Olayemi A, Sarapak J, Wilhelm K
… +4 more, Günther S, Sommer S, Fichet-Calvet E, Melville DW
PLoS Pathog
· 2026 Apr · PMID 41996453
·
Full text
Identifying genes under local adaptation is an essential step to understand the mechanisms of adaptive evolution. Pathogen-mediated selection is expected to enhance host fitness by favouring resistance to locally prevale...Identifying genes under local adaptation is an essential step to understand the mechanisms of adaptive evolution. Pathogen-mediated selection is expected to enhance host fitness by favouring resistance to locally prevalent pathogens. However, such pathogen-driven adaptation has been documented in only a few natural systems. Here, we sequenced the Major Histocompatibility Complex Class I region (MHC-I) of 739 Mastomys natalensis captured in Guinea and Nigeria, where the rodent is reservoir to two distinct Lassa virus (LASV) lineages. As predicted, the MHC-I profiles of the two countries, while showing overlap, did not cluster together. Moreover, different MHC-I alleles were associated with active or past infection measured as PCR-positive or IgG-positive, respectively, in each population. MHC-I allele ManaMHC-I*017 showed a diametric response, with individuals carrying this allele less likely to be found with an ongoing LASV infection in Guinea while more likely in Nigeria. Similarly, individuals with ManaMHC-I*069 were less likely to have a positive antibody test in Guinea but the same allele had little effect on IgG detection in Nigeria, suggesting that an individual's fitness depends on its immunogenetic repertoire. Together, these findings encapsulate a genetically characterised case of local adaptation in a wild virus-rodent system. Moreover, we hypothesise that aside from differences in virus diversity, genetic variation within regional LASV lineages contributes to the marked differences in host immunogenetic diversity.
Wang Q, Hao P, Zhu SY
… +7 more, Zhou JF, Feng S, Dai Q, Wei JC, Go YY, Chen J, Zhou B
PLoS Pathog
· 2026 Apr · PMID 41996449
·
Full text
Flaviviruses intricately rewire host metabolic networks to establish a replication-permissive environment; however, the role of glucose transporter-mediated uptake, particularly via glucose transporter 4 (GLUT4), remains...Flaviviruses intricately rewire host metabolic networks to establish a replication-permissive environment; however, the role of glucose transporter-mediated uptake, particularly via glucose transporter 4 (GLUT4), remains insufficiently defined. Japanese encephalitis virus (JEV) infection induces extensive remodeling of glucose metabolism, exemplified by the coordinated upregulation of critical metabolic effectors. Pharmacological blockade of glucose metabolic pathways markedly attenuates JEV replication, whereas exogenous glucose supplementation enhances viral propagation in a concentration-dependent manner. A targeted screen of 111 metabolism-oriented compounds identified selective GLUT4 inhibitors with potent antiviral efficacy. Notably, GLUT4 expression is consistently upregulated during JEV infection across multiple cell types, albeit to varying degrees, and is similarly induced by duck Tembusu virus (DTMUV), suggesting a potentially conserved mechanism shared by these two flaviviruses. However, broader validation across additional members of the Flavivirus genus remains warranted. Mechanistically, the viral nonstructural protein 3 (NS3) engages insulin receptor substrate 1 (IRS1), thereby activating the IRS1-PI3K-Akt-mTORC1-SREBP-1c signaling axis to transcriptionally drive GLUT4 expression. Concurrently, JEV infection induces PI3K-Akt-dependent phosphorylation of AS160, promoting GLUT4 vesicular trafficking via the coordinated action of Rab8 and Rab10. Collectively, these findings delineate a previously unrecognized mechanism whereby JEV commandeers host insulin signaling to orchestrate GLUT4 biosynthesis and membrane translocation, thereby ensuring continuous metabolic substrate availability to sustain replication. This GLUT4-centric metabolic circuitry represents a mechanistically tractable target for host-directed antiviral strategies against Flavivirus.
