Biology subjects

Masonou, T.

Publications and source records attributed to Masonou, T..

5 recordsLinked to original sources

bioRxiv2026

Bovine H5N1 influenza viruses have adapted to more efficiently use receptors abundant in cattle

Sustained mammal-to-mammal transmission of high pathogenicity H5N1 avian influenza viruses is reshaping the host range of these pathogens. One of the longest-running mammalian transmission chains involves the B3.13 genotype circulating in U.S. dairy cattle which was detected in early 2024. Genomic analyses revealed selection and rapid fixation of haemagglutinin mutations D104G and V147M. We demonstate, via glycomic profiling, that bovine tissues, including the mammary gland, are enriched in N- and O-linked glycans capped with N-glycolylneuraminic acid (NeuGc), a sialic acid absent in humans and birds, which instead express only N-acetylneuraminic acid (NeuAc). Early cattle H5 viruses poorly recognized NeuGc, but D104G and V147M enabled efficient engagement of both NeuAc- and NeuGc-containing receptors. These mutations enhanced replication in bovine mammary tissue without major attenuation of replication in human lung and primary nasal epithelial cells. NeuGc-driven receptor adaptation therefore promotes viral fitness in cattle while potentially limiting immediate zoonotic risk. Deep mutational scanning further identified alternative haemagglutinin substitutions that confer NeuGc usage and represent surveillance markers for emerging cattle H5 lineages.

microbiology↗

bioRxiv2025

Polymerase mutations underlie adaptation of H5N1 influenza virus to dairy cattle and other mammals.

In early 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA1. As of mid-2025 the epidemic is ongoing, resulting in spillbacks into poultry, wild birds and other mammals including humans2. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells and tissues, as well as cells of other mammalian species including humans and pigs. We find evidence of several mammalian adaptations gained early in the evolution of these viruses in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor for viral genome replication. We show that this mutation adapts the polymerase to better interact with bovine ANP32 proteins, particularly ANP32A, and thereby enhances virus replication in bovine mammary systems and primary human airway cultures. Importantly, we show that ongoing evolution during 2024 and 2025 in the PB2 gene, including E627K and a convergently arising D740N substitution, further increase polymerase activity and virus replication in a range of mammalian cells. Thus, the continued circulation of H5N1 in dairy cattle not only allows virus adaption improving replicative ability in cattle, but also increases the risk of zoonotic spillover.

microbiology↗

bioRxiv2023

The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30- 50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/524211v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@dab12aorg.highwire.dtl.DTLVardef@1a57334org.highwire.dtl.DTLVardef@12e7983org.highwire.dtl.DTLVardef@2bbe6e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation

The cytokine interleukin-1{beta} (IL-1{beta}) has pivotal roles in antimicrobial immunity, but also incites inflammatory pathology. Bioactive IL-1{beta} is released following proteolytic maturation of the pro-IL-1{beta} precursor by caspase-1 inflammasomes. UBE2L3/UBCH7, a conserved ubiquitin conjugating enzyme, promotes pro-IL-1{beta} ubiquitylation and proteasomal disposal. However, UBE2L3 actions in vivo and ubiquitin ligases involved in this process are unknown. Here we report that deletion of Ube2l3 in mice markedly reduces pro-IL-1{beta} turnover in macrophages, leading to excessive mature IL-1{beta} production, neutrophilic inflammation and disease symptoms following inflammasome activation. A family-wide siRNA screen identified two ubiquitin ligases, TRIP12 and AREL1, which we show add K27-, K29- and K33- poly-ubiquitin chains on lysine residues in the pro domain and destabilise pro-IL-1{beta}. Mutation of ubiquitylation sites increased pro-IL-1{beta} stability, but did not affect proteolysis by caspase-1. The extent of mature IL-1{beta} production is therefore determined by precursor abundance, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1{beta}. Our study has uncovered fundamental processes governing IL-1{beta} homeostasis and provided molecular insights that could be exploited to mitigate its adverse actions in disease.

immunology↗

bioRxiv2019

Differential spatiotemporal targeting of Toxoplasma and Salmonella by GBP1 assembles caspase signalling platforms

Guanylate binding proteins (GBPs), a family of interferon (IFN)-inducible GTPases, can promote cell-intrinsic defense by removal of intracellular microbial replicative niches through host cell death. GBPs target pathogen-containing vacuoles or the pathogen itself, and assist in membrane-disruption and release of microbial molecules that trigger cell death by activating the inflammasomes. We previously showed that GBP1 mediates atypical apoptosis or pyroptosis of human macrophages infected with Toxoplasma gondii (Tg) or Salmonella enterica Typhimurium (STm), respectively. In mice, the p47 Immunity-related GTPases (IRGs) control the recruitment of GBPs to microbe-containing vacuoles and subsequent cell death. However, humans are devoid of functional IRGs, and the pathogen-proximal immune detection mechanisms by GBP1 are poorly understood. Here, we describe two novel single-cell assays which show that GBP1 promotes the lysis of Tg-containing vacuoles and Tg plasma membrane, resulting in the cytosolic detection of Tg-DNA. In contrast, we show GBP1 only targets cytosolic STm and does not contribute to bacterial escape into the cytosol of human macrophages. GBP1 interacts with caspase-4 and recruits it directly to the bacterial surface, where caspase-4 can be activated by LPS. During STm infection, caspase-1 cleaves and inactivates GBP1 at Asp192, a site conserved in related mammalian GBP1 proteins but not in murine Gbps. STm-infected human macrophages expressing a cleavage-deficient GBP1 mutant exhibit higher pyroptosis due to the absence of caspase-1-mediated feedback inhibition of the GBP1-caspase-4 pathway. Our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in detecting infection and the assembly and regulation of divergent caspase signaling platforms.

microbiology↗