PLoS Pathogens[JOURNAL]
Sun
200 papers
PrP turnover in vivo and the time to effect of prion disease therapeutics.
Corridon TL, O'Moore J, Seerley A … +20 more , Sprague DA, Lian Y, Laversenne V, Noble B, Kamath NG, Serack FE, Shaikh AB, Erickson B, Braun C, DeSouza-Lenz K, Howard M, Chan N, Jackson WS, Reidenbach AG, Cabin DE, Vallabh SM, Grindeland Panter A, Oberbeck N, Zhao HT, Minikel EV
PLoS Pathog · 2026 May · PMID 42189860 · Full text
PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-li...
PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-life. We hypothesized that PrP's half-life may be a rate-limiting factor for the time to effect of PrP-lowering drugs, and one reason why late treatment of prion-infected mice is not as effective as early treatment. Using isotopically labeled diet with targeted mass spectrometry, as well as antisense oligonucleotide treatment followed by timed PrP measurement, we estimate a half-life of 5-6 days for PrP in the brain. PrP turnover is not affected by over- or under-expression. Mouse PrP and human PrP have similar turnover rates measured in wild-type or humanized knock-in mice. CSF PrP appears to mirror brain PrP in real time in rats. PrP in the colon is readily quantifiable and has a half-life just slightly shorter than in brain. An under-expressed pathogenic mutant PrP, corresponding to D178N in humans, exhibits an accelerated turnover rate. Our data may inform the design of both preclinical and clinical studies of PrP-lowering drugs.
Flipping the script: Using mucosal immune obstacles to inform vaccine design.
Antia A, Ding S
PLoS Pathog · 2026 May · PMID 42189800 · Full text
Abstract loading — click title to view on PubMed.
Editorial Note: Recruitment of a SAP18-HDAC1 Complex into HIV-1 Virions and Its Requirement for Viral Replication.
PLOS Pathogens Editors
PLoS Pathog · 2026 May · PMID 42189772 · Full text
Abstract loading — click title to view on PubMed.
A murine cytomegalovirus cell cycle regulator (m54.5p) evolved within the conserved viral DNA polymerase gene.
Zheng Y, Bertovic I, Han X … +8 more , Hennig T, Whisnant AW, Lamer S, Schlosser A, Lisnic VJ, Kay-Fedorov P, Dölken L, Lodha M
PLoS Pathog · 2026 May · PMID 42172299 · Full text
Ribosome profiling (Ribo-seq) and transcription start site profiling recently unveiled hundreds of novel viral gene products in lytic murine cytomegalovirus (MCMV) infection. One of these is the highly expressed m54.5 op...
Ribosome profiling (Ribo-seq) and transcription start site profiling recently unveiled hundreds of novel viral gene products in lytic murine cytomegalovirus (MCMV) infection. One of these is the highly expressed m54.5 open reading frame (ORF) located within the highly conserved viral DNA polymerase locus (M54). Here, we show that m54.5 encodes a nuclear protein (m54.5p) that contributes to cell cycle regulation during MCMV infection. m54.5p interacts with the anaphase-promoting complex/cyclosome (APC/C) and protein phosphatase-6 (PP6). Ectopic m54.5p expression resulted in nuclear accumulation of PP6C and multiple APC/C subunits, accompanied by increased nuclear levels of the APC/C substrates. Accordingly, ectopic m54.5p expression resulted in G1 cell cycle arrest in nocodazole mitotic arrest and serum starvation assays. While an m54.5p-null mutant virus replicated with wild-type kinetics in vitro, it was mildly attenuated in mouse lungs by 14 days post-infection. Our findings highlight the surprising plasticity of herpesvirus genomes, facilitating the evolution of a > 200 aa viral open reading frame within the highly conserved viral DNA polymerase gene locus.
Equine infectious anemia virus blocks interferon responses through Rev-mediated activation of the stress granule-PKR-eIF2α pathway.
Ren H, Chen K, Zhou B … +3 more , Zhang W, Wang XF, Wang X
PLoS Pathog · 2026 May · PMID 42166486 · Full text
Type I interferons (IFNs) play a pivotal role in antiviral defence by inducing interferon-stimulated genes (ISGs) that target multiple stages of viral replication. Equine infectious anemia virus (EIAV) is an ancient lent...