Liu Y, Xu M, Huang X
… +10 more, Liu X, Fan K, Zhang Y, Xing C, Tang H, Jiang J, Xu K, He M, Xu G, Zhang C
PLoS Pathog
· 2026 Apr · PMID 41984992
·
Full text
SFTSV, a tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), exhibits symptoms such as thrombocytopenia, leukocytopenia, hemorrhage, disseminated intravascular coagulation, and even mult...SFTSV, a tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), exhibits symptoms such as thrombocytopenia, leukocytopenia, hemorrhage, disseminated intravascular coagulation, and even multiple-organ failure. Nevertheless, the underlying pathogenic pathways of this disease remain poorly understood. In this study, by utilizing a lethal mouse model of IFNAR-/- mice, we discovered that complement hyperactivation occurs in the spleen, and the spleen serves as a source of the central complement component C3 in SFTSV-infected mice. Infection of spleen stromal fibroblastic reticular cells with SFTSV significantly induces intracellular complement pathways through a type I IFN-independent manner and generates the active component C3a through the alternative pathway. The transcription of C3 and complement factor B (Cfb) in SFTSV-infected fibroblastic reticular cells is regulated by C/EBP-β. Administration of a C3aR antagonist leads to a reduction in virus load and the inflammatory response, alleviates spleen injury, and prolongs the survival time in IFNAR-/- mice. Collectively, our findings suggest that targeted complement therapy holds potential for the intervention of severe SFTS.
Lotoux A, Bertrand M, Douarre PE
… +11 more, Kortebi M, Riveiro H, Palma F, Lakisic G, Fox EM, Guillier L, Oevermann A, Roussel S, Bierne H, Pagliuso A, Milohanic E
PLoS Pathog
· 2026 Apr · PMID 41984808
·
Full text
During infection in epithelial cells, after invading the cytosol, multiplying, and spreading, Listeria monocytogenes (Lm) ceases to produce ActA and becomes trapped in Listeria-containing vacuoles (LisCVs). These persist...During infection in epithelial cells, after invading the cytosol, multiplying, and spreading, Listeria monocytogenes (Lm) ceases to produce ActA and becomes trapped in Listeria-containing vacuoles (LisCVs). These persistence acidic vacuoles harbor bacterial subpopulations that resist to stress in a metabolically dormant state. Although LisCVs have been proposed as a hallmark of Lm persistence in epithelial cells, their prevalence across strains and the bacterial factors underlying their formation remain uncharacterized. Given the significant genetic diversity within the species, it is important to consider this variability when studying persistence phenotype. Therefore, we screened over one hundred Lm isolates spanning two major evolutionary lineages and belonging to 23 clonal complexes from diverse ecological origins. Strikingly, the vast majority of strains, including both clinical and environmental isolates, were capable of forming LisCVs, suggesting that vacuolar persistence is a widespread and conserved feature of Lm pathogenesis. Nevertheless, among the group of hypo-virulent strains mostly associated with food and carrying a truncated InlA, we identified four isolates with an altered persistence phenotype. Two of them showed defects in the early stages of infection and carried mutations in key virulence genes (hly and gshF). The other two, instead, were specifically affected in the persistence stage by showing a reduced ability to form LisCVs. Comparative genomic analysis revealed that a mutation in the folP gene, required for folate biosynthesis, was responsible for impaired persistence. Live-imaging and microscopy analysis highlighted a reduced bacterial motility and intercellular spreading of the folP mutant, although the level of ActA at the bacterial surface was increased. Together, our work identifies folate biosynthesis as a critical metabolic pathway governing Lm persistence by regulating ActA levels and activity. Downregulation of ActA at the bacterial surface is therefore a crucial event for the establishment of the intracellular persistent niche during long-term infection of epithelial cells.
Niu K, Fang Y, Deng Y
… +7 more, Wang Z, Xie S, Zhu J, Song B, Wu W, Jing Z, Peng C
PLoS Pathog
· 2026 Apr · PMID 41973769
·
Full text
Many poxviruses are significant zoonotic pathogens threatening public health. Autophagy, a regulated process vital for cellular homeostasis, can participate in defense against virus invasion. However, the relationship be...Many poxviruses are significant zoonotic pathogens threatening public health. Autophagy, a regulated process vital for cellular homeostasis, can participate in defense against virus invasion. However, the relationship between poxviruses and host cell autophagy is not fully understood. This study shows that vaccinia virus (VACV) induces autophagy but blocks autophagosome-lysosome fusion. Modified vaccinia virus Ankara (MVA), an attenuated VACV strain that cannot replicate in most mammalian cells, fails to do so. Both pharmacological inhibition of early autophagy via 3-MA treatment and genetic ablation of ATG3 and ATG7 led to a significant enhancement of MVA replication. The VACV protein A52 inhibits autolysosome formation by disrupting interactions between SNAP29, STX17, and VAMP8, which is crucial for autophagic flux. Importantly, A52 also promotes the degradation of SNAP29, thereby aiding viral replication. Furthermore, SNAP29 is a newly identified host restriction factor for MVA, as its suppression enables MVA replication in human cells. These findings elucidate how poxviruses modulate autophagy for their own replication and further explain MVA's restriction in human cells.
