Zhang Q, Gao Y, Gao W
… +3 more, Zhang X, Xu S, Zhang W
PLoS Pathog
· 2026 Jul · PMID 42391313
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A persistent evolutionary arms race exists between enteroviruses and their hosts, in which viruses employ multiple strategies to antagonize host antiviral defenses and sustain efficient replication. However, how host res...A persistent evolutionary arms race exists between enteroviruses and their hosts, in which viruses employ multiple strategies to antagonize host antiviral defenses and sustain efficient replication. However, how host restriction factors are broadly targeted by enteroviruses during this process, as well as the underlying molecular mechanisms, remain poorly understood. Here, we identify Ring Finger Protein 31 (RNF31) as a previously unrecognized host restriction factor that limits enterovirus A71 (EV-A71) replication through a dual antiviral mechanism. Specifically, RNF31 enhances innate antiviral immune signaling by promoting K63-linked polyubiquitination of Retinoic acid-inducible gene I (RIG-I). Simultaneously, RNF31 directly suppresses EV-A71 replication by inducing K27- and K48-linked polyubiquitination of the Viral Protein 4 (VP4), thereby facilitating its proteasome-dependent degradation. Furthermore, we demonstrate that the viral 3C protease (3Cpro) cleaves RNF31 at residue Q400, abolishing both RNF31-mediated activation of innate immunity and VP4 degradation, ultimately resulting in the loss of its antiviral activity. Notably, 3Cpro from multiple enteroviruses, including Coxsackievirus A16 (CV-A16), Coxsackievirus B3 (CV-B3), and Enterovirus D68 (EV-D68), cleave RNF31 at this same conserved site. Consistent with these findings, RNF31 significantly inhibits the replication of these diverse enteroviruses. Collectively, this study establishes RNF31 as a host restriction factor that suppresses the replication of multiple enteroviruses and reveals a shared immune evasion strategy employed by enteroviruses.
Kassupá JEA, Andrade AO, Bastos AS
… +13 more, Moura GLL, Rocha ML, Martinez LN, S Afonso EK, Costa WJ, Bargieri DY, Teles CBG, Medeiros JF, Kumar N, R Guimarães AC, Paton DG, Catteruccia F, Araujo MS
PLoS Pathog
· 2026 Jul · PMID 42391120
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Malaria, caused by protozoa of the genus Plasmodium and transmitted to humans through the bite of mosquitoes of the genus Anopheles, remains a public health problem. Long-Lasting Insecticide -treated Bed Nets (LLINS) and...Malaria, caused by protozoa of the genus Plasmodium and transmitted to humans through the bite of mosquitoes of the genus Anopheles, remains a public health problem. Long-Lasting Insecticide -treated Bed Nets (LLINS) and Indoor Residual Spraying (IRS) represent the main vector control measures for malaria prevention. However, to address the concerns of mosquito resistance to pyrethroids, other malaria control strategies are being explored for effectively blocking malaria transmission by eliminating or reducing the parasite in the vector. This study evaluated the use of antimalarials through tarsal contact of female Anopheles darlingi infected with Plasmodium vivax via a Direct Membrane Feeding Assay (DMFA). Female An. darlingi were exposed tarsally using Petri dishes impregnated with antimalarials at 1 mmol/m2 for exposure times of 6 or 60 minutes. Among the antimalarials evaluated were Atovaquone (ATQ), Tafenoquine (TQ), Chloroquine (CQ), Mefloquine (MQ), Primaquine (PQ), and the compound Nanchangmycin (NCG). Atovaquone was the only antimalarial evaluated before and after DMFA at exposure times of 60 min and 6 min. The results demonstrate complete elimination of P. vivax in female An. darlingi exposed to ATQ by tarsal contact 60 min before infection. ATQ was also effective 6 min before or after infection, reducing infection prevalence. In addition, MQ also significantly reduced infection intensity, but there was no difference in infection prevalence. No significant differences were observed for the other antimalarials.