Type I interferons (IFNs) play a pivotal role in antiviral defence by inducing interferon-stimulated genes (ISGs) that target multiple stages of viral replication. Equine infectious anemia virus (EIAV) is an ancient lentivirus that establishes long-term asymptomatic infections in equids, suggesting its exceptional immune evasion capabilities. However, the mechanisms by which EIAV modulates IFN responses remain unclear. Here, we demonstrate that EIAV infection attenuates ISG expression at the post-transcriptional level. The viral Rev protein plays a central role by interacting with the stress granule (SG) nucleating protein Ras-GTPase-activating protein binding protein 1 (G3BP1) to induce SG formation. This triggers the phosphorylation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor 2α (eIF2α), which then block the translation of ISGs. Knockdown of G3BP1 or inhibition of PKR activation restores ISGs expression and enhances the antiviral effect of IFN against EIAV. Furthermore, the dimerization and RNA-binding domains of Rev are essential for SG assembly and the subsequent inhibition of IFN responses. Collectively, our findings reveal that EIAV has evolved a unique strategy to evade IFN responses, where the Rev protein reprograms SGs into proviral platforms by suppressing the translation of ISGs.
Structural basis for sarbecovirus Rc-o319 spike adaptation to Rhinolophus cornutus Bat ACE2 and constraints on switching to human ACE2.
Wang J, Li Z, Ma Y … +13 more , Li Z, Yuan H, Niu C, Teng Y, Liu B, Li M, Zhou M, Liu W, Feng H, Chen J, He J, Chen X, Xiong X
PLoS Pathog · 2026 May · PMID 42166485 · Full text
Bat sarbecoviruses often exhibit species-dependent ACE2 specificity. Understanding the determinants of receptor specificity enables better assessment of the cross-species transmission potential of sarbecoviruses. Here, w...
Bat sarbecoviruses often exhibit species-dependent ACE2 specificity. Understanding the determinants of receptor specificity enables better assessment of the cross-species transmission potential of sarbecoviruses. Here, we characterize the S-protein of Rc-o319, a sarbecovirus identified in Japanese Rhinolophus cornutus bats. Featuring an unusual 9-amino-acid deletion within its receptor binding motif (RBM), Rc-o319 S-protein utilizes its cognate R. cornutus ACE2 (bACE2R.cor) but not human ACE2 (hACE2), demonstrating highly restricted receptor specificity. Cryo-EM structures reveal two locked prefusion conformations of the Rc-o319 S-trimer and define a novel type of receptor-binding domain (RBD), featuring a distinct beta-loop (BL) within the RBM due to the RBM-deletion. The Rc-o319-RBD:bACE2R.cor complex structure reveals unique interactions mediated by the specialized BL and RBM-loop of Rc-o319-RBD and by a bACE2R.cor glycan. Structure-guided mutagenesis demonstrates that changes in BL and RBM-loop within the Rc-o319 S-RBD must occur simultaneously to allow medium-to-high-affinity hACE2 binding. Comparative assays further show that the bACE2R.cor receptor supports only a subset of sarbecoviruses, highlighting its restricted sarbecovirus compatibility. Our findings establish the Rc-o319 S-protein as a structurally and functionally specialized adaptation to R. cornutus ACE2 and identify the structural constraints limiting its cross-species transmission potential.
The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration.
Hart DJ, Uddin MJ, Dodd RJ … +10 more , Brovero SG, Fleming C, Moreau GB, Natale NR, Naz F, Mann BJ, Sutherland TE, Allen JE, Day AJ, Petri WA
PLoS Pathog · 2026 May · PMID 42160404 · Full text
The novel respiratory disease COVID-19 caused by the coronavirus SARS-CoV-2 continues to be a public health emergency worldwide, and there is a need for more effective therapy for patients. The relationship between the e...
The novel respiratory disease COVID-19 caused by the coronavirus SARS-CoV-2 continues to be a public health emergency worldwide, and there is a need for more effective therapy for patients. The relationship between the extracellular matrix and the host immune response to infection is severely understudied. Deposition of the polysaccharide hyaluronan (HA) into the lungs is associated with more severe COVID-19 disease outcomes. HA is a major component of the extracellular matrix in connective tissues and is abundant in many parts of the body, including cartilage, skin, brain, and vitreous body. HA is a major component of the extracellular matrix in connective tissues and is abundant in many parts of the body, including cartilage, skin, brain, and vitreous body. Polymers consist of repeating units of N-acetylglucosamine and glucuronic acid and are synthesized by the three hyaluronan synthase (HAS) enzymes, HAS1-3. CD44 is the primary receptor for HA and is found on almost all immune cells in the lung. Known functions of CD44 include mediation of immune cell migration, activation, and differentiation. We hypothesized that increased HA deposition during COVID-19 increases CD44-mediated immune cell infiltration into lungs and results in more severe pathology. Here, we report that in mice infected with a mouse-adapted strain of SARS-CoV-2, treatment with a combination of two anti-CD44 monoclonal antibodies confers a significant survival benefit and reduces weight loss and clinical score of the mice on Day 4 post infection. We show that anti-CD44 treatment decreases many key cytokines and chemokines in the bronchoalveolar lavage fluid on Day 4. With flow cytometry, we show that anti-CD44 reduces the numbers of neutrophils in infected lungs. We also show through immunofluorescence that treatment with anti-CD44 antibodies reduces colocalization of HA and CD45 in lung sections, indicating that HA's interaction with immune cells contributes to pathology. Our findings demonstrate that disruption of HA-receptor interactions is a way to prevent inflammatory pathology in pulmonary infection.