Hernandez GE, Valencia-Bacca JD, Bennett EF
… +10 more, Islam MM, Maiti S, Nutter NA, Young TM, Caudell DL, Costa-Terryll A, Skelly JJ, Floyd ET, Atkins HM, Zafar MA
PLoS Pathog
· 2026 Apr · PMID 41973764
·
Full text
Hypervirulent Klebsiella pneumoniae (hvKP) is an emerging pathotype capable of causing severe systemic infections. Gastrointestinal (GI) colonization often precedes invasive disease, but the mechanisms driving translocat...Hypervirulent Klebsiella pneumoniae (hvKP) is an emerging pathotype capable of causing severe systemic infections. Gastrointestinal (GI) colonization often precedes invasive disease, but the mechanisms driving translocation to extra-intestinal sites are not known. A hallmark of hvKP is a large virulence plasmid encoding a number of virulence factors, including aerobactin, a siderophore associated with enhanced virulence. Using a murine GI colonization model with an intact microbiota, we examined if aerobactin enabled hvKP to translocate, by comparing an hvKP clinical isolate (hvKP1) to an isogenic aerobactin biosynthesis mutant (iucA-). Both strains colonized the GI tract similarly, but mice colonized with the iucA- mutant exhibited significantly lower bacterial burdens in the extra-intestinal organs, indicating a defect in translocation. This defect was not observed in a systemic infection model, suggesting a specific role for aerobactin in GI translocation. In cell culture based assays, the iucA- mutant showed reduced adhesion, invasion, and translocation. Both in vivo and in vitro data supported a transcellular route of translocation. Notably, the iucA- mutant displayed increased hypermucoviscosity (HMV) linked to the upregulation of the rmp locus, likely impairing host cell adhesion. These findings demonstrate that tight regulation of HMV through metal homeostasis mediated by aerobactin, promotes hvKP translocation across the intestinal epithelium by enhancing adhesion and cellular entry. This work offers new insight into hvKP pathogenesis and informs potential strategies to limit its invasive potential.
Doratt BM, Wagner SB, Malherbe DC
… +3 more, Smith G, Marzi A, Messaoudi I
PLoS Pathog
· 2026 Apr · PMID 41961912
·
Full text
Sudan virus (SUDV) has caused multiple outbreaks of human disease with case fatality rates ranging from 41 to 100%. We have previously shown that a single vaccination with a recombinant vesicular stomatitis virus-based v...Sudan virus (SUDV) has caused multiple outbreaks of human disease with case fatality rates ranging from 41 to 100%. We have previously shown that a single vaccination with a recombinant vesicular stomatitis virus-based vaccine expressing the SUDV-Gulu glycoprotein (VSV-SUDV) prevented clinical and fatal disease from lethal SUDV challenge in cynomolgus macaques. With the high probability of future outbreaks, it is critical to determine the molecular mechanisms of VSV-SUDV-mediated protection and the ability to impart rapid protection against SUDV infection. In this study, RNA from whole blood samples obtained from nine cynomolgus macaques that were challenged with SUDV-Gulu post-vaccination with either VSV-EBOV (28 days before challenge, n = 3) or VSV-SUDV (28 or 7 days before challenge, n = 3/group) was subjected to bulk RNA sequencing. EdgeR, STEM, MaSigPro, and CIBERSORTx were used to assess longitudinal transcriptional changes elicited by vaccination and challenge. Our analysis revealed that VSV-SUDV and VSV-EBOV elicited distinct transcriptional responses. Moreover, NHPs vaccinated with VSV-EBOV (non-protective) generated a transcriptional response following SUDV challenge indicative of dysregulated inflammation. In contrast, NHPs that received VSV-SUDV vaccine generated a transcriptional response indicative of a recall adaptive immune response. Finally, in-silico deconvolution methods indicated changes in immune cell frequency consistent with immune response and resolution in the VSV-SUDV-vaccinated NHPs that are not observed with VSV-EBOV-vaccinated NHPs. These data indicate that VSV-SUDV vaccination results in a protective humoral response as late as 7 days before challenge despite transcriptional evidence of subclinical features of infection.
Tang S, Patel A, Takeda K
… +2 more, Peden K, Krause PR
PLoS Pathog
· 2026 Apr · PMID 41961905
·
Full text
HSV ICP27, a multifunctional essential immediate early (IE) viral protein, regulates both viral and host pre-mRNA processing in a gene/sequence-specific manner. Using viral mutagenesis studies, we investigated the mechan...HSV ICP27, a multifunctional essential immediate early (IE) viral protein, regulates both viral and host pre-mRNA processing in a gene/sequence-specific manner. Using viral mutagenesis studies, we investigated the mechanisms underlying ICP27-mediated co-transcriptional splicing inhibition. We report that ICP27 inhibits pre-mRNA splicing by hijacking host serine/arginine-rich splicing factor 3 (SRSF3), which binds to an exonic ICP27/SRSF3-responsive motif near the 5' splice site of targeted transcripts, revealing that interaction with SRSF3 enhances both target specificity and efficiency of ICP27-mediated aberrant splicing, in a way independent of its RNA-binding RGG domain. Furthermore, ICP27 co-opts SRSF3 to promote nuclear-export of unspliced mRNA targets via the nuclear RNA export factor 1 (NXF1). Viruses with mutations both in the ICP27 N-terminal nuclear export signal (NES), via which ICP27 interacts with NXF1, and in the RGG RNA-binding domain, are defective in ICP27-mediated splicing inhibition, expression of ICP27-dependent genes, and viral growth, revealing that ICP27-mediated nuclear export of unspliced mRNA is indispensable for ICP27-mediated splicing inhibition and gene expression. Preventing U1 small nuclear ribonucleoprotein (U1 snRNP) binding by knockdown of U1-70K, a component of U1 snRNP that binds to the 5' splice site, led both to splicing inhibition and to enhanced expression of ICP27-dependent genes. Together, these results suggest a spatiotemporal role for ICP27 in regulating sequence-specific pre-mRNA splicing by hijacking SRSF3, preventing spliceosome formation, and subsequently promoting nuclear export of aberrantly processed mRNAs containing restrictive elements including intact 5' splice sites, which would otherwise be detained, spliced or degraded in the nucleus. We hypothesize that during latency, HSV likely takes advantage of the host mRNA processing machinery to restrict expression of randomly activated antigenic viral genes to achieve immune evasion when ICP27 is absent during latency. Upon reactivation, ICP27 is essential for ensuring both the quality and quantity of viral gene expression, enabling optimal viral replication.