Mukherjee S, Grouza V, Tchung A
… +14 more, Even A, Yaqubi M, Tuznik M, Cannon T, Recinto SJ, Gavino C, Bourque MJ, Giguère N, McBride H, Desjardins M, Gruenheid S, Stratton JA, Rudko DA, Trudeau LE
PLoS Pathog
· 2026 Jun · PMID 42378309
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A growing body of research suggests a link between immune system activation and the development of Parkinson's disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can in...A growing body of research suggests a link between immune system activation and the development of Parkinson's disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can induce PD-like motor dysfunction in Pink1 knockout (KO) mice, along with immune cell infiltration into the brain. To better understand mechanisms underlying immune-mediated brain attack in this model, we tested whether mild infections are sufficient to increase blood-brain barrier (BBB) permeability and trigger brain inflammation. Pink1 wild-type (WT) and KO mice were infected with C. rodentium, and gadolinium-enhanced magnetic resonance imaging (MRI) was performed at days 13 and 26 post-infection to assess BBB integrity. Quantitative MRI analysis revealed increased BBB permeability at day 26 in both WT and KO mice, particularly in the striatum, dentate gyrus, somatosensory cortex, and thalamus. Notably, this permeability was not associated with changes in tight junction protein expression or dopamine system markers in the striatum at either time point. However, persistent microglial activation was observed at day 26 post-infection, along with elevated levels of inflammatory mediators such as eotaxin, IFN-γ, CXCL9, IL-17, and MIP-2 in the striatum. Additionally, serum levels of IL-17 and CXCL1 were increased in infected Pink1 KO mice. Flow cytometry revealed neutrophil infiltration in the brain at day 26 post-infection. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. These findings support the hypothesis that even mild gastrointestinal infections can increase BBB permeability, disrupt brain homeostasis, and promote chronic neuroinflammation. In genetically susceptible individuals, such as those with Pink1 deficiency, this may represent a first hit that contributes to subsequent induction of PD pathology with aging.
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 Jun · PMID 42378242
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[This corrects the article DOI: 10.1371/journal.ppat.1014125.].[This corrects the article DOI: 10.1371/journal.ppat.1014125.].
PLoS Pathog
· 2026 Jun · PMID 42378238
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Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly under...Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly understood. Here, we establish a comprehensive structural database of norovirus VP1 P-domains across nine genogroups (GI-GIX) through large-scale AlphaFold2 predictions. By integrating phylogenetic analysis of VP1 sequences and structures, we demonstrate that sequence and structural evolution show overall concordance under purifying selection, yet significant local discrepancies reveal distinct patterns of convergent evolution shaped by structural constraints and functional divergence. Focusing on the predominant GII.4 genotype, we found that compared to near-full-genome and nucleotide trees, only the VP1 amino acid tree reliably clustered GII.4 variants in chronological order as monophyletic groups. We further identify a hierarchical evolutionary strategy: positive selection may drive structural hypervariability in major antigenic epitopes D and C for immune escape, with epitope D exhibiting pronounced structural flexibility that complicates its structural characterization, whereas coevolutionary analysis uncovers a broad network of compensatory interactions spanning multiple epitopes, with striking enrichment in epitope A. These epitopes exhibited a pattern of "sequence plasticity with structural conservation", maintained by coevolutionary constraints that preserve conformational integrity. Together, these findings suggest that norovirus vaccine strategies targeting the structurally conserved conformations of epitopes A and G could overcome the limitations of traditional strain-specific approaches, offering a pathway toward broad protection against evolving viral diversity.