Characterization of a novel cell wall-associated nucleotidase of Enterococcus faecalis that degrades extracellular c-di-AMP.
Morales Rivera AG, Bala A, Casella LG … +8 more , Brunson DN, Wongso E, Patel A, Cuvilly IE, Walker AR, Wallet SM, Flores-Mireles AL, Lemos JA
PLoS Pathog · 2026 May · PMID 42160400 · Full text
Enterococcus faecalis is a prolific opportunistic pathogen responsible for a range of life-threatening infections, notorious for its ability to withstand environmental stressors. Second messengers are small molecules tha...
Enterococcus faecalis is a prolific opportunistic pathogen responsible for a range of life-threatening infections, notorious for its ability to withstand environmental stressors. Second messengers are small molecules that relay signals in response to stimuli and are thought to be crucial for bacteria like E. faecalis to modulate their adaptation to stress. The second messenger nucleotide c-di-AMP has emerged as an essential bacterial signaling molecule due to its impact on physiological processes, including adaptation to osmotic stress, cell wall homeostasis, antibiotic tolerance, and virulence. In addition, c-di-AMP is a pathogen-associated molecular pattern (PAMP) molecule that can trigger a potent stimulation of the host immune system. In previous work, we identified and characterized the enzymes responsible for the synthesis and degradation of intracellular c-di-AMP in E. faecalis, demonstrating that maintenance of c-di-AMP homeostasis is vital for its fitness and virulence. In addition to the intracellular enzymes that regulate c-di-AMP levels, a small number of bacteria encode surface-associated nucleotidases that cleave extracellular c-di-AMP and are potentially associated with immune evasion. Here, we characterize a novel and unique cell wall-anchored nucleotidase, termed EecP (E. faecalis extracellular c-di-AMP phosphodiesterase), which features duplicated catalytic domains and degrades extracellular c-di-AMP. Through competition experiments, we show that EecP likely uses c-di-GMP, and to a lesser extent AMP, as additional substrates. While a ΔeecP strain failed to display relevant phenotypes under most in vitro conditions, it exhibited increased susceptibility to killing by phagocytic cells, a phenotype at least partly associated with cGAS-STING immune signaling. NanoString analysis revealed distinct innate immune signatures in murine macrophages infected with the parent strain OG1RF or ΔeecP, uncovering differential expression of host targets known to be impacted by c-di-AMP, as well as novel targets. Using two murine infection models, we show that the impact of eecP deletion and the consequent buildup of extracellular c-di-AMP on E. faecalis pathogenesis might depend on the site of infection. Notably, disseminated infection was more severe in mice infected with ΔeecP, suggesting that extracellular c-di-AMP influences infection outcomes, likely through modulation of host immune responses.
p1/s1, a 3'-nucleotidase/nuclease, allows Leishmania major to circumvent host innate immune response mechanisms.
Schmelzle SM, Bergmann M, Walber B … +9 more , Shamsara J, Ziesmann T, Distler U, Miskey C, Childs L, Kolb P, Tenzer S, Bagola K, van Zandbergen G
PLoS Pathog · 2026 May · PMID 42160378 · Full text
3'-nucleotidases/nucleases, distinct class I nucleases of protozoan parasites, play a pivotal role in extracellular purine salvage. As Leishmania are purine auxotrophs and lack de novo synthesis, ectoenzymes facilitating...
