PLoS Pathogens[JOURNAL]
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200 papers
Characterization of the virus-host RNA-RNA interactome across important human pathogenic RNA viruses.
Damas ND, Seemann SE, Costa R … +8 more , Krambrich J, Fossat N, Rivera-Rangel LR, Fahnøe U, Nielsen L, Gorodkin J, Bukh J, Scheel TKH
PLoS Pathog · 2026 May · PMID 42139316 · Full text
Viruses make extensive use of host cell machinery, however, most systematic studies of virus-host interactions focused on proteins with less attention to nucleic acids. RNA plays important roles in storing, conveying, an...
Viruses make extensive use of host cell machinery, however, most systematic studies of virus-host interactions focused on proteins with less attention to nucleic acids. RNA plays important roles in storing, conveying, and regulating genetic information. Our understanding of functional interactions between viral and host RNA is dominated by interactions with micro-RNAs (miRNAs), such as the interaction between hepatitis C virus (HCV) and the liver specific miR-122, critical for viral replication. Methodological developments, however, allow for broader exploration of the RNA interaction landscape beyond that of miRNAs. We here set out to identify virus-host RNA interactions by optimizing RNA antisense purification to systematically map RNA-RNA interactions (RAP-RNA) for viral RNA. After using the HCV/miR-122 interaction for validation, we applied RAP-RNA to determine the RNA interactomes for three important human pathogens; HCV, yellow fever virus (YFV) and chikungunya virus (CHIKV). Comparing virus-host RNA interactomes, we observed patterns of mRNAs encoding factors involved in translation and the proteasome, mitochondrial (mt)RNAs, small nucleolar (sno)RNAs and small nuclear (sn)RNAs, thereby providing a more comprehensive understanding of cellular RNA interactions for RNA viruses. Experimental targeting of selected HCV interactors did not lead to significant impact on viral infection, suggesting that the majority of virus-host RNA interactions are not critical for the virus. In contrast, transcription data were consistent with a possible role in viral stabilization of host RNA interactors. These findings may guide future research directions, e.g., for the role of snoRNAs and snRNAs in viral RNA regulation, with potential to provide further insight to viral exploitation of host factors.
Cryptosporidium secreted proteins form a complex layered interface with the host cell.
Puthenpurackal A, Moreno Sanchez S, Schaer T … +4 more , Falconnet L, Niu C, Vadas O, Guérin A
PLoS Pathog · 2026 May · PMID 42133745 · Full text
Cryptosporidium parvum, one of the leading causes of diarrheal death in children, remodels its infection site through secreted effector proteins. Several of them accumulate at the host-parasite interface, forming a compl...
Cryptosporidium parvum, one of the leading causes of diarrheal death in children, remodels its infection site through secreted effector proteins. Several of them accumulate at the host-parasite interface, forming a complex structure whose function and importance for infection remain poorly understood. Here, we localized and functionally characterized the putative dense granule protein DG8. We confirmed the protein to be in the dense granules, forming a ring structure once secreted at the host-parasite interface. Deletion of DG8 showed reduced infection in mice in vivo and early defect in vitro, revealing the importance of DG8 for parasite fitness. Additional secreted proteins were identified as potential partners, among which SG4, a small granule protein, was shown to partially co-localize with DG8. Applying ultrastructure expansion microscopy on intestinal sections with newly generated antibodies against DG8 and SG4, we could precisely position the ring structure above the electron-dense band, around the feeder organelle at the base of the parasitophorous vacuole membrane with an unprecedent resolution. Altogether, better visualization and understanding of the host-parasite interface through expanded intestinal tissue and effectors characterization reveal a complex and essential layered host-parasite interface.
How resistance-nodulation-division (RND) efflux pumps contribute to virulence.
Detweiler CS, Alav I
PLoS Pathog · 2026 May · PMID 42133740 · Full text
In Gram-negative bacteria, multi-subunit efflux pumps transport molecules across the inner membrane, periplasm, and outer membrane to the extracellular environment. These efflux pumps include the Resistance-Nodulation-Ce...
In Gram-negative bacteria, multi-subunit efflux pumps transport molecules across the inner membrane, periplasm, and outer membrane to the extracellular environment. These efflux pumps include the Resistance-Nodulation-Cell Division (RND) superfamily, which utilize the membrane proton motive force to export a wide range of substrates against a concentration gradient. RND efflux pumps have been extensively studied for their fundamental role in the export of antibiotics, but they also play multifaceted roles in bacterial physiology. Notably, they are required for pathogen survival in the mammalian host when antibiotics are absent, an emerging aspect of their biology that is not well understood. Here, we analyze the evidence supporting several intertwined mechanistic hypotheses regarding the requirement for RND efflux pumps during infection. To do this, we explore why host- and bacterial-derived substrates need to be exported during pathogenesis, and the effects of proton translocation from the periplasm to the cytosol. We close by highlighting knowledge gaps and directions for future work regarding the role of RND efflux pumps in bacterial virulence.
