Cao W, He S, Schulz H
… +17 more, Wight J, Chan M, Emeterio K, Liu G, Audet J, Tierney K, Azaransky K, Frost K, Gee L, McQueen P, Chong P, Sulkosky SB, Booth S, Westmacott G, Saphire EO, Zeng X, Banadyga L
PLoS Pathog
· 2026 May · PMID 42081574
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Ebola virus (EBOV) infection typically results in severe-and often lethal-acute disease. However, increasing evidence suggests that EBOV can persist in certain immune-privileged tissues, which may then serve as reservoir...Ebola virus (EBOV) infection typically results in severe-and often lethal-acute disease. However, increasing evidence suggests that EBOV can persist in certain immune-privileged tissues, which may then serve as reservoirs for the later reemergence of EBOV and disease recrudescence. Here, we report atypical EVD recrudescence in a ferret model inoculated with an otherwise lethal dose of EBOV and treated with low doses of a highly potent monoclonal antibody cocktail. Among 32 antibody-treated ferrets, 14 animals survived, while 8 succumbed to acute EVD within about 5-8 days. The remaining 10 animals succumbed to atypical EVD between 12 and 18 days post-infection (DPI) despite having shown no, or very minor, signs of illness during the acute phase of disease. While viremia disappeared by 14 DPI in most animals that succumbed to atypical EVD, it rebounded modestly just prior to death. Unlike animals that died of acute EVD, those that died of atypical EVD showed only a moderate systemic inflammatory response and few signs of organ dysfunction, in line with low levels of virus in the liver and spleen. Interestingly, however, ferrets that died of atypical EVD showed high levels of virus in the brain, consistent with increased markers of inflammation in the central nervous system and significant pathological changes, including a breakdown in the blood-brain barrier and severe meningoencephalitis. Not only does this study shed important light on the atypical and underappreciated manifestations of EVD, but it also establishes the ferret as a valuable model of EBOV recrudescence.
Vigneron A, Weiss BL, Feng Y
… +7 more, Wang J, Awuoche E, Nguyen H, Orfano A, Yang L, Aksoy E, Aksoy S
PLoS Pathog
· 2026 May · PMID 42081573
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Peptidoglycan Recognition Proteins (PGRPs) are conserved proteins regulating immune responses to the peptidoglycan microbe-associated molecular patterns (MAMPs). Compared to other dipterans, the tsetse fly (Glossina mors...Peptidoglycan Recognition Proteins (PGRPs) are conserved proteins regulating immune responses to the peptidoglycan microbe-associated molecular patterns (MAMPs). Compared to other dipterans, the tsetse fly (Glossina morsitans morsitans) genome encodes only five PGRPs- PGRP-LA, -LB, -LC, -SA, and -SB - far fewer than most dipterans, likely reflecting its sterile blood diet and streamlined microbiota. Here, we identify PGRP-LA as a critical regulator of peritrophic matrix (PM) integrity in the cardia (proventriculus), the tissue responsible for PM production. The PM is a chitinous sleeve-like barrier that separates the midgut epithelium from the ingested bloodmeal, supporting digestive homeostasis and infection resistance. We show that pgrp-la is prominently expressed in the cardia, transiently induced after a bloodmeal in newly eclosed flies, and reinduced following subsequent feedings, likely in response to blood- constituents or mechanical stretch. This induction is sustained during microbial exposure and prolonged in trypanosome-infected flies. RNAi-mediated reduction of pgrp-la significantly increased the prevalence of midgut trypanosome infections, indicating a protective role during early infection. PGRP-LA did not mediate infection resistance via canonical IMD pathway signaling, as its silencing did not affect antimicrobial peptide expression. Instead, PGRP-LA modulated the expression of PM-associated genes and gut barrier integrity. Silencing pgrp-la reduced PM structure, increased midgut weights and enhanced fly survival following oral challenge with entomopathogen Serratia marcescens, likely due to earlier epithelial immune responses through a compromised PM. Similar phenotypes were observed when flies were fed anti-PGRP-LA antibodies, supporting a structural role for PGRP-LA. In addition, soluble variant surface glycoproteins (sVSGs) from trypanosomes and knockdown of microRNA-275 (miR-275), also decreased pgrp-la expression, suggesting that PGRP-LA is part of a broader regulatory network, including the miR-275/Wingless signaling. Collectively, our results identify PGRP-LA as novel regulator of PM biogenesis and vector competence in tsetse, expanding the functional repertoire of PGRPs in insect gut barrier maintenance beyond canonical immune signaling pathways.