3'-nucleotidases/nucleases, distinct class I nucleases of protozoan parasites, play a pivotal role in extracellular purine salvage. As Leishmania are purine auxotrophs and lack de novo synthesis, ectoenzymes facilitating nucleotide and nucleic acid cleavage are indispensable for subsequent uptake. Employing quantitative proteomics, we characterized a class I nuclease p1/s1 cluster in L. major that comprises enzymes exhibiting dual 3'-nucleotidase and endonuclease activity. Expression of these enzymes is induced upon miltefosine or staurosporine treatment and was specifically detected in stationary-phase, but not in logarithmic-phase promastigotes. After confirming secretion of p1/s1, ecto-enzymatic activity was detected on parasites and in the culture supernatant. Viable null mutants deficient for the p1/s1 cluster were only obtained when a diCre-based inducible knockout system was applied, whereas direct deletion approaches were lethal. The viable knockout strains exhibited significantly reduced 3'-nucleotidase/nuclease activity. Notably, these parasites adapted by compensatory enrichment of various alternative purine salvage proteins at the proteomic level. Furthermore, both enzymatic functions implied mechanisms of host-pathogen interactions to facilitate infection establishment: Utilizing 3'-nucleotidase activity, Leishmania generate extracellular adenosine to suppress inflammatory cytokine secretion from macrophages and reduce lymphocyte proliferation in a human primary cell model. The presence of ecto-nucleases also allowed these parasites to degrade and survive neutrophil extracellular traps, a potent first-line innate immune mechanism in pathogen defense. In summary, our integrative approach combining proteomics, immunological and genome editing methods expands current knowledge about Leishmania major 3'-nucleotidases/nucleases. By offering new insights into the diverse involvements in host-pathogen interactions, we highlight p1/s1 as pivotal factor during infection and potential drug target.
Chemotaxis to plant defense compounds in phytopathogens.
Genova R, Holmes A, Cano-Muñoz M … +6 more , Ishihara A, Ube N, Nomura T, Gavira JA, Matilla MA, Krell T
PLoS Pathog · 2026 May · PMID 42160375 · Full text
Plant pathogens possess about twice as many chemoreceptors as the bacterial average, suggesting broad chemotactic capacities. The signals recognized by most phytopathogen chemoreceptors are unknown, and the reasons for t...
Plant pathogens possess about twice as many chemoreceptors as the bacterial average, suggesting broad chemotactic capacities. The signals recognized by most phytopathogen chemoreceptors are unknown, and the reasons for this elevated chemoreceptor number is unclear. We identified the signals recognized by three chemoreceptors, PacH, PacI and PacG, in the global phytopathogen Pectobacterium atrosepticum. The ligand-binding domains (LBDs) of these chemoreceptors share modest sequence similarity, but the signals they recognize are structurally similar, and their biosynthetic pathways are interwoven. Whereas PacH and PacI recognized benzoate derivatives, including salicylate, vanillin and p-hydroxybenzoate, PacG bound agmatine, feruloylagmatine and p-coumaroylagmatine. These compounds are known plant defense compounds, their production is induced by pathogen attack, and they typically accumulate at infection sites. All compounds, except agmatine, induced chemoattraction, which was abolished by mutations in the corresponding genes. Agmatine competed with feruloylagmatine and p-coumaroylagmatine for PacG-LBD binding in vitro and antagonized chemotaxis in vivo. A mutant in pacG, but not in other chemoreceptor genes, showed reduced virulence in planta. We report high-resolution structures of PacG-LBD that were used for ligand-docking experiments to identify its binding pocket. PacH, PacI and PacG homologs were identified in other important phytopathogens belonging to the Burkholderia, Erwinia, Ralstonia, Pectobacterium and Dickeya genera. This is the first report of chemotaxis to feruloylagmatine, p-coumaroylagmatine and p-methoxybenzoate, expanding the range of chemoeffectors. Bacteria thus exploit plant defense responses by moving to compounds that are secreted at infection sites in response to pathogen attack. Chemotaxis to plant defense compounds may be a means to access infected plants and infection sites.
The Nipah virus threat in India: Epidemiological trends, risk drivers, and lessons for pandemic preparedness.
Apoorva, Singh SK
PLoS Pathog · 2026 May · PMID 42160364 · Full text
Nipah virus (NiV), a WHO-priority zoonotic pathogen, poses a recurrent public health threat in India. Since its initial detection in 2001, India has encountered multiple NiV spillover events, including repeated outbreaks...
Nipah virus (NiV), a WHO-priority zoonotic pathogen, poses a recurrent public health threat in India. Since its initial detection in 2001, India has encountered multiple NiV spillover events, including repeated outbreaks in Kerala and recent cases reported in West Bengal in 2026. Although the pig-amplified epidemic in Malaysia (1998-1999) and the seasonal outbreaks associated with NiV-contaminated date palm sap consumption in Bangladesh are extensively documented, India represents a unique and relatively understudied epidemiological setting. NiV outbreaks in India are primarily linked to the NiV-Bangladesh clade and are marked by direct spillover transmission from bats to humans, elevated case-fatality rates, clustered emergence, and effective household/nosocomial transmission without an intermediate amplifying host. Spillover risk is influenced by region-specific ecological and socio-economic factors, including contamination of peri-domestic fruit, proximity of bat roosts to human settlements, deforestation, and urban expansion. To date, no treatment or vaccine is available for humans or animals. This review synthesizes evidence from India spanning 2001 to 2026. It integrates aspects of epidemiology, bat reservoir ecology, viral genomics, clinical manifestations, surveillance experiences, and health system responses, while contrasting India's transmission dynamics with those observed in Malaysia and Bangladesh. Furthermore, we explore India's current preparedness and response strategies, highlighting the critical shift from reactive outbreak control to a proactive, integrated "One Health" framework. The strategy to strengthen integrated surveillance, contact tracing, isolation, and quarantine of suspected and confirmed cases, advance India-developed vaccines and therapeutics, and address the root ecological drivers of zoonotic emergence is essential for national and global health security.