Collectin-11, a complement pattern recognition molecule, mediates pulmonary SARS-CoV-2 neutralization and protection.
Sutta A, Offersgaard A, Hernandez CRD … +9 more , Plchová TA, Zhou Y, Pérez-Alós L, Rosbjerg A, Bayarri-Olmos R, Bukh J, González-García B, Gottwein JM, Garred P
PLoS Pathog · 2026 May · PMID 42127164 · Full text
BACKGROUND: Collectin-11 (CL-11) is a complement-activating pattern recognition molecule with structural and functional similarities to mannose-binding lectin (MBL), produced in different tissues, including lung epitheli...
BACKGROUND: Collectin-11 (CL-11) is a complement-activating pattern recognition molecule with structural and functional similarities to mannose-binding lectin (MBL), produced in different tissues, including lung epithelium. Given its tissue localization and role in innate immunity, we investigated its potential to recognize and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to activate complement. METHODS: We produced recombinant CL-11, MBL, as well as wild-type, variant, and glycan-mutated SARS-CoV-2 Spike (S) proteins. We evaluated CL-11 binding to the S protein, complement activation, and inhibition of S protein-receptor binding using ELISA, as well as neutralization of SARS-CoV-2 in cell-based neutralization assays. RESULTS: CL-11 bound different SARS-CoV-2 S protein variants with similar binding preferences as MBL, targeting multiple glycan sites. Upon S protein binding, CL-11 mediated activation of both the lectin and alternative complement pathways, and inhibited S protein-receptor binding. Notably, CL-11 neutralized SARS-CoV-2, inhibiting infection of permissive cells. CONCLUSION: CL-11 binds different SARS-CoV-2 variants and neutralizes SARS-CoV-2 in an antibody-independent manner, suggesting a crucial role in early-stage infection control.
Chemical genetics reveals Leishmania KKT2 and CRK9 kinase activity is required for cell cycle progression.
Carnielli JBT, Brannigan JA, Ramos PZ … +6 more , Jones NG, Couñago RM, Sjö P, Lima APCA, Wilkinson AJ, Mottram JC
PLoS Pathog · 2026 May · PMID 42127156 · Full text
Protein kinases are key regulators of the eukaryotic cell cycle and have consequently emerged as attractive targets for drug development. Their well-defined active sites make them particularly amenable to inhibition by s...
Protein kinases are key regulators of the eukaryotic cell cycle and have consequently emerged as attractive targets for drug development. Their well-defined active sites make them particularly amenable to inhibition by small molecules, underscoring their druggability. The Leishmania kinome, shaped by diverse evolutionary processes, harbours a unique repertoire of potential drug targets. Here, we used the cysteine-directed protein kinase probe SM1-71 to identify four essential protein kinases MPK4, MPK5, MPK7 and AEK1 as candidates for covalent kinase inhibitor development, as well as CLK1/CLK2 for which covalent inhibitors have already been identified. We leveraged the absence of natural analog-sensitive (AS) kinases in L. mexicana to establish an in vivo chemical-genetic AS kinase platform for investigating essential functions of protein kinases. Using CRISPR-Cas9-mediated precision genome editing, we endogenously engineered two kinetochore-associated protein kinases, KKT2 and KKT3, and cyclin-dependent kinase CRK9, to generate AS kinases. We show that KKT2 and CRK9 kinase activities are essential for both promastigote and intracellular amastigote survival; KKT2 kinase activity being required for progression through mitosis at a stage preceding mitotic spindle assembly, while CRK9 kinase activity is required for S phase, consistent with its role in trans-splicing. This study demonstrates the utility of AS chemical genetics in Leishmania and identifies KKT2 and CRK9 as having critical roles in Leishmania cell cycle regulation and therefore being promising drug targets.
Poliovirus 3Dpol polymerase region is essential for cleavage of poliovirus 3AB in vivo.
Arita M
PLoS Pathog · 2026 May · PMID 42127148 · Full text
Poliovirus (PV) genome encodes a large single polyprotein that is processed by viral proteases to form an active replication complex through either cis or trans interactions between the viral proteins (i.e., interactions...