Ahmed M, Carlson J, Das A
… +4 more, Hoque SF, Benoit JB, Chiurillo MA, Lander N
PLoS Pathog
· 2026 Jun · PMID 42371989
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Cyclic AMP (cAMP) signaling is crucial for environmental sensing and response to stress conditions in trypanosomatids. However, the mechanisms driving the specificity of cAMP signals remain poorly understood in these pro...Cyclic AMP (cAMP) signaling is crucial for environmental sensing and response to stress conditions in trypanosomatids. However, the mechanisms driving the specificity of cAMP signals remain poorly understood in these protozoan parasites. We recently identified two putative cAMP microdomains in Trypanosoma cruzi, the causative agent of Chagas disease. Here, considering the localization of three phosphodiesterases, PDEC at the contractile vacuole complex (CVC), and PDEB1 and PDEB2 along the flagellum, we modulated their expression to functionally characterize the flagellar tip (FT) and the CVC as individual PDE-defined cAMP signaling compartments, named FT-cAMP and CVC-cAMP, respectively. We generated PDE knockout and overexpression cell lines to selectively alter cAMP signals generated in each compartment. Our results indicate that FT-cAMP mediates cell adhesion, metacyclogenesis, host cell invasion, and intracellular replication, while CVC-cAMP is important for osmoregulation and epimastigote proliferation. In addition, ablation of flagellar PDEB1 and PDEB2 enhanced the parasite's ability to colonize the hindgut of the triatomine vector, whereas PDEC-KO parasites were impaired in their establishment in the insect's hindgut. The observed phenotypes were PDE-specific, demonstrating functional segregation between the two compartments. Our data provide robust evidence on the presence of compartmentalized cAMP signals in T. cruzi, linking the role of PDE-defined cAMP pools to specific cellular responses during the parasite's life cycle.
Munera Lopez J, Arias Padilla LF, Tengganu IF
… +5 more, Hao Y, Zhang Y, Florens L, Murray JM, Hu K
PLoS Pathog
· 2026 Jun · PMID 42361143
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The phylum Apicomplexa contains ~ 6000 known species of unicellular eukaryotic parasites. A unifying feature among the apicomplexans is the apical complex, which varies in complexity in different lineages, but always con...The phylum Apicomplexa contains ~ 6000 known species of unicellular eukaryotic parasites. A unifying feature among the apicomplexans is the apical complex, which varies in complexity in different lineages, but always contains an annulus (a.k.a. the apical polar ring) into which the minus ends of an array of cortical microtubules are embedded. In Toxoplasma gondii, the apical complex also includes the conoid, which contains several signaling and structural proteins critical for parasite motility. The conoid extends and retracts through the apical polar ring in a calcium-dependent manner. Here we report the identification of several new apical polar ring components, including APR9, which is highly conserved among the apicomplexans and their free-living relative Chromera velia. The loss of APR9 alone has only a moderate impact on the parasite lytic cycle. However, the knockout of both APR9 and KinesinA (another apical polar ring component) paralyzes the parasite and drastically impairs invasion, egress and the lytic cycle. The double-knockout displays multiple subcellular abnormalities, including the formation of an apical actin concentration, impaired conoid extension, and significantly reduced secretion of a major adhesin (MIC2) upon stimulation with a calcium ionophore. These findings reveal that the apical polar ring plays a critical role in parasite motility and contributes to multiple subcellular processes.
PLoS Pathog
· 2026 Jun · PMID 42361119
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Orthoflaviviruses are genetically related, yet cause distinct disease patterns ranging from hepatitis and vascular shock syndrome to encephalitis and congenital abnormalities. There is an incomplete understanding of the...Orthoflaviviruses are genetically related, yet cause distinct disease patterns ranging from hepatitis and vascular shock syndrome to encephalitis and congenital abnormalities. There is an incomplete understanding of the cellular pathways co-opted by orthoflaviviruses, and differences in host response to infection may underlie the diverse pathologies caused. We present a single-cell approach (Quantification of Infection and CRISPR guide sequencing; QIC-seq) that combines CRISPR/Cas9 knockout with virus-inclusive transcriptomics to systematically compare host factor requirements and host transcriptional response to orthoflaviviral challenge. Using a CRISPR library focused on select ER-proteostasis genes, we show that dengue and yellow fever viruses are strictly dependent on subunits of the oligosaccharyltransferase complex, while the more distantly related West Nile and Langat viruses are dependent on components of the ER-associated degradation machinery. Our data further shows virus-induced upregulation of interferon-stimulated genes, and activation of the unfolded protein response. QIC-seq enables quantitative comparisons of viral host factor utilization, which may inform development of host-directed antiviral therapies.