Tripartite motif-containing 34 (TRIM34) protein interacts with the nucleocytoplasmic transport machinery and negatively modulates antiviral responses.
Vázquez-Utrilla P, Rivero V, DeDiego ML
PLoS Pathog · 2026 May · PMID 42160298 · Full text
The tripartite motif-containing (TRIM) 34 protein is an interferon (IFN)-induced protein whose expression is upregulated after influenza A virus (IAV) infection. Here, we identify a previously unknown function for TRIM34...
The tripartite motif-containing (TRIM) 34 protein is an interferon (IFN)-induced protein whose expression is upregulated after influenza A virus (IAV) infection. Here, we identify a previously unknown function for TRIM34 as a negative regulator of innate immune responses following IFN treatment and IAV infection, even in mice, suggesting that this effect is broad and conserved. Complementary overexpression and silencing experiments in cultured cells show that TRIM34 expression positively correlates with IAV titers, indicating that TRIM34 promotes viral replication, likely by counteracting antiviral responses. Moreover, we show novel interactions of TRIM34 with cellular proteins involved in the nucleocytoplasmic transport of host mRNAs and proteins, even in mock-infected cells. Remarkably, these TRIM34 interactions seem independent of TRIM34 E3 ubiquitin ligase activity and affect the nuclear import of IFN-regulatory factor 3 (IRF3) and the nuclear export of host mRNAs encoding antiviral functions, without affecting the nuclear export of viral mRNAs. These results provide a likely mechanism by which TRIM34 dampens host innate immune responses. These TRIM34-mediated effects could be further exploited to develop new antiviral drugs against IAV, and potentially other viral infections.
β-Klotho inhibited the epithelial-mesenchymal transition of liver sinusoidal endothelial cells to alleviate schistosomiasis liver fibrosis.
Jiang T, Li Q, Yu Z … +9 more , Cui X, Mo X, Chen Q, Chen Y, Li X, Wei M, Guo Z, Hu Y, Li S
PLoS Pathog · 2026 May · PMID 42154778 · Full text
Schistosomiasis is a neglected zoonotic disease, and the liver fibrosis induced by Schistosoma japonicum infection poses a significant threat to human health. Traditionally, liver fibrosis in schistosomiasis has been att...
Schistosomiasis is a neglected zoonotic disease, and the liver fibrosis induced by Schistosoma japonicum infection poses a significant threat to human health. Traditionally, liver fibrosis in schistosomiasis has been attributed to eggs deposited in the liver, which trigger hepatic inflammation and fibrosis. However, our study reveals that schistosomula migration to the liver induces epithelial-to-mesenchymal transition (EMT) in liver sinusoidal endothelial cell (LSEC), thereby contributing to the progression of liver fibrosis. In the early stage of S. japonicum infection, mice exhibited a reduction in the proportion of LSEC and impairment of their function. RNA-sequencing revealed significant alterations in β-Klotho (KLB) expression in injured LSEC. Although KLB is known to exert anti-inflammatory functions as a co-receptor for fibroblast growth factor (FGF) in the liver, its role in LSEC EMT and schistosomiasis-induced liver fibrosis was unclear. Using SK-Hep1 cells, we found that KLB knockdown exacerbated EMT, whereas KLB over-expression attenuated EMT and decreased TGFβ1 secretion from LSEC, thereby suppressing LX-2 activation. In mice infected with S. japonicum, treatment with recombinant KLB protein or AAV8-KLB increased the LSEC population, mitigated EMT in both LSEC and liver tissues, ameliorated hepatic fibrosis, and inhibited TGFβ1 pathway activation. Our study reveals that KLB suppresses LSEC EMT induced by liver-stage schistosomula and TGFβ1 secretion, thereby inhibiting HSC activation and reducing liver fibrosis. Our findings highlight KLB as a promising therapeutic target for hepatic fibrosis in schistosomiasis.
Update and reuse: Structure-guided nanobody evolution against SARS-CoV-2 escape.