Poliovirus (PV) genome encodes a large single polyprotein that is processed by viral proteases to form an active replication complex through either cis or trans interactions between the viral proteins (i.e., interactions between viral proteins encoded on the same polyprotein molecule or between those encoded on different polyprotein molecules, respectively). In the processing of polyprotein, the cleavage of viral 3AB into 3A and 3B is unique, as it requires host factors (PI4KB/OSBP) and viral protease (3Cpro/3CDpro) in cultured cells (i.e., in vivo). Here, we show viral/host requirements for the cleavage of 3AB in vivo. In a polyprotein encoding 2BC3ABCD of PV, cleavage of 3AB requires the activity of PI4KB as well as the entire 3Dpol region; even a partial deletion of the 3Dpol region severely affects the cleavage in the polyprotein. The activity of OSBP and the binding activity of 3CDpro to negatively charged molecules are not required for the cleavage in the polyprotein. PV mutants with premature termination codons or in-frame deletions in the 3Dpol-coding region are generally quasi-infectious in trans-rescued replication with 3CDpro, causing extensive in-frame genome duplication or deletion. Surprisingly, some PV mutants lacking the C-terminal peptides of 3Dpol showed stable replication without any reversion in the presence of 3CDpro provided in trans; 3Dpol provided in trans could rescue the defect in 3AB cleavage via amino acid residues involved in 3Dpol-3AB and 3Dpol-3Dpol interactions, indicating a remarkable overlap with those required for the uridylylation of 3B. This work reveals novel roles of the 3Dpol region, offering insights into the polyprotein processing and recombination.
Tristetraprolin attenuates schistosomiasis-induced liver fibrosis through m⁶A-mediated regulation of TGF-β1 mRNA stability.
Zhao X, Wang X, Liu K … +18 more , Fang Q, Wang C, Mei G, Qu L, Zhang J, Feng J, Yang W, Zhu J, Zhuo H, Kuang N, Qiu X, Deng Z, Luo Q, Jin X, Jiang L, Li X, Dong H, Zhou R
PLoS Pathog · 2026 May · PMID 42127137 · Full text
Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and...
Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in Schistosoma japonicum-induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during S. japonicum-induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology in vivo. We further identify that TTP negatively regulates TGF-β1 mRNA stability by promoting N6-methyladenosine (m6A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein (WTAP) gene through its interaction with SMAD2/3. Furthermore, treatment with an m6A RNA methylation inhibitor confirms that TTP-mediated protection against S. japonicum-induced liver fibrosis, an effect associated with increased m⁶A RNA methylation in vivo. Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP/m6A epitranscriptomic machinery in the pathogenesis of S. japonicum-induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m6A RNA methylation in S. japonicum-induced liver fibrosis.
Leptospiral dissemination is restrained by liver macrophages through Clec4d-driven capture via C/EBPβ activation.
Chen X, Liu X, Liu J … +4 more , Huang H, Zhang W, Xie X, Cao Y
PLoS Pathog · 2026 May · PMID 42127134 · Full text
Leptospirosis, caused by pathogenic Leptospira species, is a globally significant zoonotic disease with high morbidity and mortality. However, the organs or cells mainly involved in capturing circulating leptospires and...
Leptospirosis, caused by pathogenic Leptospira species, is a globally significant zoonotic disease with high morbidity and mortality. However, the organs or cells mainly involved in capturing circulating leptospires and the related mechanisms remain poorly understood. In this study, we firstly proved that the liver was the primary organ that captured leptospires during the very early intravascular phase of infection in mice. Then, we used unbiased flow sorting of leptospires-positive cells and intravital microscopy of mice infected with leptospires, and found that liver macrophages were the main leptospires-capturing immune cells. The depletion of liver macrophages abolished the ability of liver to capture leptospires and prompted leptospiral spread in other organs. The C-type lectin receptor signaling pathway and Clec4d were identified as the differential pathways and gene through RNA-seq analysis, respectively. The ectopic expression of Clec4d in HEK-293T cells or treatment with a Clec4d inhibitor, mannan proved that Clec4d functioned as a capture receptor of leptospires. Mechanistically, the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) was activated and directly bound to the promoter of Clec4d to promote the expression of Clec4d in liver macrophages, thereby enhancing leptospiral capture. Mice treated with C/EBPβ inhibitor showed a significant inhibition of liver macrophages in capturing leptospires and increased leptospiral load in other organs. Our findings identify a novel mechanism by which the liver macrophages restrict leptospiral dissemination through C/EBPβ-Clec4d axis, and suggest a therapeutic strategy to prevent leptospiral dissemination through enhancing liver macrophages functions.
Host-specific platelet-activating factor acetylhydrolase selectively remodels diacylglycerophospholipids to control schistosome development.
Ertl J, Prodjinotho UF, Rao Z … +12 more , Anisuzzaman, Schluckebier J, Hamway Y, Baar P, Zhao H, Haslbeck M, Grevelding CG, Haeberlein S, Falcone FH, Schulz S, Koeberle A, Prazeres da Costa C
PLoS Pathog · 2026 May · PMID 42118807 · Full text
BACKGROUND: Schistosomiasis, one of the most prevalent neglected tropical diseases, is treated exclusively with praziquantel, which targets only adult worms. High reinfection rates and the potential emergence of drug res...