Woods RA, Acosta IC, Resko ZJ
… +7 more, Agbavor C, Svet L, Yousef M, Teoh WP, Torres VJ, Cahoon LA, Alonzo III F
PLoS Pathog
· 2026 May · PMID 42081561
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The nutritional demands imposed by disparate infection sites represent a significant barrier to bacterial survival. Yet, the proclivity of pathogens such as Staphylococcus aureus to cause disease at nearly all host sites...The nutritional demands imposed by disparate infection sites represent a significant barrier to bacterial survival. Yet, the proclivity of pathogens such as Staphylococcus aureus to cause disease at nearly all host sites implies significant metabolic flexibility to promote infection. S. aureus catabolizes glucose in several ways, including the phosphotransacetylase (Pta) - acetate kinase (AckA) pathway. The Pta-AckA pathway uses acetyl-CoA derived from the major glycolytic end-product, pyruvate, to rapidly generate ATP, producing acetate as a byproduct. Yet, flux through Pta-AckA necessitates coordinating glycolytic activity with the production of acetyl-CoA and its delivery to Pta-AckA. The generation of acetyl-CoA occurs through the pyruvate dehydrogenase (PDH) complex, an enzyme that requires attachment of the metabolic cofactor, lipoic acid, for its function. Thus, delivery of lipoic acid to enzyme complexes has the potential to serve as a determinant of metabolic adaptation. Here, we provide evidence for a functional link between the lipoic acid transfer enzyme, LipL, and Pta. We demonstrate pta and lipL are transcriptionally coupled and that Pta and LipL directly interact, with potential to direct metabolic flux through Pta-AckA. Both Δpta and ΔlipL mutants are defective for acetate production with evidence for alternative fates for pyruvate that depend on blockade upstream or downstream of the pyruvate node. The functional pairing of Pta and LipL is required for optimal skin infection, whereas Pta and LipL have separable functions in bloodstream infection. Furthermore, we found that a complete block to acetate production leads to significant attenuation in vivo, cementing a direct role for acetogenesis in infection. Together, our results establish a mechanism by which S. aureus regulates metabolite flux by coupling enzymes in linked metabolic pathways to promote energy balance and survival during infection.
Hu J, Gao X, Li G
… +14 more, He X, Ke Y, Zhang Z, Pang D, Lin Z, Xie C, Chen X, Jiang M, Zheng S, Yu S, Lin M, Pan D, Shen X, Hu X
PLoS Pathog
· 2026 Apr · PMID 42060684
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Sepsis is a life-threatening condition characterized by dysregulated immune responses and high mortality, driven by persistent pathogens and compromised antimicrobial defenses. We identify BRD4, an epigenetic regulator,...Sepsis is a life-threatening condition characterized by dysregulated immune responses and high mortality, driven by persistent pathogens and compromised antimicrobial defenses. We identify BRD4, an epigenetic regulator, as a crucial modulator of macrophage antimicrobial function and survival in sepsis. Sepsis significantly reduces BRD4 expression in monocytes/macrophages in both human patients and murine models, with decreased BRD4 levels correlating with disease severity. Myeloid-specific deletion of Brd4 exacerbates mortality by impairing macrophage phagocytosis and bactericidal activity. BRD4 interacts with NRF2, disrupting the NRF2-KEAP1 complex, which enhances NRF2 stability and nuclear translocation, leading to the upregulation of scavenger receptors essential for bacterial clearance. Notably, restoration or activation of NRF2 rescues the macrophage functional defects induced by Brd4 deficiency both in vitro and in vivo, highlighting the therapeutic potential of this pathway. Our findings reveal that BRD4 downregulation in human sepsis predicts disease severity, presenting BRD4 as both a biomarker and a therapeutic target. The BRD4-NRF2 axis offers a novel approach to restoring host defense and improving sepsis treatment strategies.
Jan HH, Kong F, MacLellan MP
… +3 more, Yang L, Dutta B, Kvitko BH
PLoS Pathog
· 2026 Apr · PMID 42060678
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Pantoea ananatis, the causative agent of onion center rot, encounters potent antimicrobial thiosulfinates, volatile organosulfur compounds released from damaged Allium tissue during pathogen-induced necrosis. The allicin...Pantoea ananatis, the causative agent of onion center rot, encounters potent antimicrobial thiosulfinates, volatile organosulfur compounds released from damaged Allium tissue during pathogen-induced necrosis. The allicin tolerance (alt) gene cluster allows P. ananatis to overcome this chemical barrier. We demonstrate that AltR, a TetR-family transcriptional repressor, specifically regulates expression of the alt cluster and thus thiosulfinate tolerance in vitro and fitness in vivo. We identified a putative AltR binding box both in the altR promoter and elsewhere in the alt cluster, show that AltR-mediated repression is relieved in response to thiosulfinates. Using cysteine to serine substitutions, we demonstrate that AltR Cys100 is essential for thiosulfinate-responsive de-repression, while other AltR cysteine residues tune responsivity. Strains expressing AltR alleles with reduced thiosulfinate responsivity have reduced fitness in planta. Our findings uncover a regulatory mechanism by which a plant antimicrobial secondary metabolite acts as an environmental cue to modulate bacterial gene expression, enabling pathogen survival and virulence.
Hao J, Qin Z, Ma J
… +6 more, Qu J, Wang Y, Folimonova SY, Liu B, Li W, Wang Y
PLoS Pathog
· 2026 Apr · PMID 42060673
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DNA-dependent RNA polymerases (DdRPs) recognize not only DNA but also RNA templates. This RNA-dependent RNA polymerase (RdRP) activity is exploited by bacterial 6S RNA, mammalian B2 RNA, viroids in plants, and hepatitis...DNA-dependent RNA polymerases (DdRPs) recognize not only DNA but also RNA templates. This RNA-dependent RNA polymerase (RdRP) activity is exploited by bacterial 6S RNA, mammalian B2 RNA, viroids in plants, and hepatitis delta virus in human. A major knowledge gap exists regarding the molecular basis conferring this RdRP activity. Here, we provide evidence supporting the reorganization of the 12-subunit polymerase II (Pol II) to 7-subunit in vivo for PSTVd transcription. Rpb4/5/6/7/9 are not involved in PSTVd transcription in planta. A splicing variant of transcription factor IIIA with seven zinc finger domains (TFIIIA-7ZF) aids the remodeled Pol II in transcribing PSTVd. Using AlphaFold3, the structure of the remodeled Pol II with PSTVd RNA and TFIIIA-7ZF was predicted. The predicted structure and experimental data both show that the N-terminus of TFIIIA-7ZF binds to the left terminal domain of PSTVd, while the C-terminus interacts with Rpb2. Interestingly, AlphaFold3 also predicts the bending at PSTVd loop 8 in the TFIIIA-7ZF/PSTVd complex. Replacing this loop 8 with a rigid double-stranded conformation impairs the TFIIIA-7ZF/PSTVd interaction. Altogether, our data demonstrate the heterogenous organization of the Pol II enzyme on RNA template in vivo and provide structural insights into the organization of Pol II transcription complex on RNA template.
Catta-Preta CMC, da Silva VL, Meneses C
… +2 more, Ghosh K, Sacks DL
PLoS Pathog
· 2026 Apr · PMID 42054421
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Genetic exchange in Leishmania is established, yet the molecular mechanisms enabling hybrid formation in sand flies remain poorly defined. In Leishmania, as in plants and several protists, two paralogs of the conserved m...Genetic exchange in Leishmania is established, yet the molecular mechanisms enabling hybrid formation in sand flies remain poorly defined. In Leishmania, as in plants and several protists, two paralogs of the conserved meiotic endonuclease SPO11 are present, but their contribution to hybridization is unknown. Here, we dissect the roles of SPO11-1 and SPO11-2 during in vivo sand fly infections using targeted gene deletions, catalytically-dead mutants, expression analyses, and genome-wide characterization of hybrid progeny. We show that both SPO11 paralogs are essential for efficient hybridization: deletion of either paralog in both parents abolishes hybrid recovery, and catalytic inactivation fails to rescue mating. When only one parent lacks SPO11-1 or SPO11-2, hybrid formation is reduced in a strain-dependent manner, revealing asymmetric requirements for each paralog. Genomic analysis of hybrids from SPO11-deficient crosses reveals polyploidy and altered parental genome contributions, including unbalanced and near-balanced triploid configurations, indicating disrupted reductional processes. Together, these results establish SPO11-dependent DNA break formation as a core requirement for Leishmania hybridization and define distinct, strain-specific roles for the two SPO11 paralogs.
Mundy RM, Waraich K, Bates EA
… +9 more, Rizkallah PJ, Baker AT, Young MT, Morris E, da Fonseca PCA, Bliss CM, Matthews D, Bhella D, Parker AL
PLoS Pathog
· 2026 Apr · PMID 42048387
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Adenoviruses are widely used as vectors for subunit vaccines and oncolytic therapies. Efficient vectors must infect target cells and deliver therapeutic transgenes at high levels. Species D adenoviruses, such as human ad...Adenoviruses are widely used as vectors for subunit vaccines and oncolytic therapies. Efficient vectors must infect target cells and deliver therapeutic transgenes at high levels. Species D adenoviruses, such as human adenovirus type 10 (HAdV-D10), are promising candidates due to low seroprevalence in humans. Here, we present the cryo-electron microscopy structure of the HAdV-D10 capsid alongside transcriptomic profiling of infected cells to inform vector development. The fiber shaft, essential for cell entry, was resolved at 10 Å, revealing a previously uncharacterized 'umbrella' motif. Viral transcript analysis using an ORF-centric pipeline uncovered key differences from HAdV-C5, including abundant expression of a transcript encoding a protein equivalent to mature protein VII. These findings highlight the importance of detailed vector characterization prior to clinical translation and support the advancement of HAdV-D10 as a next-generation platform for gene delivery and vaccine development.
Kim HG, Chan A, Vimonpatranon S
… +15 more, Girard A, Jiang A, Wertz S, Hwang IY, Kehrl JH, Schmeisser H, Seemiller MM, Lusso P, Huang D, Wei D, Goes LR, Soares M, Martinelli E, Arthos J, Cicala C
PLoS Pathog
· 2026 Apr · PMID 42048367
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[This corrects the article DOI: 10.1371/journal.ppat.1014052.].[This corrects the article DOI: 10.1371/journal.ppat.1014052.].
Bachmann A, Bruske E, Krumkamp R
… +13 more, Turner L, Wichers JS, Petter M, Held J, Duffy MF, Sim BKL, Hoffman SL, Kremsner PG, Lell B, Lavstsen T, Frank M, Mordmüller B, Tannich E
PLoS Pathog
· 2026 Apr · PMID 42048364
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[This corrects the article DOI: 10.1371/journal.ppat.1007906.].[This corrects the article DOI: 10.1371/journal.ppat.1007906.].
PLoS Pathog
· 2026 Apr · PMID 42044193
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The antiviral response to several clinically significant viruses, including respiratory syncytial virus and parainfluenza virus, is driven by copy-back viral genomes (cbVGs) generated during virus replication. However, t...The antiviral response to several clinically significant viruses, including respiratory syncytial virus and parainfluenza virus, is driven by copy-back viral genomes (cbVGs) generated during virus replication. However, the broader impact of cbVGs on the functional states of host cells remains undefined. Here, we developed a single-cell RNA-sequencing and computational framework to map cbVG-driven host responses during Sendai virus infection. Unsupervised profiling identified distinct transcriptional states throughout the course of infection, highlighting a shift from early antiviral signaling to later inflammatory and remodeling programs. Stratifying infected cells by cbVG status demonstrated that cbVG-positive cells initiate interferon and chemokine programs, which later spread to cbVG-negative cells. At later stages, cbVG-positive cells acquire additional signaling, cytoskeletal, transcriptional, and stress-adaptation programs, which are absent in cbVG-clean infection. This work defines the broader cbVG-driven layered and dynamic host response and provides a valuable high-resolution resource of the temporal cellular response to a virus infection.
Kulkarni M, Bourne CM, Mahale AB
… +11 more, Exconde PM, Murphy C, Goodrow HT, Cervantes S, Kardhashi M, Kambayashi M, Yoo W, Wrong TJ, Patio RC, Discher BM, Taabazuing CY
PLoS Pathog
· 2026 Apr · PMID 42044191
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Inflammasomes are signaling platforms that activate inflammatory caspases to initiate innate immune responses. Canonical inflammasomes sense diverse threats and activate CASP1, which cleaves the pro-inflammatory cytokine...Inflammasomes are signaling platforms that activate inflammatory caspases to initiate innate immune responses. Canonical inflammasomes sense diverse threats and activate CASP1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 and the pore-forming protein gasdermin D (GSDMD) to induce pyroptosis. In contrast, the non-canonical inflammasome senses bacterial lipopolysaccharide (LPS) through CASP4 and CASP5 to induce pyroptosis. While CASP1 substrates are well defined, those of CASP4 and CASP5 remain less understood. Here, we show that intracellular LPS and the gram-negative bacterial pathogen Salmonella activate CASP4/5 in macrophages to directly cleave and activate CASP3 and CASP7. Activated CASP3 subsequently cleaves gasdermin E (GSDME). Surprisingly, CASP3, but not GSDME, was required for restricting intracellular Salmonella replication, suggesting a protective role for apoptotic signaling. We further find that most GSDMD cleavage during non-canonical signaling is mediated by CASP1. Consistent with this, loss of GSDMD, but not GSDME, reduced LDH release, establishing GSDMD as the primary driver of pyroptosis during LPS transfection. In contrast, during Salmonella infection, cell lysis occurred independently of both GSDMD and GSDME, suggesting the involvement of alternative lytic mechanisms. Finally, we demonstrate that CASP4/5 activation of CASP3/7 and GSDME occurs in human primary macrophages, defining CASP4/5 as dual apoptotic initiator and inflammatory caspases in innate immunity.
Rubin IN, Bushman M, Lipsitch M
… +1 more, Hanage WP
PLoS Pathog
· 2026 Apr · PMID 42044189
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Seasonal trends in infectious diseases are shaped by climatic and social factors, with many respiratory viruses peaking in winter. However, the seasonality of COVID-19 remains in dispute, with significant waves of cases...Seasonal trends in infectious diseases are shaped by climatic and social factors, with many respiratory viruses peaking in winter. However, the seasonality of COVID-19 remains in dispute, with significant waves of cases across the United States occurring in both winter and summer. Using wavelet analysis of COVID-19 cases during the pandemic period, we find that the periodicity of epidemic COVID-19 varies markedly across the U.S. and correlates with winter temperatures, indicating seasonal forcing. However, seasonal forcing alone cannot explain the pattern of multiple waves per year that has been so characteristic of COVID-19. Using a modified SIRS model that allows specification of the tempo of waning immunity, we show that specific forms of non-durable immunity can sufficiently explain the sub-annual waves characteristic of the COVID-19 epidemic.
PLoS Pathog
· 2026 Apr · PMID 42044120
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The mechanisms that underlie protective immunity to Mycobacterium tuberculosis (Mtb) remain incompletely defined. To identify immune correlates associated with protection, we performed single-cell RNA sequencing of lung...The mechanisms that underlie protective immunity to Mycobacterium tuberculosis (Mtb) remain incompletely defined. To identify immune correlates associated with protection, we performed single-cell RNA sequencing of lung immune cells after aerosol Mtb infection of naïve mice and mice with contained Mtb infection (CoMtb), a model of naturally acquired resistance, across multiple time points, mouse strains, and Mtb strains. Protection was associated with distinct temporal patterns of immune activation, cell recruitment, and resolution. Early after challenge, CoMtb mice exhibited rapid, transient recruitment and activation of CD4 ⁺ T cells, macrophages, NK, and NKT cells, accompanied by short-lived bursts of type I and II interferon signaling, increased oxidative phosphorylation, and enhanced chemokine-mediated cell-cell communication. In contrast, primary infection elicited delayed but sustained interferon and neutrophil responses and higher bacterial burdens. These data indicate that protection involves dynamically coordinated immune pathways rather than the magnitude of any single response. Transcriptional features of CoMtb overlapped with those observed in nonhuman primates following intravenous BCG vaccination, including enrichment of activated tissue-resident CD4 ⁺ T cells and innate effector populations. Together, these findings support a model in which effective immunity to Mtb depends on the timing and coordination of immune activation, providing a framework for vaccine strategies that reproduce protective lung immune dynamics.
PLoS Pathog
· 2026 Apr · PMID 42030513
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Chronic wasting disease (CWD) is a strictly fatal and highly contagious prion disease of wild and farmed cervids currently expanding in North America. Prion diseases are caused by conversion of the cellular prion protein...Chronic wasting disease (CWD) is a strictly fatal and highly contagious prion disease of wild and farmed cervids currently expanding in North America. Prion diseases are caused by conversion of the cellular prion protein to its pathological isoform PrPSc. Vaccination is considered a promising strategy to contain CWD, even though prion diseases do not show classical immune responses. For CWD containment, it is important that vaccines reduce shedding of prions in excreta, a major contributor to transmission. Here, we tested the effect of vaccines on prion shedding in feces and urine by vaccinating and prion infecting knock-in mice that recapitulate CWD pathogenesis as found in cervids. Vaccination reduced or even prevented CWD shedding in feces and urine collected between 30-90% of incubation time to disease. This is the first report showing that prion shedding can be blocked in a prion disease. For CWD specifically it may reduce the environmental prion burden and break the disease transmission cycle.
Omole TE, Nguyen HM, Marcinow A
… +13 more, Jahan N, Severini G, Naicker N, Thomas K, Celum C, Mugo N, Mujugira A, Kublin J, Corey L, Sivro A, Lingappa J, Gray G, McKinnon LR
PLoS Pathog
· 2026 Apr · PMID 42030410
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Interleukin-17-producing T helper (Th17) CD4+ T cells are highly susceptible to HIV infection and are depleted early in people living with HIV. Here, we investigated whether systemic Th17 cell levels prior to HIV infecti...Interleukin-17-producing T helper (Th17) CD4+ T cells are highly susceptible to HIV infection and are depleted early in people living with HIV. Here, we investigated whether systemic Th17 cell levels prior to HIV infection are associated with subsequent HIV disease progression. We analyzed archived cryopreserved peripheral blood mononuclear cells (PBMCs) collected within one year prior to HIV acquisition from participants enrolled in a South African cohort (HIV Vaccine Trials Network [HVTN] 503; n = 35) and an East African cohort (Partners Pre-exposure Prophylaxis/Couples' Observational Study [PP/COS]; n = 32). Th17 cell frequencies were quantified by flow cytometry. In HVTN 503, higher pre-HIV IL-17+ CD4+ T cell frequencies were inversely correlated with CD4/CD8 ratio measured both within 180 days (Spearman rank rs = -0.42, p = 0.012) and ≥180 days (rs = -0.55, p = 0.001) after HIV infection, and were associated with faster CD4+ T cells decline (adjusted hazard ratio [aHR] = 3.5, 95% CI: 1.2 - 9.9, p = 0.020). In contrast, no significant association with CD4 decline was observed in the PP/COS cohort (HR = 1.2, 95% CI: 0.4 - 3.4, p = 0.795). Sex-stratified analyses in HVTN 503 indicated a more pronounced association between pre-HIV IL-17+ CD4+ T cells and faster CD4 decline in males than females. In analyses combining all cohorts, higher pre-HIV IL-17+ CD4+ T cell frequencies remained associated with faster CD4 decline, particularly among younger participants (HR = 3.5; 95% CI: 1.35 - 9.22, p = 0.010). Pre-HIV IL-17+ CD4+ T cell frequencies were not associated with peak or set-point viral load in either cohort. Together, these findings suggest that pre-HIV Th17 cells abundance may influence subsequent HIV disease progression independently of early viral replication.
Tian Y, Tian B, Ran R
… +17 more, Cai D, Xiao Z, Wang M, Wu Y, Yang Q, Zhang S, Zhu D, Liu M, Zhao X, Sun D, Huang J, Ou X, Wu Z, He Y, Jia R, Chen S, Cheng A
PLoS Pathog
· 2026 Apr · PMID 42030364
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Duck plague, caused by the alphaherpesvirus Duck plague virus (DPV), is an acute, hemorrhagic, and economically devastating disease of waterfowl. DPV infection induces severe immunosuppression, yet the mechanisms by whic...Duck plague, caused by the alphaherpesvirus Duck plague virus (DPV), is an acute, hemorrhagic, and economically devastating disease of waterfowl. DPV infection induces severe immunosuppression, yet the mechanisms by which this pathogen subverts host innate immunity, particularly through manipulation of the host ubiquitin system, remain unclear. The cGAS-STING signaling pathway is a cornerstone of anti-DNA viral immunity. In avian species, where IRF3 has been evolutionarily lost, the transcription factor IRF7 plays a pivotal role in activating type I interferons (IFN-I). Here, we identify duck RNF34 (DuRNF34) as a host E3 ubiquitin ligase that broadly suppresses the duck cGAS-STING pathway by targeting multiple components, including DucGAS, DuSTING, and DuIRF7, for ubiquitination and degradation. Importantly, DPV infection upregulates DuRNF34 expression, which selectively targets DuIRF7 for degradation to facilitate viral replication. Further affinity purification-mass spectrometry (AP-MS) analysis revealed that LORF2, a DPV-specific protein, recruits DuRNF34 to catalyze K11- and K48-linked polyubiquitination of DuIRF7 at lysine residues K51 and K453, leading to DuIRF7 degradation and suppression of IFN-β and downstream antiviral genes. Functional validation confirmed that siRNA-mediated knockdown of LORF2 markedly attenuated DPV-induced DuIRF7 degradation and impaired viral replication. Collectively, these findings reveal a novel immune evasion strategy in which DPV hijacks the host E3 ligase DuRNF34 via its unique protein LORF2, thereby targeting DuIRF7 for degradation to subvert innate immunity. This work provides new insights into herpesviral immune evasion and suggests potential targets for therapeutic intervention.
Wang S, Hong W, Zhong S
… +16 more, Liang Z, Xiao T, Zhang C, Liu X, Dai Z, Li Y, Wu S, Cai Q, Wu C, Huang Y, Hong P, Ren H, Li S, Lin T, Chen X, Huang S
PLoS Pathog
· 2026 Apr · PMID 42030356
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Praziquantel (PZQ) is currently the only agent for treating schistosomiasis, but it is plagued by suboptimal efficacy to juvenile parasites, looming drug resistance, and inability to prevent reinfection. Thioredoxin glut...Praziquantel (PZQ) is currently the only agent for treating schistosomiasis, but it is plagued by suboptimal efficacy to juvenile parasites, looming drug resistance, and inability to prevent reinfection. Thioredoxin glutathione reductase (TGR) is regarded as a promising therapeutic target due to its essential role in maintaining schistosome redox homeostasis. Herein, the crystal structures of Schistosoma japonicum TGR (SjTGR) in multiple redox states and in complex with NADPH, GSH, and the anti-helminthic agent Auranofin were elucidated. Structural analyses identified the hook-shaped conformation at the C-terminal redox center, which DTNB assays further confirmed enhances electron transfer efficiency. Structural and ITC data indicated that R317 was critical for NADPH binding via hydrogen-bond interactions. The analysis also indicated that the structure basis of Auranofin's potency was its tripartite interaction at the redox-active sites. In addition, we investigated the substrate specificity of SjTrx1i and SjTRP14, downstream proteins regulated by SjTGR, and elucidated the structural basis for this specificity by determining their oxidized/reduced structures. Furthermore, in vivo RNAi indicated knockdown of SjTGR or SjTRP14 blocked the survival and oviposition of schistosomes, thus ameliorating egg-induced granulomatous pathology in mice. This work provided a framework for knowledge-based design of novel anti-schistosomals targeting parasite-specific redox vulnerabilities.