Bu F, Saxena D, Turner-Hubbard H … +11 more , Delaney A, Batra L, Fricke C, Moye S, Verma A, Perlman S, Bhandari J, Liu B, Ye G, Zheng J, Li F
PLoS Pathog · 2026 May · PMID 42149970 · Full text
SARS-CoV-2 continues to accumulate spike mutations that erode the efficacy of antibody therapeutics. The Q493E mutation in the spike RBD, present in recent Omicron subvariants, enables escape from many antibodies and nan...
SARS-CoV-2 continues to accumulate spike mutations that erode the efficacy of antibody therapeutics. The Q493E mutation in the spike RBD, present in recent Omicron subvariants, enables escape from many antibodies and nanobodies, including our Nanosota-9A nanobody, which neutralizes Omicron JN.1 (Q493) but not KP.3 (E493). To address this, we applied a structure-guided in vitro evolution strategy to engineer Nanosota-9A, generating Nanosota-9B, which binds the KP.3 RBD with high affinity but shows reduced binding to JN.1 RBD. To regain breadth, we engineered a bispecific nanobody combining Nanosota-9A and -9B, which effectively neutralizes both JN.1 and KP.3 in infection assays. Our results provide proof of concept for an "update and reuse" strategy: applying structure-guided engineering to update and reuse validated nanobodies to overcome variant escape. This strategy offers a practical path to maintain therapeutic coverage as the virus evolves, supporting more efficient use of research resources and faster responses to emerging variants.
The RNA promoter for pathogenic orthoflaviviruses replication is universal and serves as target for viral inhibition.
Oviedo-Rouco S, Bertoni L, Mikkelsen E … +8 more , Sarto C, Gonzalez Lopez Ledesma MM, Pallarés HM, Filomatori CV, Bruce A, Hargrove AE, Arrar M, Gamarnik AV
PLoS Pathog · 2026 May · PMID 42149960 · Full text
Orthoflaviviruses comprise a diverse genus of positive-strand RNA viruses that includes major human pathogens such as dengue, yellow fever, Zika, Japanese encephalitis, tick-borne encephalitis, and West Nile viruses. Des...
Orthoflaviviruses comprise a diverse genus of positive-strand RNA viruses that includes major human pathogens such as dengue, yellow fever, Zika, Japanese encephalitis, tick-borne encephalitis, and West Nile viruses. Despite their global impact, the molecular constraints that preserve viral replication across distinct vectors and host environments remain incompletely understood. Viral RNA replication depends on Stem-Loop A (SLA), a structured RNA element located at the 5' end of the genome that recruits the viral polymerase NS5. Here, we examine the structural diversity of this RNA promoter across orthoflaviviruses. Using infectious clones, reporter viruses, and computational structural analyses, we show that SLAs from diverse mosquito- and tick-borne viruses are functionally interchangeable in the context of dengue and Zika virus infectious clones. Structure-function analyses reveal that conserved nucleotide contacts between the SLA top loop and the NS5 polymerase domain form a conserved interaction interface maintained across orthoflaviviruses, including insect-specific viruses. In contrast, other SLA sub-elements, such as the three-way junction and side stem, have diverged in a group-specific manner, yet co-evolution in mosquito and tick-borne viruses preserves the three-dimensional architecture and NS5 binding competence for viral replication. Guided by this conservation, we identify small molecules that bind SLA and inhibit replication across multiple pathogenic orthoflaviviruses. These findings uncover fundamental principles governing viral RNA promoter evolution and establish conserved RNA structures as promising targets for viral control.
FUT8-mediated core fucosylation of receptor APN drives entry of multiple alphacoronaviruses.
Sun L, Xiang Y, Yang Y … +6 more , Tan Y, Su Z, Fu Z, Fu Y, Xie S, Peng G
PLoS Pathog · 2026 May · PMID 42149951 · Full text
Understanding the interaction mechanisms between coronaviruses (CoVs) and their hosts is crucial for understanding the viral replication cycle and identifying novel antiviral targets. In this study, we found alpha-(1,6)-...