BACKGROUND: Schistosomiasis, one of the most prevalent neglected tropical diseases, is treated exclusively with praziquantel, which targets only adult worms. High reinfection rates and the potential emergence of drug resistance emphasize the need for a deeper understanding of host-parasite developmental biology for innovative therapeutic targets. Most studies have focused on parasite-derived immunomodulators and proteolytic enzymes essential for host invasion, while the contribution of host-derived factors to parasite development has remained largely unexplored. Here, we identify and functionally characterize a host phospholipase that modulates parasite diacylglycerophospholipid metabolism and development. METHODS: Large-scale proteomic screening identified host platelet-activating factor acetylhydrolase (PAFAH) as a candidate schistosomicidal factor. Using a mouse model of schistosomiasis, we produced recombinant mouse PAFAH (MsPAFAH) and performed ex vivo killing assays on juvenile stages and adult worms. Parasite morphology and reproductive organ integrity were assessed by confocal and scanning electron microscopy. Alterations in glycerophospholipid distribution were quantified by UPLC-MS/MS-based fatty acid profiling, followed by rescue experiments with free fatty acid supplementation. RESULTS: MsPAFAH was upregulated in schistosome-infected mice and exhibited potent schistosomicidal activity against all life stages in the host. MsPAFAH treatment led to profound impairments in worm fecundity, pairing stability, reproductive organ integrity, and stem cell development. This activity was associated with substantial sex-dependent changes in ether-phospholipid composition and distribution within the schistosome. MsPAFAH specifically decreased the availability of phospholipid species containing namely eicosenoic (20:1) and docosatetraenoic acid (22:4), while increasing levels of respective hydrolysis (lyso) products carrying 20:1 or stearic acid (18:0), predominantly in males. Supplementation of metabolized fatty acids C20:1/eicosenoic acid and 22:4/adrenic acid rescued the viability of female worms, confirming the essential role of the metabolism of these diacylglycerophospholipids in schistosome survival. CONCLUSIONS: Our findings reveal a previously unrecognized host-derived regulator of schistosome development, highlighting phospholipid metabolism as a promising therapeutic axis for consideration in schistosomiasis interventions.
Extensive diversity and impact of drug-resistant HIV-1 variants in individuals with prior virologic failure.
Pillay M, Choudhary MC, Deo R … +28 more , Naumenko S, Tamura TJ, Etemad B, Edelstein G, Khan A, Govender K, Govender S, Tzou P, Mick M, Herbert ZT, Muyindike W, Moosa MS, Brijkumar J, Sunpath H, McCluskey S, Chimukangara B, Manyana SC, Gounder L, Parboosing R, Francois KL, Shafer R, Ho Sui S, Pillay S, Marconi V, Siedner MJ, Moodley P, Msomi N, Li JZ
PLoS Pathog · 2026 May · PMID 42118783 · Full text
HIV-1 drug resistance remains a major challenge to treatment and control efforts, particularly in sub-Saharan Africa (sSA). However, standard resistance genotyping does not adequately capture linked drug resistance mutat...
HIV-1 drug resistance remains a major challenge to treatment and control efforts, particularly in sub-Saharan Africa (sSA). However, standard resistance genotyping does not adequately capture linked drug resistance mutations within the viral quasispecies that may influence virologic failure (VF). We used a next-generation sequencing primer ID (NGS-Primer ID) assay to characterize linked HIV-1 drug resistance mutations in plasma from participants in the Resistance Testing to Improve Management of Virologic Failure (REVAMP) study who had detectable viremia on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and were maintained on NNRTI-based regimens. For each participant, we calculated a weighted genotypic susceptibility score (wGSS) based on the GSS of each reported pattern and its sequence-supported frequency within the sample. Plasma specimens from 108 participants were sequenced. Sanger sequencing showed a median GSS of 1.0 (IQR, 1.0-2.0), whereas NGS-Primer ID identified a median of 10 distinct resistance patterns per participant (IQR, 5-17), with 67% (IQR, 8-92) of reported DRM-pattern frequency within participants corresponding to linked dual-class mutations. A broad spectrum of drug-susceptible and resistant- DRM patterns were observed, with the median difference between the highest and lowest pattern-specific GSS being 2.0 (2.0-2.75). Within each participant, a median of 10% of reported patterns showed less resistance, while 19% showed more resistance compared to that predicted by Sanger sequencing. Individuals with persistent VF had significantly lower wGSS at study entry than those who later achieved virologic re-suppression (median, 1.3 vs 2.1; p < 0.001). NGS-Primer ID revealed substantial intra-host diversity in linked HIV-1 drug resistance patterns that was not captured by conventional Sanger sequencing. Incorporating linked resistance patterns into susceptibility assessment may improve prediction of subsequent virologic failure.