PLoS Pathog
· 2026 Jun · PMID 42361067
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Most plant viruses rely on insect vectors for transmission. In general, nonviruliferous vectors acquire viruses from infected plants, whereas viruliferous vectors subsequently move to uninfected plants for virus inoculat...Most plant viruses rely on insect vectors for transmission. In general, nonviruliferous vectors acquire viruses from infected plants, whereas viruliferous vectors subsequently move to uninfected plants for virus inoculation. However, they are not merely passive passengers within their vector. Persistent-propagative plant viruses, which invade and replicate in insect vectors, can actively and directly reshape their physiology, morphology, and feeding behavior to facilitate efficient transmission. Recent studies have uncovered both indirect plant-mediated mechanisms and direct vector-targeted mechanisms, including modulation of neural signaling, olfactory systems, wing development, and feeding activity. Here, we summarize current understanding of how persistent-propagative plant viruses integrate indirect plant-mediated effects with direct manipulation of insect vectors. We further discuss the ecological implications of these virus-plant-vector interactions, highlight major bottlenecks in virus-insect interaction research, and emerging technological advances that may facilitate future mechanistic studies and support innovative strategies for controlling vector-borne plant viral diseases.
Vassilieff H, Serfraz S, Choisne N
… +4 more, Geering ADW, Lefeuvre P, Teycheney PY, Maumus F
PLoS Pathog
· 2026 Jun · PMID 42360994
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Endogenous viral elements (EVEs) are viral sequences integrated into host genomes, functioning as molecular fossils of past infections. Most characterised EVEs in plants are derived from the Caulimoviridae, the only fami...Endogenous viral elements (EVEs) are viral sequences integrated into host genomes, functioning as molecular fossils of past infections. Most characterised EVEs in plants are derived from the Caulimoviridae, the only family of dsDNA viruses infecting this kingdom. Endogenous caulimovirids (ECVs) occur across taxonomically diverse vascular plant species and represent a significant resource for studying host-virus coevolution, host range dynamics, and the evolution of viral genomes over deep timescales. Previous evolutionary studies utilising ECVs have proposed cospeciation or host switching as the primary drivers of Caulimoviridae diversification; however, these studies were limited by poor representation of genomic data from basal plant lineages. Here, we analysed 93 plant genomes spanning all major embryophyte groups, including ferns and lycophytes, and identified 47,135 ECVs across 75 genomes. These sequences were classified into 71 operational taxonomic units (OTUs), including 35 previously undescribed groups, revealing substantial and previously unrecognised diversity within the Caulimoviridae. Notably, we identified a basal clade restricted to the Araucariaceae, an ancient lineage of Gondwanan conifers. Phylogenetic comparisons between ECVs and host plant lineages support a macroevolutionary model in which cospeciation with tracheophytes played a dominant role in shaping Caulimoviridae diversification. Together, these findings establish Caulimoviridae and their endogenous counterparts as a powerful model system for paleovirology, offering unprecedented insights into the coevolution, diversification, and extinction of plant viruses over deep evolutionary timescales.
PLoS Pathog
· 2026 Jun · PMID 42348559
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Honey bees are commonly infected with viruses, including deformed wing virus (DWV-A and DWV-B) and sacbrood virus (SBV), which cause morphological symptoms and death in developing bees and primarily asymptomatic infectio...Honey bees are commonly infected with viruses, including deformed wing virus (DWV-A and DWV-B) and sacbrood virus (SBV), which cause morphological symptoms and death in developing bees and primarily asymptomatic infections in adult bees. Co-infections occur regularly in colonies, but they have rarely been studied, especially in adult bees. In this study, we co-inoculated young adult honey bees with DWV by injection (simulating vectored transmission by Varroa) and feeding them with SBV (simulating oral transmission) before reintroducing them in colonies. Through the use of optical counters and regular sampling, we tracked their survival and behaviour, and quantified the dynamics of viral loads in treated bees as well as the expression of eight immune genes involved in honey bee anti-viral immunity. Here, we show that co-inoculations of DWV and SBV synergistically increase the virulence of DWV and conditionally promote the replication of SBV. We also show that SBV may play a role in the replication of DWV in specific contexts. Finally, our results show that immune responses in adult honey bees depend on virus genotype (i.e., DWV), their relative abundance and the pre-existing natural infections before virus injection). Together, these results confirm the existence of deleterious interactions between deformed wing virus and sacbrood virus, impacting honey bee health and colony dynamics.
Hook LM, Cairns TM, Awasthi S
… +7 more, Egan KP, Gopalakrishnan M, Syeda Z, Pardi N, Bergstrom T, Cohen GH, Friedman HM
PLoS Pathog
· 2026 Jun · PMID 42348550
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Our vaccine candidate for genital herpes includes three immunogens involved in virus entry and immune evasion. HSV-2 glycoprotein C (gC2) is one of the immune evasion molecules that inhibits complement activation by bind...Our vaccine candidate for genital herpes includes three immunogens involved in virus entry and immune evasion. HSV-2 glycoprotein C (gC2) is one of the immune evasion molecules that inhibits complement activation by binding C3b, and is the focus of this manuscript. Mice were immunized with 0.25, 0.5, 1, 10, or 30 µg of gC2 lipid nano particle (LNP)-encapsulated nucleoside-modified mRNA and challenged intravaginally with HSV-2. The gC2 mRNA-LNP, even at the lowest dose, was highly protective as a single immunogen. We measured antibody responses to six gC2 epitopes. Both neutralizing and C3b binding epitopes on gC2 were targeted. We passively immunized mice with monoclonal antibodies (mAbs) to gC2 and determined that the mAbs that enhance complement activation by blocking C3b binding were protective, while the mAb that neutralizes the virus, but does not block C3b binding, failed to protect. These results highlight the importance of a vaccine immunogen that induces antibodies that block the ability of gC to inhibit complement activation.
Qiu R, Zhang Y, Zhou J
… +11 more, Wang J, Tang W, Xie X, Cheng Y, Ding T, Sun P, Shi Y, Xi C, Zhou Y, Fang L, Xiao S
PLoS Pathog
· 2026 Jun · PMID 42348500
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Uridine diphosphate N‑acetylglucosamine (UDP‑GlcNAc) has often been overlooked because its source pathway contributes little to glucose flux. However, through O‑GlcNAcylation, even small fluctuations in UDP‑GlcNAc levels...Uridine diphosphate N‑acetylglucosamine (UDP‑GlcNAc) has often been overlooked because its source pathway contributes little to glucose flux. However, through O‑GlcNAcylation, even small fluctuations in UDP‑GlcNAc levels can be amplified to shape immune responses. In this study, we utilized porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential, as a model to investigate the role of UDP-GlcNAc in viral infection. Our findings demonstrate that upon PDCoV infection, host cells increase the synthesis of UDP-GlcNAc, which inhibits viral replication by remodeling metabolic pathways. Mechanistically, O-linked N-acetylglucosamine transferase (OGT) transfers an O-GlcNAc moiety from UDP-GlcNAc to RNF166 at T157, resulting in O-GlcNAcylation. This modification enables RNF166 to ubiquitinate the PDCoV membrane (M) protein at K207, thereby promoting its degradation via the ubiquitin-proteasome pathway. Notably, these effects are common in the host response to porcine coronavirus infections, highlighting the intricate interplay among metabolism, glycosylation, and ubiquitination in immune responses.
Tian X, Wang X, Wang S
… +7 more, Zhong Y, Xia Y, Chen Y, He L, Pan D, Lan K, Zhang J
PLoS Pathog
· 2026 Jun · PMID 42341060
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Host restriction factors serve as intrinsic barriers against viral infection, and are frequently counteracted by viral antagonists. Previous studies, including our own, have identified SMCHD1 as a restriction factor that...Host restriction factors serve as intrinsic barriers against viral infection, and are frequently counteracted by viral antagonists. Previous studies, including our own, have identified SMCHD1 as a restriction factor that suppresses the replication of multiple viruses. Here, we reveal that the antiviral activity of SMCHD1 is dynamically regulated by two different post-translational modifications. SUMOylation of SMCHD1 promotes its association with the viral genome and enhances its antiviral activity. In contrast, during herpes simplex virus 1 (HSV-1) infection, the viral E3 ligase ICP0 induces SMCHD1 ubiquitination and proteasomal degradation, thereby relieving viral restriction. Loss of ICP0 stabilizes SMCHD1 and leads to marked accumulation of SUMOylated SMCHD1, rendering ICP0-deficient HSV-1 more sensitive to SMCHD1-mediated inhibition. Together, our findings uncover a reciprocal SUMO-ubiquitin regulatory mechanism that governs SMCHD1 antiviral activity and highlight a refined virus-host arms race centered on biphasic modification of a single restriction factor.
Höppner YD, Krumkamp R, Nagaoka H
… +20 more, Wapler C, Honner H, Turner L, Dejon-Agobé JC, Honkpehedji YJ, Zinsou JF, Held J, Esen M, von Thien H, Bruchhaus I, Sim BKL, Hoffman SL, Kremsner PG, Gilberger TW, Lell B, Tsuboi T, Lavstsen T, Takashima E, Mordmüller B, Bachmann A
PLoS Pathog
· 2026 Jun · PMID 42341059
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Antibody-mediated immunity directed against Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important immune mechanism for protection against clinical malaria and control of parasitemia. Current studi...Antibody-mediated immunity directed against Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important immune mechanism for protection against clinical malaria and control of parasitemia. Current studies on PfEMP1-based immunity are constrained by the protein's high molecular weight, complex multidomain architecture, and extensive polymorphism. Controlled human malaria infection (CHMI) studies uniquely enable the assessment of strain-specific PfEMP1 immunity prior to exposure and its correlation with infection outcomes using the same parasite strain. In this study, different serological assays targeting both full-length native PfEMP1 and individual domains were applied to plasma samples obtained prior to challenge infection at study baseline from 25 individuals enrolled in a CHMI study of PfSPZ Challenge (NF54), that included malaria-naïve Europeans and lifelong malaria-exposed Africans with varying degrees of immunity. All assays showed strong predictive value of both PfEMP1 antibody levels and breadth at study baseline for CHMI outcome. A random forest machine learning analysis of antibody recognition profiles, measured by AlphaScreen nearly covering all extracellular PfEMP1 domains of the NF54-CHMI parasite strain, suggested that a broad antibody repertoire, including antibodies against the most diversified group B PfEMP1s, represents a discriminative feature distinguishing volunteers with high versus low susceptibility to CHMI. In parasites re-isolated from the volunteers, dominant var transcripts encoded PfEMP1 variants are not recognized by the individuals' pre-existing antibodies at study baseline. Given that the CHMI strain NF54 predominantly expresses B-type var genes at the onset of blood-stage infection, effective control of CHMI was associated with a broad antibody repertoire, particularly including antibodies targeting B-type PfEMP1. In line with the "hole-in-the-wall" theory, this likely reflects an antibody-mediated restriction of the parasite population emerging from the liver to parasites expressing PfEMP1 variants not previously encountered by the host immune system.
PLoS Pathog
· 2026 Jun · PMID 42341027
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Organisms can activate innate immunity not only by detecting pathogens but also by sensing disturbances to essential cellular processes. Such damage-based surveillance provides a means to identify cellular disruptions th...Organisms can activate innate immunity not only by detecting pathogens but also by sensing disturbances to essential cellular processes. Such damage-based surveillance provides a means to identify cellular disruptions that prime host immunity even in the absence of infection. To uncover pathways that enhance immunity, we perform a forward genetic screen in Caenorhabditis elegans for mutants with elevated intestinal immune activation. This screen identifies a hypomorphic allele of the conserved mRNA cap 2'-O-methyltransferase cmtr-1, which strongly induces immune effector expression. Transcriptomic profiling reveals the broad activation of innate immune responses, and functional analyses demonstrate that this response requires the GATA transcription factor ELT-2. Notably, loss of cmtr-1 increases resistance to Pseudomonas aeruginosa, indicating that reduced RNA cap methylation can elicit protective immunity. Together, these findings reveal a previously unrecognized mechanism of immune surveillance and demonstrate that perturbation of CMTR-1 serves as a danger signal, triggering an ELT-2-dependent protective immune response.
