Biology subjects

Landrein, N.

Publications and source records attributed to Landrein, N..

4 recordsLinked to original sources

bioRxiv2026

A distinct signature of interferon-stimulated genes linked to cross-protection against secondary viral infections in primary bronchial epithelial cells

Respiratory viral infections, such as those caused by rhinovirus, adenovirus, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2, represent a major global health challenge. Despite extensive research, effective and specific antiviral treatments for these infections are still lacking, with patient care often limited to symptomatic relief. The SARS-CoV-2 pandemic, alongside the emergence of avian flu H1N1 and Nipah virus, has underscored the critical role of the respiratory tract as a critical viral target. Respiratory viral infections exhibit marked variability in infectivity and disease severity across different age groups. Epidemiological and cell-based evidence highlights distinct impacts on pediatric and adult populations. For instance, the COVID-19 disproportionately affected the elderly, while viruses like rhinovirus and adenovirus often cause severe morbidity in children. Additionally, clinical studies indicate that a primary respiratory infection can provide transient protection against subsequent infections by the same or different respiratory viruses. In this study, we utilized a differentiated bronchial epithelial (BE) model derived from pediatric and adult donors to assess age-dependent differences under resting conditions and during viral infections. We investigated how donor age influences infection susceptibility and viral spread within the BE, focusing on the transcriptional response to rhinovirus types A and C, and adenovirus type 5. Importantly, we demonstrate that prior viral infection confers protection against subsequent infections, regardless of donor age or the initial virus type. This cross-protection is driven by interferon signaling, leading to the expression of a narrow and specific set of interferon-stimulated genes (ISGs) in both infected and bystander cells. Notably, IFI44L shows the strongest correlation with the level of cross protection and that its overexpression alone significantly reduces viral infection of BE. These findings suggest a distinctive, interferon-driven innate immune response profile in the BE, offering critical insights for the development of new therapeutic strategies against respiratory viral infections.

microbiology↗

bioRxiv2025

Flagellar pocket collar biogenesis: Cytoskeletal organization and novel structures in a unicellular parasite

Understanding how cells build and organize their internal structures is a fundamental question in biology, with important implications for human health and disease. Trypanosomes are single-celled flagellated parasites that cause life-threatening diseases in human and animals. Their survival relies on a specialized compartment called the flagellar pocket (FP), which serves as a gateway for nutrient uptake, and immune evasion. The formation and function of the FP are supported by an intricate cytoskeletal structure known as the flagellar pocket collar (FPC). However, the mechanisms underlying its assembly remain poorly understood. In this study, we used cutting-edge ultrastructure expansion microscopy (U-ExM) to investigate FPC biogenesis in Trypanosoma brucei. We mapped the formation of the new microtubule quartet (nMtQ) alongside flagellum growth, providing new insights into its assembly. Additionally, we tracked the localization dynamics of key structural proteins - BILBO1, MORN1, and BILBO2 - during the biogenesis of the FPC and the hook complex (HC). Notably, we identified two previously undetected structures: the proFPC and the transient FPC-interconnecting fibre (FPC-IF), both of which appear to play crucial roles in linking and organizing cellular components during cell division. By uncovering these novel aspects of FPC biogenesis, our study significantly advances the understanding of cytoskeletal organization in trypanosomes and opens new avenues for exploring the functional significance of these structures.

microbiology↗

bioRxiv2025

LAVR-289, a New Orally Bioavailable Inhibitor of Adenovirus Replication in vitro and in vivo.