Retraction: The Uptake of Apoptotic Cells Drives Coxiella burnetii Replication and Macrophage Polarization: A Model for Q Fever Endocarditis.
PLOS Pathogens Editors
PLoS Pathog · 2026 May · PMID 42118727 · Full text
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A bacterial-type cardiolipin synthase in Plasmodium spp. supports mitochondrial respiration and is important for liver stage maturation.
Adhur KA, Nirdosh N, Chandramouli A … +5 more , Basu S, Lahiri A, Kamat SS, Mishra S, Habib S
PLoS Pathog · 2026 May · PMID 42113902 · Full text
The mitochondrion of malaria-causing Plasmodium spp. supports parasite energy requirements, pyrimidine and ubiquinone biosynthesis and [Fe-S] formation. As parasites transition from the host liver to asexual and sexual b...
The mitochondrion of malaria-causing Plasmodium spp. supports parasite energy requirements, pyrimidine and ubiquinone biosynthesis and [Fe-S] formation. As parasites transition from the host liver to asexual and sexual blood stages, metabolic shifts of ATP generation through glycolysis or mitochondrial oxidative phosphorylation are accompanied by change in mitochondrial number, branching complexity and development of cristae. The final step of synthesis of cardiolipin (CL), a critical phospholipid for mitochondrial biogenesis and function, is catalyzed by cardiolipin synthase (Cls). Plasmodium spp. carry an uncharacterized, putative bacterial-type Cls distinct from Cls of mammalian hosts. We probed enzyme activity of the phospholipase D-type recombinant Plasmodium falciparum Cls. Antibodies generated against PfCls localized it to the mitochondrion in asexual blood stages; additional PfCls signal was observed in the cytosolic periphery in late-gametocytes, accompanied by CL staining in the parasite plasma membrane. To investigate the impact of Cls on parasite life cycle progression, we generated its knockout in the rodent parasite P. berghei. PbCls KO parasites had significantly impaired asexual blood-stage proliferation associated with lower abundance of CL molecular species. They showed a marked reduction in mitochondrial membrane potential and basal oxygen consumption rate. While PbCls-deficient parasites completed development within the mosquito and generated sporozoites capable of hepatocyte invasion, they exhibited a severe defect in liver-stage maturation. Plasmodium Cls is thus a vital component of malaria parasite development with a critical role in maintaining mitochondrial function.
Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress.
Dedkhad W, Tran T, Fierro MA … +2 more , Brooks C, Muralidharan V
PLoS Pathog · 2026 May · PMID 42113900 · Full text
Malaria, caused by intracellular Plasmodium falciparum parasites, remains a major global health concern. These parasites reside and replicate within a vacuole in host red blood cells. Egress of daughter parasites out of...
Malaria, caused by intracellular Plasmodium falciparum parasites, remains a major global health concern. These parasites reside and replicate within a vacuole in host red blood cells. Egress of daughter parasites out of the vacuolar and host membranes is tightly regulated via a complex mechanism. Prior studies have suggested that a cyclic-GMP driven calcium signaling pathway leads to the signal-dependent exocytosis of egress-specific vesicles that discharge several proteases into the parasitophorous vacuole. However, signal-dependent exocytosis during egress has not yet been observed in live parasitized RBCs. We targeted the exocytosis reporter, superecliptic pHlourin or SEP, to these egress-specific vesicles and utilized live imaging to observe exocytosis. The spatiotemporal relationship between exocytosis and the breakdown of the parasitophorous vacuolar membrane (PVM) as well as parasite egress was also determined using a fluorescent reporter fused to EXP2. Our data showed that exocytosis is triggered as early as 3 hours prior to merozoite egress. These data suggest that the PVM rupture occurs at a single site and rapidly expands from that initial site of rupture, releasing the merozoites into the RBC. This is followed by RBC membrane rupture and egress of merozoites. Using conditional mutants of Plasmodium endoplasmic reticulum calcium-binding protein (PfERC), we demonstrate that loss of PfERC inhibits signal-dependent exocytosis of egress-specific vesicles. Together, these data demonstrate that signal-dependent exocytosis of egress-specific vesicles starts well before merozoites are formed via cytokinesis, PVM ruptures at a single site, and that PfERC is required for exocytosis of egress-specific vesicles.
Platelet-leucocyte interactions drive MMP-mediated tissue damage in tuberculosis.
Kirwan DE, Chong DLW, Gayoso O … +12 more , Coronel J, Loader MC, Ugarte-Gil CA, Cabrera L, Medrano RC, Taylor KA, Emerson M, Lozada-Requena I, Kutschenreuter J, Zimic M, Gilman RH, Friedland JS
PLoS Pathog · 2026 May · PMID 42113884 · Full text
Tuberculosis causes inflammation and excess matrix metalloproteinase (MMP) activity which lead to tissue damage and adverse patient outcomes. Platelets are emerging as key drivers of inflammation, and platelet-leucocyte...
