavior accordingly is critical to adaptive behavior. Despite this, little is known about the brain networks that encode time and how this ultimately impacts decision-making. One established finding is that the prefrontal cortex (PFC) and its non-human analogues (e.g., the rodent prelimbic cortex; PL) mediate timing. This provides a starting point for exploring the networks that support temporal processing by identifying areas that interact with the PFC during timing tasks. For example, substantial work has explored the role of frontostriatal circuits in timing. However, other areas are undoubtedly involved. The mediodorsal nucleus of the thalamus (MD) is an excellent candidate region. It shares dense, reciprocal connections with PFC-areas in both humans and non-human species and is implicated in cognition. However, causal data implicating MD-PFC interactions in cognition broadly is still sparse, and their role in timing specifically is currently unknown. To address this, we trained male rats on a time-based, decision-making task referred to as the peak-inter- val procedure. During the task, presentation of a cue instructed the rats to respond after a specific interval of time elapsed (e.g., tone-8 seconds). We incorporated two cues; each requiring a response after a distinct time-interval (e.g., tone-8 seconds / light-16 seconds). We tested the effects of either reversibly inactivating the MD or PL individually or functionally disconnecting them on performance. All manipulations caused a comparable timing deficit. Specifically, responses showed little organization in time, as if primarily guided by motivational systems. These data expand our understanding of the networks that support timing and suggest that MD-PL interactions specifically are a core component. More broadly, our results suggest that timing tasks provide a reliable assay for characterizing the role of MD-PL interactions in cognition using rodents, which has been difficult to establish in the past.

neuroscience↗