Biology subjects

Biquand, E.

Publications and source records attributed to Biquand, E..

3 recordsLinked to original sources

bioRxiv2026

Hijacking of inflammasome responses by the complement system during Pseudomonas aeruginosa-Aspergillus fumigatus sur-infection

Patients with cystic fibrosis (pwCF) are highly susceptible to chronic pulmonary infections due to mutations in the CFTR gene. From early childhood, pwCF experience repeated lung infections and often develop chronic bacterial and/or fungal colonization. Among the most clinically relevant pathogens, Pseudomonas aeruginosa and Aspergillus fumigatus frequently co-infect and are associated with worse outcomes, including excessive IL-1{beta}-driven inflammation and accelerated lung function decline. Here we investigated the mechanisms underlying inflammasome overactivation during super-infection. We found that inflammasome hyperactivation occurred across macrophage populations, was independent of exogenous priming, and required live co-infection with both pathogens. P. aeruginosa and A. fumigatus cooperatively activated the NLRP3 inflammasome, and this response required both caspase-1 and caspase-8. Unexpectedly, gasdermin D was dispensable for IL-1{beta} release. Bacterial flagellin, type IV pili and the type III secretion system, as well as the fungal polysaccharide galactosaminogalactan (GAG), were each required for overactivation. Mechanistically, P. aeruginosa activated the MyD88-TLR pathway, enhancing macrophage responses and promoting ITGAM (CD11b) expression. Under fungal super-infection, macrophages secreted complement component C3, which may bound fungal surface and engaged the complement receptor C3R (CD11b/CD18). Downstream SYK and ERK signaling amplified inflammasome activation and IL-1{beta} release. Single-cell transcriptomic analysis of pwCF broncho-alveolar lavage and lung samples supported coordinated upregulation of complement and inflammasome pathways during bacterial-fungal infection. Together, these findings identify a complement-inflammasome signaling axis that drives pathological inflammation during bacterial-fungal co-infection in airways of pwCF and may represent a therapeutic target.

immunology↗

bioRxiv2021

The immediate early protein 1 of the human herpesvirus 6B counteracts NBS1 and prevents homologous recombination repair pathways

Viral infection often trigger an ATM-dependent DNA damage response (DDR) in host cells that suppresses viral replication. To counteract this antiviral surveillance system, viruses evolved different strategies to induce the degradation of the MRE11/RAD50/NBS1 (MRN) complex and prevent subsequent DDR signaling. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing the host cells ability to induce ATM-dependent signaling pathways. Expression of immediate early protein 1 (IE1) phenocopies this phenotype and blocks further homology-directed double-strand break (DSB) repair. In contrast to other viruses, IE1 does not affect the stability of the MRN complex. Instead, it uses two distinct domains to inhibit ATM serine/threonine kinase (ATM) activation at DSBs. Structure-based analyses revealed that the N-terminal domain of IE1 interacts with the BRCA1 C-terminal domain 2 of nibrin (NBN, also known as NBS1), while ATM inhibition is attributable to on its C-terminal domain. Consistent with the role of the MRN complex in antiviral responses, NBS1 depletion resulted in increased HHV-6B replication in infected cells. However, in semi-permissive cells, viral integration of HHV-6B into the telomeres was not strictly dependent on NBS1, supporting models where this process occurs via telomere elongation rather than through DNA repair. Interestingly, as IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases. Significance StatementMany viruses have evolved ways to inhibit DNA damage signaling, presumably to prevent infected cells from activating an antiviral response. Here, we show that this is also true for human herpesvirus 6B (HHV-6B), through its immediate early protein 1 (IE1). However, in contrast to adenovirus immediate early proteins, HHV-6B IE1 is recruited to double-strand breaks in an NBS1-dependent manner and inhibits ATM serine/threonine kinase activation. Characterizing this phenotype revealed a unique mechanism by which HHV-6B manipulates DNA damage signaling in infected cells. Consistently, viral replication is restricted by the MRN complex in HHV-6B infected cells. Viral integration of HHV-6B into the hosts telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair.

microbiology↗

bioRxiv2019

OTUB1 is a key regulator of RIG-I dependent immune signalling and is targeted for proteasomal degradation by influenza A NS1

Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host innate immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, DUBs that regulate this pathway have not been identified. Using a ubiquitin C-terminal electrophile, we profiled DUBs that function during influenza A virus (IAV) infection, and isolated OTUB1 as a key regulator of RIG-I dependent antiviral responses. OTUB1 was interferon-inducible, and interacted with RIG-I, viral PB2 and NS1. Upon infection, OTUB1 relocalised from the nucleus to mitochondrial membranes, and activated the RIG-I signaling complex via hydrolysis of K48 polyubiquitin chains and by forming a repressive complex with UBCH5c. Using a reconstituted system composed of in vitro translated [35S]IRF3, purified RIG-I, mitochondrial membranes and cytosol expressing OTUB1 variants, we recapitulated the mechanism of OTUB1-dependent RIG-I activation. A wide range of IAV NS1 proteins triggered proteasomal degradation of OTUB1, thereby antagonizing the RIG-I signaling cascade and antiviral responses.\n\nHighlightsO_LIOTUB1 is induced during influenza A virus infections in an IFN-I dependent manner\nC_LIO_LIOTUB1 regulates the RIG-I complex by hydrolysing K48-linked polyubiquitin chains and by sequestering UBCH5c to prevent K48 polyubiquitylation\nC_LIO_LIOptimal K63 versus K48 polyubiquitin chain concentrations determine RIG-I activation\nC_LIO_LIInfluenza NS1 targets OTUB1 for proteasomal degradation\nC_LI

biochemistry↗