Tuberculosis causes inflammation and excess matrix metalloproteinase (MMP) activity which lead to tissue damage and adverse patient outcomes. Platelets are emerging as key drivers of inflammation, and platelet-leucocyte aggregate formation via interactions between platelet P-selectin and monocyte PSGL-1 receptors may regulate tissue destruction in tuberculosis. First, a platelet-monocyte co-culture model was utilised to assess platelet-leucocyte interactions. We then examined M.tb-infected and control lymph node tissue using immunofluorescence microscopy. Finally, we investigated tuberculosis patients (TB, n = 17), healthy controls (HC, n = 14), and patients undergoing bronchoscopy subsequently classified as TB (n = 10) or respiratory symptomatic (RS, n = 14). Whole blood was collected to quantify platelet aggregation using light transmission aggregometry, and platelet-monocyte aggregates (PMA), platelet-neutrophil aggregates (PNA), and platelet receptor expression using flow cytometry. In M.tb-infected monocytes, addition of platelets significantly increased secretion of MMP-1 and MMP-10 and upregulated mmp1 gene expression 4.7-fold. MMP-1 secretion was also increased by addition of platelet-derived soluble factors, and by monocyte PSGL-1 receptor ligation. We observed abundant platelets in M.tb-infected lymph node tissue, localising to PSGL-1 receptors on monocytic cells, and this was not seen in M.tb-uninfected control tissue from patients with reactive hyperplasia or with lymphoma. Ex vivo platelet aggregation in response to stimulation with platelet agonist ADP (3µM, 10µM, and 30µM) was reduced in patients with TB versus HC. PMA were increased in TB and RS versus HC, while PNA were raised only in TB; platelet receptor expression was unchanged. Platelet P-selectin expression, PMA, and PNA correlated with each other but were independent of platelet expression of GPIIb/IIIa, indicating dissociation from thrombotic pathways. In summary, PSGL-1/P-selectin mediated platelet-leucocyte interactions drive inflammation and secretion of MMPs in pulmonary TB. This identifies platelets as important regulators of tissue-damaging inflammatory responses in tuberculosis. Targeting this pathway represents a potential host-directed therapeutic strategy in tuberculosis, and possibly in other lung diseases.
Playing both sides - Epstein-Barr Virus accumulates select cellular transcripts to counter virus-mediated host shut-off in lytic cells.
Daigle D, Creasy-Marrazzo A, Gradoville L … +9 more , El-Guindy A, Mukherjee R, Das S, Baral B, Rousseau BA, Park R, McIntosh MT, Miller G, Bhaduri-McIntosh S
PLoS Pathog · 2026 May · PMID 42113877 · Full text
Epstein-Barr virus (EBV), an oncogenic virus, actively remodels the intracellular environment during its lytic (replicative/productive) phase to facilitate genome replication, virion packaging, and egress while attemptin...
Epstein-Barr virus (EBV), an oncogenic virus, actively remodels the intracellular environment during its lytic (replicative/productive) phase to facilitate genome replication, virion packaging, and egress while attempting to evade immune responses. A key aspect of this remodeling is the downregulation of host gene expression, a phenomenon known as host shutoff. This process is prominently mediated by the EBV-encoded nuclease BGLF5, but BGLF5-independent mechanisms also contribute - most notably, the viral lytic switch protein ZEBRA, which can suppress host protein synthesis. Despite this broad suppression, the expression of certain host genes essential for lytic progression must be preserved or even enhanced. To investigate how such genes evade host shutoff, we analyzed the expression of a set of cellular transcripts in Burkitt lymphoma cells, sorted 24 hours after exposure to lytic triggers, into lytic and refractory (non-lytic) populations. We identified a subset of host transcripts consistently upregulated in lytic cells across Burkitt lymphoma lines reactivated by functionally distinct lytic stimuli, indicating that such upregulation is independent of pleiotropic lytic cycle inducing stimuli. Importantly, we found that while ZEBRA suppresses protein expression of some of these host (and select viral) genes, EBV also transcriptionally upregulates two related host genes, ELAVL4 and PABPC4L. Both encode RNA-binding proteins, and we found that they differentially modulate viral transcript abundance - enhancing some while repressing others - ultimately supporting the transcriptional demands, efficient genome replication and virion release during the EBV lytic cycle. These findings highlight the virus's finely tuned regulation of both host and viral gene expression to ensure successful completion of the lytic cycle. Specifically, they suggest that EBV selectively upregulates critical host genes to counteract/escape host shutoff and promote virus propagation.
LP.8.1-directed COVID-19 mRNA vaccines durably boost neutralizing antibodies and mitigate ancestral immune imprinting.