Press KD, Bach F, Sola E
… +25 more, Camanag K, Dooley NL, Ivanawati A, Oyong D, Nalubega M, Kakuru A, Matsiko S, Nankya F, Musinguzi K, Nalwoga A, Nansubuga E, Ategeka J, Ebusu C, Odongo B, Kashiwagi C, Ji X, Miranda M, Tachiwa-Appiah J, Sandhu K, Kamalyan L, van der Ploeg K, Boyle M, Wagar LE, Davis MM, Jagannathan P
PLoS Pathog
· 2026 Apr · PMID 41961880
·
Full text
Vaccine effectiveness against malaria is dramatically reduced in malaria-exposed compared to malaria-naïve populations, potentially due to altered immune responses in secondary lymphoid organs following repeated infectio...Vaccine effectiveness against malaria is dramatically reduced in malaria-exposed compared to malaria-naïve populations, potentially due to altered immune responses in secondary lymphoid organs following repeated infection. Newly developed human tonsil and spleen organoids, which replicate key features of B and T cell immunity, provide an exciting opportunity to overcome challenges of other models and to improve our understanding of innate-adaptive interactions in lymphoid tissue. The objectives of this study were to use these organoids to investigate the impact of malaria parasites on 1) cells within lymphoid tissues and 2) responses to a heterologous antigen. When we exposed organoids from malaria-naïve donors to Plasmodium falciparum-infected red blood cells (iRBC), we observed that iRBC exposure did not disrupt organoid formation and significantly increased Vδ2 + γδ T cell frequencies in both tonsil and spleen organoids at multiple timepoints. Single-cell RNA/TCR sequencing revealed that iRBC-responsive Vδ2 + T cells in organoids were clonally expanded and exhibited activated, cytotoxic phenotypes with upregulated expression of granzymes, interferon-stimulated genes, and antigen presentation machinery. TCR repertoire analysis demonstrated that malaria exposure drove clonal expansion of cytotoxic Vδ2 + T cells, contrasting with the diverse, smaller clones observed in control conditions. To validate these findings, we analyzed tonsils from Ugandan children with asymptomatic parasitemia and found expanded Vδ2 + T cells with enhanced cytotoxic potential compared to uninfected controls. When we tested whether malaria pre-exposure affected subsequent recall responses to influenza vaccine, malaria pre-exposure or γδ T cell depletion did not significantly alter cellular frequencies or influenza-specific antibody responses in most donors, though modest reductions were observed in some individuals. This work demonstrates the utility of human lymphoid organoids for studying malaria-host interactions and provides novel insights into Vδ2 + T cell biology, including evidence for clonal expansion and cytotoxic differentiation in response to malaria parasites within secondary lymphoid tissues.
Li Y, Zhang X, Liang R
… +6 more, Li R, Yang R, Zhang L, Zhao Y, Zhang G, Zhao J
PLoS Pathog
· 2026 Apr · PMID 41955273
·
Full text
Infectious bronchitis virus (IBV), a Gammacoronavirus with strict host tropism, infects chickens and avian-derived primary cells but not mammalian cells. The classical Beaudette strain, isolated in the 1930s, is a well-e...Infectious bronchitis virus (IBV), a Gammacoronavirus with strict host tropism, infects chickens and avian-derived primary cells but not mammalian cells. The classical Beaudette strain, isolated in the 1930s, is a well-established IBV strain capable of replicating in Vero cells. Although sporadic reports have described similar adaptation in other strains, the molecular mechanisms underlying IBV cell tropism remain unclear. Here, a prevalent IBV strain was passaged in embryonated eggs and primary host cells to generate quasispecies diversity, followed by an alternating host-nonhost passage strategy that enabled efficient replication in BHK-21 cells within ten passages. Reverse genetics identified mutations in nsp4 (T53I), the E protein (E10G), and the S2 subunit as key contributors to mammalian cell tropism expansion. Notably, some of these mutations were detectable prior to BHK-21 passaging, suggesting that pre-existing variants laid the foundation for subsequent adaptation. Furthermore, introducing this minimal mutation set into the GI-1 H120 virus backbone similarly enabled efficient replication in BHK-21 cells, yielding titers of 105.4 TCID50/ml. In vivo, the nsp4-E-S2 mutant exhibited a 40% reduction in mortality compared with the wild type, and RNA sequencing revealed attenuated inflammatory responses. Collectively, our findings indicate that mammalian cell tropism expansion in IBV is associated with the stepwise selection of pre-existing variants, resulting in coordinated mutations in the S protein and other structural and non-structural proteins that reduced pathogenicity while maintaining protective efficacy, highlighting BHK-21 cells as a promising platform for next-generation vaccine development.
