Biology subjects

Maluquer de Motes, C.

Publications and source records attributed to Maluquer de Motes, C..

4 recordsLinked to original sources

bioRxiv2023

Type I IFN expression is inhibited during cell division by CDK4/6

Cells are equipped to defend themselves from invading pathogens through sensors such as cGAS, which upon binding DNA induces type I interferon (IFN) expression. Whilst IFNs are crucial for limiting viral infection and activating adaptive immunity, uncontrolled production causes excessive inflammation and autoimmunity. cGAS binds DNA of both pathogenic and cellular origin and its activity is therefore tightly regulated. This is particularly apparent during mitosis, where cGAS association with chromatin following nuclear membrane dissolution and phosphorylation by mitotic kinases negatively regulate enzymatic activity. Here we describe a novel mechanism by which DNA sensing and other innate immune pathways are regulated during cell division, dependent on cyclin dependent kinases (CDK) 4 and 6. Inhibition of CDK4/6 using chemical inhibitors, shRNA-mediated depletion, or overexpression of cellular CDK4/6 inhibitor p16INK4a, greatly enhanced DNA- or cGAMP-induced expression of cytokines and IFN-stimulated genes (ISG). Mechanistically, CDK4/6-dependent inhibition mapped downstream of cytoplasmic signalling events including STING and IRF3 phosphorylation, limiting innate immune induction at the level of IFN{beta} mRNA expression. This regulation was universal, occurring in primary and transformed cells of human and murine origin, and broad, as IFN{beta} expression was inhibited in a CDK4/6-dependent manner downstream of multiple pattern recognition receptors. Together these findings demonstrate that host innate responses are limited by multiple mechanisms during cell division, thus defining cellular replication as an innate immune privileged process that may be necessary to avoid aberrant self-recognition and autoimmunity.

immunology↗

bioRxiv2023

A maturation defective HIV-1 activates cGAS

BackgroundDetection of viruses by host pattern recognition receptors induces the expression of type I interferon (IFN) and IFN-stimulated genes (ISGs), which suppress viral replication. Retroviruses such as HIV-1 are subject to sensing by both RNA and DNA sensors, and whether there are any particular features of the viral genome or reverse transcripts that facilitate or enhance this sensing is currently unknown. ResultsWhilst investigating the determinants of innate detection of HIV-1 we noticed that infection of THP-1 cells or primary macrophages with a virus expressing Gag fused to a reporter gene (luciferase or GFP) induced a robust IFN and ISG response that was not observed with an equivalent virus with similar genome length and composition, but expressing wild-type Gag. Innate immune activation by Gag-fusion HIV-1 was dependent on reverse transcription and DNA sensor cGAS, suggesting activation of an IFN response by viral DNA. Further investigation of the Gag-fusion viral particles revealed maturation defects, as evidenced by incomplete Gag cleavage and a diminished capacity to saturate restriction factor TRIM5, likely due to aberrant particle formation. We propose that expression of the Gag fusion protein disturbs the correct cleavage and maturation of wild-type Gag, yielding viral particles that are unable to effectively shield viral DNA from detection by innate sensors including cGAS. ConclusionsThese data highlight the crucial role of capsid in innate evasion and support growing literature that disruption of Gag cleavage and capsid formation induces a viral DNA- and cGAS-dependent innate immune response. Together these data demonstrate a protective role for capsid and suggest that antiviral activity of capsid-targeting antivirals may benefit from enhanced innate and adaptive immunity in vivo.

microbiology↗

bioRxiv2023

Different Coexisting Mpox Lineages Were Continuously Circulating in Humans Prior to 2022

The origin and hazardous potential of human mpox is obscured by a lack of genomic data between the 2018, when exportations from Nigeria were recorded, and 2022 when the global outbreak started. Here, 18 genomes from patients across southern Nigeria in 2019/20 reveal multiple lineages of Monkeypox virus have achieved sustained human-to-human transmission, co-existing in humans for several years and accumulating mutations consistent with APOBEC3 activity suggesting the virus in humans is now segregated from its natural reservoir. Remarkably, three genomes have disruptions in the A46R gene, which contributes to innate immune modulation. The data demonstrates that the A.2 lineage, multiply exported to North America since 2021 independently of the global outbreak, has persisted in Nigeria for more than two years prior to its latest exportation. One-Sentence SummaryMpox is now a human diseae evolving in humans with multiple variants taking separate paths towards adaptation, some analogous to those of Variola

microbiology↗

bioRxiv2019

Beneficial bacteria activate type-I interferon production via the cytosolic sensors STING and MAVS

Type-I interferon (IFN-I) cytokines are produced by innate immune cells in response to microbial infections, cancer and autoimmune diseases. These cytokines trigger protective responses in neighbouring cells through the activation of IFN-I stimulated genes. One of the most predominant pathways associated with IFN-I production is mediated by the cytosolic sensors STING and MAVS, intracellular adaptors that become activated in the presence of microbial nucleic acids in the cytoplasm, leading to IFN-I production via TANK-binding kinase (TBK)-1 and IFN regulatory factors. However, the role of these sensors in responses induced by beneficial microbes has been relatively unexplored. Here we have screened 12 representative strains of lactic acid bacteria (LAB), a group of beneficial microbes found in fermented food and probiotic formulations worldwide, for their ability to trigger IFN-I responses. Two isolates (Lactobacillus plantarum and Pediococcus pentosaceus) induced an IFN-I production that was significantly higher that the rest, both in macrophage cell lines and human primary macrophages. This response correlated with stronger interaction with macrophages and was susceptible to phagocytosis inhibitors, suggesting bacterial internalisation. Accordingly, macrophages deficient for STING and, to a lesser extent, MAVS failed to respond to the two LAB, showing reduced TBK-1 phosphorylation and IFN-I activation. Furthermore, LAB-induced IFN-I was biologically active and resulted in expression of interferon stimulated genes, which was also STING- and MAVS-dependent. Our findings demonstrate a major role for STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to modulate protective responses in the host.

immunology↗