Mellis IA, Wu M, Hong H … +8 more , Bowen A, Daniel K, Gherasim C, Pierce VM, Yin MT, Gordon A, Guo Y, Ho DD
PLoS Pathog · 2026 May · PMID 42113876 · Full text
As SARS-CoV-2 evolves, it evades existing immunity elicited by exposure to earlier strains of the virus. In response, vaccine manufacturers have updated COVID-19 vaccines annually since 2022, though immune imprinting to...
As SARS-CoV-2 evolves, it evades existing immunity elicited by exposure to earlier strains of the virus. In response, vaccine manufacturers have updated COVID-19 vaccines annually since 2022, though immune imprinting to the ancestral strain has blunted antibody responses to modern viral variants. In early 2025, the JN.1 subvariant LP.8.1 was dominant and manufacturers updated mRNA vaccine formulations to target LP.8.1 (LP.8.1 MV). However, by late 2025, other subvariants were dominant (XFG and NB.1.8.1) or emerging (e.g., PE.1.4, BA.3.2, PY.1.1.1) around the world. It is critical to understand the extent to which updated vaccine boosters elicit titers against both their target strain and recent variants. Further, it is important to quantify the extent to which immune imprinting continues to shape antiviral immune responses. Using pseudoviruses, we measured neutralizing antibody titers against a panel of 11 SARS-CoV-2 variants in serum samples from 36 adult participants in the United States before and approximately 1 month after LP.8.1 MV booster. We found that neutralizing antibody titers were substantially increased by the boost, with the greatest increases elicited against LP.8.1 and XFG. For the first time, post-boost titers were higher against the homologous vaccine target (LP.8.1) than against D614G (representing the ancestral strain). Combined, these results indicate that ancestral immune imprinting is mitigated to the greatest extent observed to date by LP.8.1 MV. Lastly, for a subset of participants, we measured neutralizing titers at approximately 4 months post-booster and found that LP.8.1-directed antibody titers were durable, with an estimated average half-life of approximately 66 days.
Excessive C5 conversion prevents C9 polymerisation and subsequent MAC-dependent killing of Klebsiella pneumoniae.
Dawoodbhoy KM, Beudeker CR, Theofilidis P … +5 more , Masson FM, van der Flier M, Rooijakkers SHM, Bardoel BW, Doorduijn DJ
PLoS Pathog · 2026 May · PMID 42113875 · Full text
Membrane Attack Complex (MAC) pores are important in the human innate immune response to directly kill pathogenic Gram-negative bacteria. MAC pores assemble when complement proteins in serum are activated on bacteria and...
Membrane Attack Complex (MAC) pores are important in the human innate immune response to directly kill pathogenic Gram-negative bacteria. MAC pores assemble when complement proteins in serum are activated on bacteria and convert complement protein C5 into C5b, which together with C6, C7, C8, and multiple copies of C9 form a pore that damages the bacterial envelope. Due to rising multidrug-resistant infections with Gram-negative pathogen Klebsiella pneumoniae (Kpn), there is interest in developing complement-activating monoclonal antibodies (mAbs) that trigger MAC-dependent killing. However, some Kpn strains resist MAC-dependent killing in serum despite potent complement activation and C5 conversion, revealing a critical gap in understanding how these strains resist MAC-dependent killing. We demonstrate that Kpn strains can resist MAC-dependent killing through a paradoxical mechanism of excessively converting C5, which limits C9 polymerisation and subsequent killing. In these strains, spiking serum with supplementary C9 restored killing. Additionally, partially inhibiting C5 conversion using complement inhibitors increased C9 polymerisation and subsequent killing. This suggests that these Kpn strains are in principle sensitive to MAC-dependent killing, but an imbalance between generated C5b and available C9 in serum limits C9 polymerisation and prevents killing. We also observed this paradoxical effect with an of excess complement-activating mAbs on Kpn strains that are typically susceptible to MAC-dependent killing in serum. Excessive C5 conversion was responsible for this reduced killing, as supplementary C9 restored killing. Lastly, in neonatal plasma, where C9 is naturally limited, complement-activating mAbs induced killing of Kpn only in the presence of supplementary C9. Our study highlights that the balance between C5 conversion and available C9 is important for MAC-dependent killing of Kpn. Additionally, absence of killing in serum does not necessarily indicate that Kpn strains are MAC-resistant. These insights are important for interpreting mAb efficacy in serum bactericidal assays and in complement-deficient populations.
Diversity and evolution of a phase-variable multi-locus antigen in Neisseria gonorrhoeae.
Yu Q, Mortimer TD, Blomqvist SOP … +4 more , Bowcutt B, Helekal D, Palace SG, Grad YH
PLoS Pathog · 2026 May · PMID 42113870 · Full text
Neisseria gonorrhoeae is a sexually transmitted bacterial pathogen that deploys multiple mechanisms to evade the immune system, including rapid variation in surface antigens. One of the most abundant and diverse antigens...