Kowarsky M, Dalman M, Moufarrej MN
… +8 more, Okamoto J, Xie Y, Neff NF, Abdool Karim SS, Garrett N, Moore PL, Camunas-Soler J, Quake SR
PLoS Pathog
· 2026 Apr · PMID 41955174
·
Full text
A small number of people living with HIV (PLWH) develop broadly neutralizing antibodies (bNAbs) targeting multiple HIV strains. Although several viral and immune factors contribute to bNAb development, the genetic and en...A small number of people living with HIV (PLWH) develop broadly neutralizing antibodies (bNAbs) targeting multiple HIV strains. Although several viral and immune factors contribute to bNAb development, the genetic and environmental factors driving this response remain largely unknown. We performed combined cell-free DNA (cfDNA) and cell-free RNA (cfRNA) sequencing in 42 plasma samples from a longitudinal cohort of 14 PLWH (7 who develop bNAbs and 7 matched controls). This approach enabled us to non-invasively monitor the host transcriptome, viral genetic variation, and microbiome composition during HIV infection, and to identify molecular correlates of bNAb development. We find that development of bNAbs is associated with a transcriptomic signature of early immune activation characterized by elevated levels of MHC class I antigen presentation genes. This signature is independent of viral load or CD4 count and declines over time. In addition to host features, we recovered sufficient viral reads to reconstruct HIV consensus sequences, supporting the utility of cfRNA for viral genotyping. Finally, we also identified an enrichment of several microbial taxa in bNAb producers and increased levels of GB virus C (GBV-C), a non-pathogenic lymphotropic virus. Our findings suggest a distinct early immune activation profile in PLWH who develop bNAbs. More broadly, we show that combined cfDNA/cfRNA sequencing can reveal relationships between a protective immunogenic response to HIV infection, the host immune system, and microbiome, highlighting its potential for biomarker discovery in future vaccine and therapeutic studies.
VanderGiessen M, Harris E, Yin L
… +8 more, Heath B, Carney SK, Woodson CM, Wu X, Johnson E, Xie H, Theus M, Kehn-Hall K
PLoS Pathog
· 2026 Apr · PMID 41950299
·
Full text
Venezuelan equine encephalitis virus (VEEV), a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Viral infections, including VEEV, have been linked to neurological diseases such as Parkinso...Venezuelan equine encephalitis virus (VEEV), a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Viral infections, including VEEV, have been linked to neurological diseases such as Parkinson's and Alzheimer's, though mechanisms remain unclear. Currently, not only are there no therapeutic options for VEEV available, but there is also limited information on the host responses following infection that contribute to neurological sequelae. To fill this gap in knowledge, longitudinal neuropathological, behavioral, and single-cell transcriptomic changes were examined in C57BL/6 mice intranasally infected with VEEV TC-83. Acute infection significantly altered inflammatory and innate immune single-cell signaling, induced astrocyte and microglia activation, and resulted in the loss of neurons in the hippocampus. Persistent motor dysfunction, memory impairment, and reduced anxiety-like behavior were observed up to 106 days post-infection (DPI) and more significantly in animals that displayed neurological symptoms during acute infection. These changes correlated with alterations in single-cell gene expression of synaptogenic signaling genes, neuron loss, and persistent glia cell activation at 106 DPI. Collectively, this study demonstrates that infection with VEEV induces chronic alterations in the hippocampus that correlate with neurological sequelae observed in human patients.
Hulswit RJG, Shamorkina TM, van der Lee J
… +6 more, Rosman F, Wetzels LS, van Kuppeveld FJM, Snijder J, Bosch BJ, Hurdiss DL
PLoS Pathog
· 2026 Apr · PMID 41950284
·
Full text
Coronaviruses (CoVs) exhibit a remarkable ability for spill-over infections into naive host populations. While much research has focused on the spike (S) glycoproteins of zoonotic alpha- and betacoronaviruses, the S prot...Coronaviruses (CoVs) exhibit a remarkable ability for spill-over infections into naive host populations. While much research has focused on the spike (S) glycoproteins of zoonotic alpha- and betacoronaviruses, the S proteins of gamma- and deltacoronaviruses, which predominantly infect avian hosts, remain poorly understood. Here, we present high-resolution cryo-EM structures of S proteins from two distinct gammacoronaviruses (75.7% sequence identity) that atypically infect marine mammals and belong to the Gammacoronavirus delphinapteri species. The cryo-EM reconstructions reveal that the spikes exhibit a unique quaternary architecture that distinguishes them from other coronaviruses. The S protein features a previously unidentified, tripodal quaternary assembly of the S1 subunit, in which S1B domains are presented in an upright position while their putative receptor binding sites are shielded by extended loops from the S1A domain of the same protomers. Additionally, the CeCoV spike proteins have evolved an additional and unique ~200 residue N-terminal domain (S10). S10 lacks homology to known protein sequences but displays structural similarity to members of the cupin protein superfamily. This represents a remarkable case of coronaviral exaptation of a host protein integrated into the S glycoprotein. Moreover, glycoproteomic analyses reveal that CeCoV S proteins are extensively N-glycosylated (>100 N-glycans per trimer), with a notable abundance of high-mannose glycans on S10 and O-glycosylation sites within a mucin-like loop at the trimer apex, all contributing to a dense glycan shield and potentially masking immunogenic epitopes. These findings demonstrate the structural diversity and adaptability of CoV S proteins, including alternative quaternary assemblies, additional domains, and diverse glycosylation strategies, offering new insights into the evolutionary mechanisms that enable coronaviruses to expand their host range and establish infections in novel species.