Adenoviruses are responsible for a range of pathologies, including respiratory infections in children, accounting for 5-10% of such cases. Although most adenovirus infections are self-resolving, they can cause serious illness, particularly in immunocompromised individuals. There is currently no approved treatment for adenovirus infections, although various therapeutic approaches are under investigation, including nucleoside analog inhibitors of replication. However, these treatments have shown limited efficacy. In this study, we report on the antiviral activity of LAVR-289, a broad-spectrum acyclonucleoside phosphonate exhibiting potent in vitro efficacy against several adenovirus serotypes, comparable to that of brincidofovir. LAVR-289 specifically inhibits viral replication, blocking the formation of viral replication centers and preventing late protein expression without affecting viral entry or delivery of viral genomes to the nucleus. In vivo using immunocompromised Syrian hamsters infected with HAdV-C6, oral administration of LAVR-289 resulted in 100% animal survival. These results suggest that LAVR-289 holds promise as a potential therapy for adenovirus infections, particularly in immunocompromised patients. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug. C_LIO_LILAVR-289 displays antiviral activity against Adenovirus with an EC50 of about 100 nM against HAdV-C5 ANCHOR. C_LIO_LILAVR-289 inhibits viral replication by targeting viral DNA polymerase, preventing DBP clustering and replication center formation. C_LIO_LIIn immunosuppressed Syrian hamsters, LAVR-289 is well tolerated and ensures 100% survival while effectively stopping virus replication. C_LIO_LILAVR-289's broad-spectrum activity positions it as a promising treatment for immunocompromised patients facing multiple viral infections. C_LI

microbiology↗

bioRxiv2021

Structural and functional studies of the first tripartite protein complex at the Trypanosoma brucei flagellar pocket collar

The flagellar pocket (FP) is the only endo- and exocytic organelle in most trypanosomes and, as such, is essential throughout the life cycle of the parasite. The neck of the FP is maintained enclosed around the flagellum via the flagellar pocket collar (FPC). The FPC is a macromolecular cytoskeletal structure and is essential for the formation of the FP and cytokinesis. FPC biogenesis and structure are poorly understood, mainly due to the lack of information on FPC composition. To date, only two FPC proteins, BILBO1 and FPC4, have been characterized. BILBO1 forms a molecular skeleton upon which other FPC proteins can, theoretically, dock onto. We previously identified FPC4 as the first BILBO1 interacting partner and demonstrated that its C-terminal domain interacts with the BILBO1 N-terminal domain (NTD). Here, we report the characterization of a new FPC component and BILBO1 partner protein, BILBO2 (Tb927.6.3240) by yeast two-hybrid screen, bioinformatics, functional and structural studies. We show that BILBO2 colocalizes with BILBO1 and can modulate the shape of the BILBO1 filament by interacting with the BILBO1 EF-hand domains. Further, we demonstrate that BILBO1 and BILBO2 share a homologous NTD domain and that both domains interact with FPC4. We have determined a 1.9 [A] resolution crystal structure of the BILBO2 NTD in complex with the FPC4 BILBO1-binding domain. Together with mutational analyses, our studies reveal key residues for the function of the BILBO2 NTD and its interaction with FPC4 and evidenced a tripartite interaction between BILBO1, BILBO2, and FPC4. Our work sheds light on the first atomic structure of an FPC protein complex and represents a significant step in deciphering the FPC function in Trypanosoma brucei and other pathogenic kinetoplastids. Author summaryTrypanosomes belong to a group of zoonotic, protist, parasites that are found in Africa, Asia, South America, and Europe and are responsible for severe human and animal diseases. They all have a common structure called the flagellar pocket (FP). In most trypanosomes, all macromolecular exchanges between the trypanosome and the environment occur via the FP. The FP is thus essential for cell viability and evading the host immune response. We have been studying the flagellar pocket collar (FPC), an enigmatic macromolecular structure at the neck of the FP, and demonstrated its essentiality for the biogenesis of the FP. We demonstrated that BILBO1 is an essential protein of the FPC that interacts with other proteins including a microtubule-binding protein FPC4. Here we identify another bona fide FPC protein, BILBO2, so named because of close similarity with BILBO1 in protein organization and functional domains. We demonstrate that BILBO1 and BILBO2 share a common N-terminal domain involved in the interaction with FPC4, and illustrate a tripartite interaction between BILBO1, BILBO2, and FPC4. Our study also provides the first atomic view of two FPC components. These data represent an additional step in deciphering the FPC structure and function in T. brucei.

cell biology↗