Neisseria gonorrhoeae is a sexually transmitted bacterial pathogen that deploys multiple mechanisms to evade the immune system, including rapid variation in surface antigens. One of the most abundant and diverse antigens is a member of the opacity-associated (Opa) family, which includes surface proteins that mediate gonococcal attachment to human receptors. Studies of Opa diversity and evolution have been limited by the inability of short-read sequencing to resolve the multiple copies of opa in each genome, preventing a comprehensive understanding of variation in gonococcal antigens for vaccine design and immunology studies. We assembled a dataset of 219 complete genomes from phylogenetically diverse clinical isolates using long-read sequencing and developed bioinformatics and phylogenetics tools to assess opa variation quantitatively. Each genome had on average 7 distinct opa alleles at 9-12 opa loci, and almost all isolates had at least one pair of identical or near-identical opa genes. Fewer opa genes were in frame (and thus inferred to be expressed) than expected by chance. While genomic distance between isolates correlated with overall opa allele sequence similarity, opa genes were on average 74 times more diverse than the rest of the genome. One opa locus evolved more rapidly than the other loci. There was little evidence that interspecies recombination contributed to N. gonorrhoeae opa diversity. Our findings reveal a continuously evolving opa repertoire that leads to diverse opa alleles even in closely related strains and indicate that there are likely unknown biological factors modulating opa reading frame.
Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity.
Uy JN, Lou Q, Zhou ZH … +1 more , Bradley PJ
PLoS Pathog · 2026 May · PMID 42113865 · Full text
Toxoplasma gondii and related apicomplexan parasites utilize a unique membrane and cytoskeletal organelle called the inner membrane complex (IMC) for maintaining cell shape, motility, host cell invasion, and replication....
Toxoplasma gondii and related apicomplexan parasites utilize a unique membrane and cytoskeletal organelle called the inner membrane complex (IMC) for maintaining cell shape, motility, host cell invasion, and replication. The cytoskeleton portion of the organelle is a network of filaments composed of proteins called alveolins, whose precise functions and organization are poorly understood. Here we describe the function of the founding member of the Toxoplasma alveolins, IMC1, which we show is expressed and loaded onto forming daughter buds with IMC4, but later than the other key alveolins IMC3, IMC6, and IMC10. Disruption of IMC1 results in severe morphological defects that impact the integrity of the parasite's cytoskeleton and disrupt invasion, replication, and egress. Loss of IMC1 in a less virulent type II strain results in a dramatic loss of infectivity and complete failure to form a chronic infection. We then use deletion analyses to dissect functional regions of the protein which reveals a key subregion of the alveolin domain that is sufficient for IMC targeting and also required for function. We then show that IMC1 interacts directly with IMC4 and the loss of IMC1 results in mislocalization of IMC4 specifically in forming daughter buds. This study thus reveals the critical role that IMC1 plays in forming and maintaining the architecture of the filamentous network of the IMC.
A circular RNA vaccine induces durable and cross-protective immunity against Neisseria meningitidis serogroup B in mice.
Zhang Q, Niu D, Jia Y … +14 more , Lu L, Wu W, Qu C, Sun Z, Li S, Liu Z, Lv J, Wang W, Yu J, Zhang L, Li C, Peng W, Zhang Q, Wei S
PLoS Pathog · 2026 May · PMID 42113852 · Full text
Neisseria meningitidis serogroup B (MenB) remains a major global cause of meningitis and septicemia. However, MenB vaccine development is hindered by antigenic diversity and manufacturing challenges associated with outer...
Neisseria meningitidis serogroup B (MenB) remains a major global cause of meningitis and septicemia. However, MenB vaccine development is hindered by antigenic diversity and manufacturing challenges associated with outer membrane vesicles (OMVs) or lipoproteins in resource-limited settings. Here, we engineered a high-purity circular RNA (circRNA) vaccine encoding a bacterial-derived, sequence-optimized fusion antigen of factor H binding protein (fHbp) and Neisserial heparin-binding antigen (NHBA) (fHbp-NHBA), which preserves key bactericidal epitopes in eukaryotic systems. The vaccine elicited potent functional antibody responses by serum bactericidal assay (SBA) using human complement and potent IFN-γ-secreting CD8 + T-cell responses. Crucially, the circRNA vaccine at a low dose provided complete protection and reduced bacteremia against lethal MenB challenge and demonstrated cross protection against a panel of prevalent strains in China. Both single- and two-dose regimens of the circRNA vaccine induced durable immune responses, and the two-dose immunization achieved strain coverage comparable to that of licensed MenB vaccines. Moreover, sera adoptively transferred from the circRNA-immunized group to neonatal rat pups dramatically reduced bacterial loads in blood. This study establishes a foundation for circRNA-based vaccines against bacterial pathogens.
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