Kavaliauskas P, Risteen R, Alkhazraji S
… +4 more, Shirtliff B, Walsh TJ, Ibrahim AS, Bruno VM
PLoS Pathog
· 2026 Apr · PMID 41950283
·
Full text
Lomentospora prolificans is an environmental fungus that can cause life-threatening infections when airborne conidia are inhaled. Airway epithelial cells are likely to be the first host cells to interact with L. prolific...Lomentospora prolificans is an environmental fungus that can cause life-threatening infections when airborne conidia are inhaled. Airway epithelial cells are likely to be the first host cells to interact with L. prolificans during pulmonary infection; however, the fungal and host factors that govern this interaction are completely unknown. Herein, we combined whole fungal cell pulldowns of surface proteins from airway epithelial cells and liquid chromatography-mass spectrometry (LC-MS) to identify host proteins that could potentially serve as host receptors for the fungus. We provide evidence that integrin β4 serves as a receptor that promotes the initial binding of L. prolificans to airway epithelial cells. Integrin β4 can associate with L. prolificans conidia that have been heat-killed or pre-treated with proteinase K suggesting that the fungal ligand is not proteinaceous. Inhibition of integrin β4 function by siRNA-mediated knockdown, or blocking with an anti-integrin β4 antibody, significantly inhibited the ability of L. prolificans to adhere to human airway epithelial cells. Integrin β4 can also associate with, and promote the adherence of, two closely related species of fungal pathogens, Scedosporium apiospermum and Scedosporium boydii. Overall, our study provides novel insight into the molecular mechanisms underlying the initiation of infection by L. prolificans, and two closely related species.
PLoS Pathog
· 2026 Apr · PMID 41950282
·
Full text
Stimulator of interferon genes (STING) is a central player of innate immunity, coordinating host defense against viral infection and cancer. While the canonical architectures of apo-STING and ligand-bound STING have been...Stimulator of interferon genes (STING) is a central player of innate immunity, coordinating host defense against viral infection and cancer. While the canonical architectures of apo-STING and ligand-bound STING have been established, current knowledge is limited to a subset of species, and a comprehensive cross-species, ligand-resolved structural atlas remains incomplete. Here, we determined the high-resolution crystal structures of duck and bovine STING ligand-binding domains (LBDs) bound to 2'3'-cGAMP and of duck, bovine, and human STING LBDs bound to the non-nucleotide agonist diABZI3. In the 2'3'-cGAMP complexes, the lid regions were ordered and completely covered the ligand-binding pocket, whereas in the diABZI3 complexes, the lid regions were completely disordered. In human and bovine STING, 2'3'-cGAMP induced a more closed dimer conformation than diABZI3, while duck STING exhibited minimal differences in closure between the two ligands. Strikingly, non-reducing SDS-PAGE revealed a distinct disulfide-linked tetramer in duck STING, which is abolished by the C195S mutation. Within the crystal lattice of the duck STING LBD-2'3'-cGAMP complex, we observed a unique Z-shaped tetramer stabilized by an interfacial disulfide bond between C195 and a network of polar interactions. Disrupting this interface, either by the C195S mutation or by ligand stimulation with 2'3'-cGAMP or diABZI3, relieved the tetrameric constraint and amplified STING signaling, establishing this tetramer as a duck-specific autoinhibitory assembly. These findings expand the structural repertoire of STING oligomeric assemblies, fill the structural gap for duck STING, and provide a comparative structural framework for species-specific STING regulation.