PLoS Pathog
· 2026 Jun · PMID 42340982
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Anaplasma phagocytophilum is an obligatory intracellular bacterium that causes an emerging infectious disease, human granulocytic anaplasmosis. It undergoes a biphasic developmental cycle inside membrane-bound vacuoles w...Anaplasma phagocytophilum is an obligatory intracellular bacterium that causes an emerging infectious disease, human granulocytic anaplasmosis. It undergoes a biphasic developmental cycle inside membrane-bound vacuoles within the host human neutrophils, maturing from a proliferating reticulate cell form to an infectious dense core (DC) form that is subsequently spontaneously released from host cells to initiate a new infection cycle. However, how A. phagocytophilum coordinates growth and release is unknown. Here, we found localized cortical F-actin disruption occurs where Anaplasma-containing vacuoles abut on the plasma membrane to release bacteria. Disruption of actin filaments by cytochalasin D and latrunculin B induced unrestrained release of almost all intracellular A. phagocytophilum from host cells, which were significantly less infectious than spontaneously released bacteria. A. phagocytophilum AnkA, a type IV secretion system (T4SS) effector, was found to localize in the cell periphery with cortical F-actin. By immunoprecipitation followed by mass spectrometry, AnkA was found to interact with actin, α-actinin 4 (Actn4) involved in actin cross-linking, and gelsolin for actin filament remodeling. shRNA-knockdown of Actn4 or gelsolin, enhanced release of premature A. phagocytophilum. Glutathione S-transferase (GST)-tagged C-terminus of AnkA (AnkA-C) interacted with actin and gelsolin, whereas the N-terminus (AnkA-N) interacted with Actn4. In vitro pyrene-actin polymerization assay showed that GST-AnkA-C has stronger actin polymerizing activity than GST-AnkA or GST-AnkA-N. Ectopically expressed GFP-AnkA-N localized to the plasma membrane and induced membrane ruffling, whereas GFP-AnkA-C colocalized with and enhanced stress fiber formation. These results demonstrate that AnkA is the first example of bacterial molecules interacting with gelsolin and Actn4. The result suggests that by colocalizing with cortical F-actin and controlling F-actin dynamics and cross-linking, AnkA regulates spatiotemporal release of A. phagocytophilum. The current study unravels a new paradigm of retention/release mechanism of intracellular pathogen regulated by a T4SS effector.
de Oliveira BCD, Arias Del Angel J, Herrmann May N
… +3 more, Barrett MP, Domagalska MA, Beneke T
PLoS Pathog
· 2026 Jun · PMID 42340977
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Treatment failure and relapse remain major challenges in leishmaniasis despite available chemotherapies. Historically, these outcomes have been interpreted through the lens of classical drug resistance driven by heritabl...Treatment failure and relapse remain major challenges in leishmaniasis despite available chemotherapies. Historically, these outcomes have been interpreted through the lens of classical drug resistance driven by heritable genetic mutations. However, drug responses are increasingly recognised to extend beyond resistance and include distinct but related phenomena such as hypersensitivity, tolerance, and persistence. Dissecting this range of responses in Leishmania requires approaches that capture both heritable genetic variation and dynamic cellular states. Here, we highlight how emerging genomics and perturb-omics technologies can resolve mechanisms underlying diverse drug responses. We emphasise that their impact depends on state-aware experimental design, including calibrated drug-selection, varied exposure regimens, and strategies to isolate rare persister populations. Together, these approaches provide a framework to move beyond resistance-centric models towards a more comprehensive understanding of parasite drug response.