Understanding the interaction mechanisms between coronaviruses (CoVs) and their hosts is crucial for understanding the viral replication cycle and identifying novel antiviral targets. In this study, we found alpha-(1,6)-fucosyltransferase (FUT8), via its fucosyltransferase activity, is involved in the several alphacoronaviruses (α-CoVs) spike-receptor aminopeptidase N (APN) interaction to regulate viral entry. Mechanistically, pAPN lacking FUT8-mediated modification showed no binding to the transmissible gastroenteritis virus (TGEV) RBD. The viral entry depends on core fucosylation at pAPN N736. Further pAPN glycoproteomic analysis confirmed that core fucosylation at N736 is indeed present in wild-type (WT) cells but almost abolished in KO cells, highlighting that FUT8 facilitates viral entry by mediating core fucosylation of pAPN N736. Interestingly, FUT8 is also essential for the entry of canine and feline CoVs, which use APN as their receptor, by mediating core fucosylation at N747 and N740 on canine and feline APN, respectively, demonstrating that FUT8 has a conserved function across these species. Overall, this study uncovers the role of FUT8 in multiple α-CoVs entry, revealing the importance of core fucosylation in viral replication and identifying FUT8 as a potential broad-spectrum antiviral target.
HCMV-pUS2 Disrupts cGAS-STING Signaling through LMAN2L Degradation.
Zhou YP, Yao YX, Wu JP … +7 more , Pan YT, Zeng WB, Sun JY, Zhao Y, Cheng H, Luo MH, Yang B
PLoS Pathog · 2026 May · PMID 42149942 · Full text
Human cytomegalovirus (HCMV) has evolved diverse strategies for immune evasion. In this study, we identified HCMV-pUS2 as an indirect antagonist of the cGAS-STING pathway by promoting the degradation of lectin mannose-bi...
Human cytomegalovirus (HCMV) has evolved diverse strategies for immune evasion. In this study, we identified HCMV-pUS2 as an indirect antagonist of the cGAS-STING pathway by promoting the degradation of lectin mannose-binding 2-like protein (LMAN2L), an unrecognized host factor involved in STING pathway. First, we discovered that HCMV, but not other DNA viruses such as HSV-1 and VACV, induces proteasomal degradation of LMAN2L during the immediate-early stage of infection. We then demonstrated that HCMV-pUS2 mediates LMAN2L degradation by recruiting the host E3 ubiquitin ligase RNF139 and E2 ubiquitin-conjugating enzyme UBE2G2, directing LMAN2L to the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. LMAN2L knockout diminishes HCMV-induced expression of type I interferons and interferon-stimulated genes. Furthermore, LMAN2L co-localizes and interacts with STING. Though it does not affect STING dimerization or TBK1 recruitment, it is essential for STING translocation from the ER to the Golgi. Our findings uncover LMAN2L as a novel host regulator of the STING pathway and identify pUS2-mediated ERAD as a previously unrecognized viral immune evasion strategy.
Nuclear transport of human cytomegalovirus tegument protein pp65 through nucleoplasmic reticulum.
Azzeh M, Santos MF, Yokomizo AMK … +3 more , Cha V, Corbeil D, Lorico A
PLoS Pathog · 2026 May · PMID 42149941 · Full text
Human cytomegalovirus (HCMV) is a widespread beta-herpesvirus that establishes lifelong infection and can cause severe disease in immunocompromised individuals as well as congenital abnormalities. While HCMV entry into f...
Human cytomegalovirus (HCMV) is a widespread beta-herpesvirus that establishes lifelong infection and can cause severe disease in immunocompromised individuals as well as congenital abnormalities. While HCMV entry into fibroblasts is classically described as plasma membrane fusion, accumulating evidence indicates that a fraction of virions undergo endocytic uptake, notably via macropinocytosis, and traffic through the endosomal system. However, the mechanisms by which internalized viral components reach the nucleus are still being elucidated. Here, we investigated whether HCMV exploits type II nuclear envelope invaginations (NEIs), rare and discrete folds of the nuclear membrane that extend into the nucleoplasm, and the associated VAP-A-ORP3-Rab7 (VOR) complex to mediate nuclear delivery of viral components, a mechanism previously described for HIV-1. Using primary human foreskin fibroblasts (HFFs), we tracked the tegument protein pp65 and immediate-early proteins IE1/2 during early infection. We show that HCMV infection induces a rapid increase in NEI formation within the first hour of infection, accompanied by the accumulation of pp65 within Rab7 ⁺ endosomal structures that localize to NEIs. Pharmacological inhibition of the VOR complex with an ORP3-targeting drug significantly reduced NEI formation, decreased the association of pp65 with NEIs, and impaired its nuclear accumulation by approximately 2.5-fold. In contrast, inhibition of this pathway did not affect immediate-early gene expression at 24 hours post-infection. Functionally, disruption of the VOR complex resulted in a 3-fold reduction in viral replication, highlighting the contribution of this pathway to efficient infection. Together, these findings support a model in which HCMV tegument proteins, but not the viral genome, access the nucleus via a NEI/VOR-dependent trafficking route. This work identifies a previously unrecognized nuclear delivery pathway exploited by HCMV and suggests that targeting nuclear-endosomal communication may represent a novel antiviral strategy.
