Misumi I, Shirasaki T, Xie L
… +7 more, Yonish B, González-López O, Hirai-Yuki A, Chen X, Li Y, Whitmire JK, Lemon SM
PLoS Pathog
· 2026 May · PMID 42113844
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Hepatitis A virus (HAV) is a globally important cause of enterically-transmitted hepatitis. It is one of 9 distinct Hepatovirus species in the Picornaviridae, among which phylogenetic reconstructions suggest multiple pas...Hepatitis A virus (HAV) is a globally important cause of enterically-transmitted hepatitis. It is one of 9 distinct Hepatovirus species in the Picornaviridae, among which phylogenetic reconstructions suggest multiple past host species jumps. HAV readily infects mice with defective type I interferon responses, suggesting the major barrier preventing human HAV from replicating in a rodent host is an inability to overcome innate immune responses. In prior studies, only a single nonsynonymous mutation of uncertain significance (3Dpol-R468K) was identified within the genome of wild-type HAV following passage in interferon-receptor knockout mice. Here, we show that R468K and other mutations in the 3Dpol polymerase (E461D and D473G) are uniformly present in virus recovered from Ifnar1-/- mice following intrahepatic injection of HAV RNA. Reverse molecular genetics experiments confirmed RNAs with R468K or D473G mutations were more likely to initiate sustained infection than wild-type RNA in mice. In competition experiments using cell culture-adapted virus, a K468 mutant out-replicated wild-type R468 in murine cells, whereas R468 rapidly replaced K468 in human cells. These 3Dpol mutations thus promote HAV replication in a host species-specific manner. AlphaFold 3 modeling indicates E461, R468, and D473 are closely positioned on the surface of the 3Dpol thumb domain, suggesting they modulate interactions with species-specific host factor(s). Proteomics analysis of proteins co-precipitating with HA-3Dpol expressed in Huh-7.5 cells identified heat shock 70 protein HSPA8 and its co-chaperone, BAG2. HSPA8 is known to be a critical hepatovirus host factor and HAV genome replication is highly dependent upon heat shock chaperone activity. The mouse-adaptive R468K mutation enhances co-immunoprecipitation of 3Dpol with murine HSPA8 and BAG2, suggesting it facilitates chaperone-dependent acquisition of polymerase function in mouse cells. Our results identify a non-immune barrier to HAV replication in mice and enable future reverse molecular genetics studies in a small animal model.
Dong J, Liang X, Chen Y
… +5 more, Peng J, Sun X, Huang J, Bai L, Lan K
PLoS Pathog
· 2026 May · PMID 42113834
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Kaposi's Sarcoma-associated herpesvirus (KSHV) is a human gamma herpesvirus, establishing two different phases in its life cycle, latent infection and lytic replication. KSHV-encoded basic leucine zipper (bZIP) family of...Kaposi's Sarcoma-associated herpesvirus (KSHV) is a human gamma herpesvirus, establishing two different phases in its life cycle, latent infection and lytic replication. KSHV-encoded basic leucine zipper (bZIP) family of protein K8 (also called K-bZIP), an immediate-early protein, plays an indispensable role in KSHV lytic replication. Recombinant virus with K8 deletion exhibits an aberrant gene expression pattern and impairs virus production in KSHV lytic replication. However, the regulatory mechanisms of K8 itself expression have not been fully elucidated. In this study, we identified a host protein named activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors, interacting with K8 in nucleus. Meanwhile, we further determined that the bZIP domain of ATF3 is necessary for their interaction. Besides, we demonstrated that ATF3 works as an antiviral factor in KSHV lytic replication, inhibiting viral genes expression and impairing the production of progeny virions. Mechanistically, ATF3 associates with K8, leading to the repression of K8 promoter activity and thereby decreases the expression of K8 at both RNA and protein levels. Interestingly, we also verified that KSHV-encoded latency-associated nuclear antigen (LANA) could antagonize the antiviral activity of ATF3 by repressing ATF3 promoter activity to reduce its expression. Collectively, we identified that the transcription factor ATF3 as a novel binding partner of K8 and their interaction represses K8 promoter activity, leading to the reduction of K8 expression and consequently impairing KSHV lytic replication, which provide new insights into the development of novel antiviral strategies.
Syed I, Chen S, Peeler DJ
… +5 more, McKay PF, Briones-Orta MA, Bohn JA, Shattock RJ, Gonçalves-Carneiro D
PLoS Pathog
· 2026 May · PMID 42102160
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Innate immune sensors rely on ubiquitin ligases to calibrate antiviral responses, yet the rules governing substrate recognition by SPRY-containing ligases remain poorly defined. Here, we establish a large-scale structure...Innate immune sensors rely on ubiquitin ligases to calibrate antiviral responses, yet the rules governing substrate recognition by SPRY-containing ligases remain poorly defined. Here, we establish a large-scale structure-based screening pipeline using AlphaFold to systematically predict interactions between human nucleic acid sensors and SPRY-containing proteins. Our approach uncovered novel transient or degradation-sensitive interactions that are typically missed by proteomic methods, including a labile TRIM58-OAS1 complex. We show that SPRY domains dictate substrate specificity: TRIM25 preferentially engages ZAP, whereas Riplet favors RIG-I. Domain-swapping experiments demonstrated that SPRY domains are sufficient to reprogram ligase specificity and antiviral activity. Phylogenetic and structural analyses revealed that TRIM25 and Riplet evolved from a common ancestor but diverged in coiled-coil architecture and oligomeric state, while retaining conserved substrate preferences. Residue-level modeling identified hypervariable SPRY loops as critical determinants of recognition, a prediction validated by targeted mutagenesis of the TRIM25-ZAP interface. Finally, we show that distinct SPRY-containing ligases surveil self-amplifying RNA (saRNA) vaccines: Riplet-RIG-I primarily responds when RNA is delivered by lipofection, whereas TRIM25-ZAP is engaged upon lipid nanoparticle delivery, with functional consequences for vaccine expression. Together, these findings demonstrate that SPRY domains encode recognition logic for ubiquitin ligases, that AlphaFold enables discovery of otherwise hidden interactions and that these principles have direct implications for RNA-based therapeutics.
Coleman BM, Cook ME, Khan MR
… +12 more, Vogel AK, Wells AJ, Miao J, Vyas SP, Taylor TC, Aggor FEY, Ponde NO, Dey I, Zou H, Jašarević E, Peters BM, Gaffen SL
PLoS Pathog
· 2026 May · PMID 42096456
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Vulvovaginal candidiasis (VVC) affects >75% of women, with considerable morbidity and high medical cost burden. While Type 17 cytokines (IL-17, IL-22) are critical for oral and dermal immunity to C. albicans, their role...Vulvovaginal candidiasis (VVC) affects >75% of women, with considerable morbidity and high medical cost burden. While Type 17 cytokines (IL-17, IL-22) are critical for oral and dermal immunity to C. albicans, their role in VVC has been less clear. Th17 gene signatures are potently upregulated in VVC, yet impairment of individual Th17 components (IL-17A, IL-17R subunits, IL-22) does not worsen disease. Rather, estrogen activity is tightly linked to VVC, leading to a paradigm that hormonal pathways, rather than immune defense, dominate susceptibility. Here, we reveal a previously unappreciated role for IL-1/Type 17 in VVC that operates independently of estrogenic hormones. In contrast to mice lacking IL-17A, IL-17RA, IL-22, or IL-22R individually, mice lacking IL-17RA and IL-22RA1 together (Il17raIl22ra1-/-) exhibited high fungal loads and exacerbated tissue damage and inflammation during estrogen-induced VVC. In human vulvar epithelial cells, IL-17 and IL-22 drive synergistic signaling. IL-1R signaling but surprisingly not IL-23 was upstream of this response. Il17raIl22ra1-/- mice expressed high IL-1β yet did not control disease, indicating that IL-1 is upstream but not downstream of Type 17 responses. Unexpectedly, Type 17-dependent control occurred in the absence of exogenous estrogen administration and persisted even when estrus was prevented by progesterone treatment. Collectively, these data indicate that susceptibility to VVC is driven not only by estrogen sensitization but through combinatorial loss of IL-17 and IL-22.
Ries HJ, Lalli J, Florek KR
… +7 more, Barlow S, Goss M, Griesser R, Danz T, Uzicanin A, Temte J, Friedrich TC
PLoS Pathog
· 2026 May · PMID 42096453
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Influenza viruses undergo antigenic drift, the gradual accumulation of mutations that cause antigenic changes in the viral surface proteins hemagglutinin (HA) and neuraminidase (NA). Although selection for antigenic vari...Influenza viruses undergo antigenic drift, the gradual accumulation of mutations that cause antigenic changes in the viral surface proteins hemagglutinin (HA) and neuraminidase (NA). Although selection for antigenic variants is detectable on the global scale, the processes by which antigenic variants are generated and selected in individual hosts remain unclear. It has been hypothesized that selection for antigenic variants may occur during the establishment of a new infection, rather than over time in a single host. Here, we leveraged a large household cohort study to assess whether selection was detectable between acutely infected hosts. We investigated influenza A virus evolution using specimens from 384 children and household contacts with RT-PCR-confirmed influenza A infection, representing infections with A(H1N1)pdm09 and A(H3N2) viruses from 2017-19. In agreement with prior studies, we found that acute infections involved weak purifying selection across the viral genome. In addition, we identified 40 transmission events occurring in 31 households. During transmission, evolution between hosts was characterized by tight transmission bottlenecks and weak purifying selection. We found variability in the strength and direction of selection on antigenic regions of HA, but no clear evidence for selection of antigenic variants during transmission. Together, our results indicate that stochastic processes and weak natural selection dominate most acute influenza A virus infections and transmission events, and that selection of antigenic variants during transmission between acutely infected hosts is likely to be exceedingly rare.
Perez C, Porter J, Warecki B
… +1 more, Sullivan W
PLoS Pathog
· 2026 May · PMID 42096450
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A common form of Wolbachia-induced manipulation of host reproduction is Cytoplasmic Incompatibility (CI). In CI, Wolbachia modification of sperm results in pronounced defects in paternal chromosome condensation, replicat...A common form of Wolbachia-induced manipulation of host reproduction is Cytoplasmic Incompatibility (CI). In CI, Wolbachia modification of sperm results in pronounced defects in paternal chromosome condensation, replication, and segregation during the first mitotic division. Recent studies in D. simulans demonstrate that CI also induces independent and distinct later developmental defects resulting in high rates of mitotic errors during the mid-blastula transition and larval lethality. Here we show that in D. melanogaster, embryos derived from CI crosses experienced significant mitotic defects during gastrulation and increased larval lethality, both of which were eliminated in the progeny of Rescue crosses (both sexes infected). Examination of CI using females from 13 genetically distinct wild-type lines of the Drosophila Genetic Reference Panel (DGRP) revealed significant variation in the strength of the CI-induced lethality. Early embryonic pre-hatching and late larval lethal phases were uncorrelated, suggesting distinct factors influence the extent of the two lethal phases. Additionally, 3rd instar larvae and adults derived from D. melanogaster CI crosses exhibited locomotor defects that were also eliminated in Rescue crosses. These studies support a model in which Wolbachia effects on the sperm chromatin produce delayed developmental and locomotor defects, suggesting the involvement of epigenetic mechanisms. Support for this idea comes from our finding that levels of the heritable chromatin mark H3K27me1 are significantly elevated in CI-derived embryos. We conclude that the full measure of CI strength should take into account pre- and post-hatching lethality as well as locomotor defects. Together our findings suggest that the strength of these CI-induced phenotypes is governed at least in part by epigenetics and the maternal genetic background.
Cheng Y, Xavier J, Kunec D
… +5 more, Reich J, Cismaru CV, Serdar DG, Höfler T, Kaufer BB
PLoS Pathog
· 2026 May · PMID 42090422
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Human herpesvirus 7 (HHV-7) is a ubiquitous betaherpesvirus and a causative agent of roseola infantum. HHV-7 harbors telomeric repeat arrays (TMR) identical to human telomeres at the ends of its genome. While similar rep...Human herpesvirus 7 (HHV-7) is a ubiquitous betaherpesvirus and a causative agent of roseola infantum. HHV-7 harbors telomeric repeat arrays (TMR) identical to human telomeres at the ends of its genome. While similar repeats contribute to human herpesvirus 6 (HHV-6) integration into host telomeres, HHV-7 integration and the role of the TMR remained elusive. Using fluorescence in situ hybridization and nanopore sequencing, we demonstrate that HHV-7 efficiently integrates into host telomeres in persistently infected cells. To determine the role of the TMR in the virus life cycle, we generated the first HHV-7 reverse genetic system and mutants lacking the TMR. These mutants revealed that the TMR are dispensable for HHV-7 replication, but play a crucial role in the integration process and genome maintenance in persistently infected cells. This study provides a reverse genetic system for HHV-7, and offers important insights into the biology of this ubiquitous human pathogen.
Schaveling AS, van Rijt L, Do Y
… +12 more, Soffree N, Langendoen D, Room H, Bertran AM, Raven M, van Kessel SP, van Heese EYJ, van de Ruitenbeek SJS, van Schaik CC, Kiewnick S, Smant G, Sterken MG
PLoS Pathog
· 2026 May · PMID 42090417
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The potato cyst nematode Globodera pallida poses a major threat to potato production in Western Europe. Current management strategies largely depend on the use of potato varieties carrying the genetic resistance GpaVvrn....The potato cyst nematode Globodera pallida poses a major threat to potato production in Western Europe. Current management strategies largely depend on the use of potato varieties carrying the genetic resistance GpaVvrn. However, reports from multiple West-European countries indicate a steady rise in virulence against GpaVvrn-containing potato varieties, raising serious concerns about G. pallida control. Although recent studies have resolved the genetic basis of virulence in two Dutch G. pallida populations, it remains unclear how conserved this genetic adaptation is in populations from different regions. To investigate this, we first selected eight Dutch G. pallida populations on the GpaVvrn-containing potato variety Seresta and confirmed a previously identified virulence locus. Second, by analysing the allele frequencies of four virulence-associated SNPs in Dutch, British, and French GpaVvrn-selected G. pallida populations, we found that the same allele is consistently selected by GpaVvrn across Western Europe. Third, we analysed the propagation of eight G. pallida populations on 26 GpaVvrn-containing potato varieties and showed that a population's allele frequency of a single SNP (T173N) accurately reflects its reproduction on GpaVvrn. Fourth, we developed an allele-specific quantitative PCR (AS-qPCR) assay to determine a population's alternative allele frequency (AAF) of T173N and showed that AS-qPCR-based AAFs reliably indicate virulence levels on GpaVvrn in Dutch and German G. pallida populations. Together, these findings suggest that a common allele is consistently selected by GpaVvrn in populations from different regions across Western Europe. The AS-qPCR assay developed in this study provides a practical tool to estimate G. pallida virulence on GpaVvrn in the field, enabling field-tailored and sustainable resistance management strategies for farmers.
Maxwell MWH, Rohilla B, Chippendale J
… +1 more, Bell CA
PLoS Pathog
· 2026 May · PMID 42090392
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The root-knot nematode Meloidogyne incognita is a globally significant plant parasite that causes substantial crop losses. While pre-parasitic juveniles rely on innate energy reserves, later life stages acquire nutrients...The root-knot nematode Meloidogyne incognita is a globally significant plant parasite that causes substantial crop losses. While pre-parasitic juveniles rely on innate energy reserves, later life stages acquire nutrients from host plants through specialized feeding structures. SWEET (Sugars Will Eventually be Exported Transporter) genes exhibit a conserved sugar transporting ability across all kingdoms of life, yet their function in plant-parasitic nematodes remains underexplored. Here, we functionally characterise the SWEET gene family in M. incognita, revealing their critical and stage-specific roles in nematode development and parasitism. We demonstrate that Mi-SWEETs segregate into two functional groups: those that facilitate mobility and invasion in motile juveniles (Mi-SWEET2, 4) and those support nutrient uptake during feeding (Mi-SWEET3, 5, 7). Although temporally distinct, all SWEET genes localise to the intestine, suggesting a conserved role in mediating sugar flux. Knockdown of Mi-SWEET2 and Mi-SWEET4 reduced root invasion, while silencing Mi-SWEET3, 5, and 7 impaired post-invasion growth, highlighting the varied roles of this large gene family across different life stages. Yeast complementation assays revealed distinct substrate preferences among Mi-SWEETs, aligning with the metabolic needs of different life stages. The transcription factor HBL1, a key regulator of nematode dietary responses, was found to control the expression of Mi-SWEET3 and is itself regulated through interaction with the post-transcriptional regulatory microRNA let-7. Our findings provide new insights into the metabolic adaptations and energy utilisation of plant-parasitic nematodes and outline a microRNA - transcription factor - target gene regulatory network. These findings have broader relevance given the fundamental importance of the regulation of resource transportation in plant-pathogen interactions.
PLoS Pathog
· 2026 May · PMID 42085507
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Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by Streptococcus pneumoniae (Spn), the first step in its pathogenesis. Spn colonization which lasts days to weeks i...Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by Streptococcus pneumoniae (Spn), the first step in its pathogenesis. Spn colonization which lasts days to weeks in WT mice was persistent (> 6 months) in the absence of IL-17RA-signaling. RNA-seq analysis confirmed the role of IL-17RA signaling in neutrophil-associated pathways. The onset of clearance required neutrophils, but there was no detectable increase in their numbers. IL-17RA-signaling was required to replenish neutrophils in nasal tissue that were otherwise depleted during infection. Enhanced neutrophil trafficking correlated with IL-17RA-dependent expression of endothelial cell adhesion molecules that promote neutrophil trafficking from the circulation into nasal tissue. Persistent colonization was also observed in mice lacking IL-1R-signaling. Recognition of IL-1-family cytokines, however, was not necessary for the expression of IL-17A or neutrophil recruitment. Instead, IL-1R-signaling was associated with the activation of neutrophils in nasal tissue that displayed increased levels of the surface marker CD11b, an important receptor for the complement-opsonized phagocytosis of Spn. Colonization of dual-knockout mice showed the contributions of IL-1 and IL-17 signaling pathways were non-redundant. Expression of the chemokine Cxcl5 was impaired in the absence of either IL-1R or IL-17RA signaling, suggesting a role in both activation and maintenance of the neutrophil population during infection. Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen.
Borrenberghs D, Chan KWK, Van Brandt S
… +17 more, Jaensch S, Choy MMJ, Geluykens P, Bouayadi AE, Lauwers D, Bist P, Stoops B, Van de Ven J, Vermeulen P, Megens S, Thys K, Peeters D, Kaptein SJF, Neyts J, Vasudevan SG, Koul A, Goethals O
PLoS Pathog
· 2026 May · PMID 42085491
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Orthoflaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV), constitute a significant public health concern with billions of p...Orthoflaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV), constitute a significant public health concern with billions of people at risk of infection. Climate change and the expanding geographical distribution of mosquito vectors transmitting orthoflaviviruses have increased their potential to cause large-scale disease outbreaks. The frequency and severity of disease outbreaks highlight the urgent need for a broad-spectrum antiviral agent targeting orthoflaviviruses. In this work, we conducted a comprehensive morphological profiling of approximately 200,000 small molecules through a fluorescence-based high-content imaging platform, which led to the identification of a singular small molecule exhibiting broad-spectrum activity against orthoflaviviruses. Subsequent hit deconvolution against DENV serotype 2 (DENV-2) revealed NS2A protein as a novel therapeutic target. Mechanistically, JNJ-1953 inhibits viral RNA synthesis, as demonstrated by robust reductions in intracellular viral RNA and infectious virus production. Additional experiments show that JNJ-1953 further impacts viral RNA packaging and interferes with the interaction between NS2A and prM, rendering the molecule a multimodal inhibitor.
Liu J, Xu Z, Li Y
… +10 more, Wu S, Ni Z, Li X, Li P, Liu X, Dang X, Wang T, Fu J, Wang M, Wang R
PLoS Pathog
· 2026 May · PMID 42085480
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Biotrophic pathogens depend on host carbon sources for proliferation. Here, we identified BnaA07.SUC2 in oilseed rape (Brassica napus cv. Westar), which encodes a plasma membrane-localized proton-dependent sucrose transp...Biotrophic pathogens depend on host carbon sources for proliferation. Here, we identified BnaA07.SUC2 in oilseed rape (Brassica napus cv. Westar), which encodes a plasma membrane-localized proton-dependent sucrose transporter. Its expression is markedly induced in roots during the late stages of Plasmodiophora brassicae infection. The Arabidopsis thaliana suc2 mutant exhibited a strong clubroot-resistant phenotype, and functional complementation with BnaA07.SUC2 restored susceptibility to P. brassicae. Overexpression of BnaA07.SUC2 in oilseed rape significantly increased sucrose accumulation and disease susceptibility, whereas CRISPR/Cas9-mediated knockout of BnaA07.SUC2 enhanced clubroot resistance. Furthermore, yeast one-hybrid, dual-luciferase, and electrophoretic mobility shift assays showed that BnaA05.MYC2 directly binds to the BnaA07.SUC2 promoter and represses its expression. Overexpression of BnaA05.MYC2 in oilseed rape enhanced clubroot resistance, which was accompanied by reduced BnaA07.SUC2 transcript levels. Conversely, co-overexpression of BnaA07.SUC2 in the BnaA05.MYC2-overexpressing oilseed rape background restored susceptibility, indicating that BnaA05.MYC2 promotes clubroot resistance by repressing BnaA07.SUC2. BnaA05.MYC2 expression is induced by jasmonate (JA) signaling. JA signaling is activated during early infection but suppressed in later stages, and accordingly, BnaA05.MYC2 expression is upregulated initially but downregulated later. This downregulation relieves the repression of BnaA07.SUC2, thereby enhancing sucrose supply to the pathogen. Our study identifies the SUC transporter BnaA07.SUC2 and its regulator BnaA05.MYC2 as key susceptibility components in P. brassicae pathogenesis, providing important insights into the interaction between P. brassicae and its host plant.
Caddell TM, Mulloy RP, Corcoran JA
… +2 more, Pringle ES, McCormick C
PLoS Pathog
· 2026 May · PMID 42085452
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Coronaviruses (CoVs) encode a variety of transmembrane proteins that are translated and processed at the endoplasmic reticulum (ER). Three host ER resident transmembrane proteins, activating transcription factor 6 (ATF6)...Coronaviruses (CoVs) encode a variety of transmembrane proteins that are translated and processed at the endoplasmic reticulum (ER). Three host ER resident transmembrane proteins, activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK), sense the accumulation of unfolded proteins in the ER and initiate the unfolded protein response (UPR) to maintain ER proteostasis. We observed that SARS-CoV-2 Spike broadly activated all three arms of the UPR, whereas the Membrane (M) protein selectively inhibited ATF6. ATF6 has a unique activation mechanism whereby ER stress triggers translocation to the Golgi where ATF6 is processed by resident proteases to release the ATF6-N transcription factor. We observed that M inhibited the stress-induced production of ATF6-N, suggesting that ATF6 failed to engage with Golgi proteases for processing. M also inhibited sterol regulatory element binding protein-2 (SREBP2)-mediated activation of sterol responses and stimulator of interferon response cGAMP interactor 1 (STING)-mediated activation of interferon responses, both of which are activated in the ER and require translocation to the Golgi for interactions that yield transcriptional responses. We observed that M accumulated in the cis-Golgi, and triggered dispersal of the trans-Golgi network (TGN). Using a cargo sorting assay, we determined that ER-to-Golgi cargo trafficking was intact in the presence of M, but cargo accumulated with M in the cis-Golgi and did not proceed further in the secretory pathway. We also observed aberrant cholesterol accumulation at the cis-Golgi with M, consistent with our observation of M association with detergent resistant membranes. Together, these data suggest that CoV M proteins interfere with Golgi architecture and trafficking. Because CoV egress does not require the canonical secretory pathway, this mechanism could allow the virus to selectively interfere with host responses to infection without impeding egress of nascent virions.
Wei HC, Yang Q, Yang H
… +11 more, Wang YH, Wang K, Linghu K, Ogando NS, Huang X, Snijder EJ, Zhong Y, Chen Y, Yuan Q, Chen L, Lin JW
PLoS Pathog
· 2026 May · PMID 42081588
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Immunoregulatory proteins expressed by SARS-CoV-2 interfere with host antiviral defences in infected cells and play critical roles in the pathogenesis and clinical manifestations of COVID-19. Here, we established a predi...Immunoregulatory proteins expressed by SARS-CoV-2 interfere with host antiviral defences in infected cells and play critical roles in the pathogenesis and clinical manifestations of COVID-19. Here, we established a prediction algorithm by integrating a pretrained protein-language model and gene weights in immune-related pathways to quantify perturbations of SARS-CoV-2 proteins in host immunity. The results revealed that the canonical NF-κB pathway was dynamically regulated by SARS-CoV-2 infection and that nonstructural protein 1 (Nsp1) significantly suppressed the activation of the NF-κB pathway by other viral proteins and proinflammatory cytokines, such as IL-1β. Nsp1 binds to TAK1 at the TAB1-binding domain, promoting TRIM21-mediated K48-linked ubiquitination and subsequent proteasomal protein degradation, leading to the inactivation of the NF-κB signalling pathway. This work presents a novel framework to identify viral immunoregulators at the pathway level and provides mechanistic insights into immune evasion by SARS-CoV-2.