The carbon starvation-inducible lipoprotein (Slp) influences differential adherence of Escherichia coli O157:H7 at the bovine rectoanal junction.
Kudva IT, Biernbaum EN, Cassmann ED … +4 more , Palmer MV, Edison LK, Castellanos-Gell J, Kariyawasam S
PLoS Pathog · 2026 May · PMID 42149937 · Full text
Shiga toxin-producing Escherichia coli O157:H7 (O157), a foodborne human pathogen, persists at the rectoanal junction (RAJ) of the bovine intestinal tract, in asymptomatic cattle reservoirs. Identifying mechanisms used b...
Shiga toxin-producing Escherichia coli O157:H7 (O157), a foodborne human pathogen, persists at the rectoanal junction (RAJ) of the bovine intestinal tract, in asymptomatic cattle reservoirs. Identifying mechanisms used by O157 for initial adherence before persistence at the RAJ could help develop effective O157 control modalities. We recently established the role of carbon starvation-inducible lipoprotein (Slp) in initial adherence of O157 to Caco-2 cells, with the human polymeric immunoglobulin receptor (pIgR) protein as the Slp-receptor. Here, we evaluated the role of Slp in O157 adherence to the bovine RAJ using the RAJ squamous epithelial (RSE) cell- and RAJ-in vitro Organ Culture (IVOC)- adherence assays. The wild-type O157 strain EDL932 (EDL932-WT), it's isogenic slp deletion mutant (EDL932 Δslp), and the slp complemented mutant (EDL932 Δslp-p:slp), were tested with no bacteria controls. Adherence was verified by culture and immunofluorescence (IF) staining of O157. Tissue integrity was determined using nuclear/cell staining dyes and histopathological examination. All test strains adhered in a diffuse-moderate pattern on RSE cells. However, differential adherence was observed on the RAJ-IVOC with the strains preferentially adhering to the columnar cells. Additionally, EDL932-WT and EDL932 Δslp-p:slp strains adhered in slightly greater numbers than the EDL932 Δslp strain to the RAJ-IVOC, causing disruptions primarily in the columnar region of otherwise intact RAJ-IVOC tissues. Interestingly, pIgR was also predominantly detected by IF microscopy and RNAscope in situ hybridization at the columnar region of the RAJ-IVOC tissue. In silico modeling demonstrated the possibility of a bovine pIgR- bacterial Slp interaction. Hence, our observations support the role for Slp in the initial adherence of O157 to the columnar cells at the bovine RAJ, unlike the squamous cells where the loss of slp did not impact attachment. In addition, a possible mucosal immune-interference resulting from the bovine pIgR-Slp interaction may contribute towards long-term O157 colonization of cattle.
Acetylation-mediated regulation of ALV viral proteins: Implications for retroviral inhibition.
Cui N, Han X, Huang Q … +4 more , Wang P, Wang L, Xu C, Su S
PLoS Pathog · 2026 May · PMID 42149916 · Full text
Avian leukosis virus (ALV), a prototypic alpharetrovirus, serves as a pivotal model for studying retroviral biology due to its well-characterized replication cycle, genetic tractability, and evolutionary conservation wit...
Avian leukosis virus (ALV), a prototypic alpharetrovirus, serves as a pivotal model for studying retroviral biology due to its well-characterized replication cycle, genetic tractability, and evolutionary conservation with clinically relevant retroviruses like HIV. This study identified 12 novel lysine acetylation (KAc) sites in ALV proteins through mass spectrometry, revealing striking conservation across multiple ALV subgroups and distributed as follows: 3 in the matrix (MA) protein, 1 in the capsid (CA) protein, 1 in the reverse transcriptase (RT) protein, and 7 clustered in the integrase (IN) protein. Functional characterization via site-directed mutagenesis demonstrated that the majority of these sites serve as critical regulatory switches during viral replication, with individual KAc modifications at distinct sites differentially regulating ALV replication. Mechanistically, we discovered that the host acetyltransferase HAT1 physically interacts with ALV RT protein to mediate its acetylation at the evolutionarily conserved RT13K residue. This modification, which is conserved across multiple ALV subgroups and other retroviral species, significantly enhances both RT enzymatic activity and viral replication efficiency. Our findings establish KAc as a critical post-translational regulator of alpharetrovirus replication and demonstrate that RT13K acetylation is a key modulator of ALV RT function. The conservation of this site across retrovirals suggests its functional importance and warrants further investigation to explore its potential as a broad-spectrum antiviral target. These results not only deepen understanding of epigenetic regulation in viral replication but also provide a framework for developing acetylation-targeted antiretroviral strategies.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe