Herpes simplex virus 1 (HSV‑1) establishes infection through coordinated interactions of multiple viral glycoproteins with host cell receptors. Interactions between the viral glycoprotein D (gD) and the immunomodulatory cellular receptor HVEM (herpesvirus entry mediator) critically influence HSV‑1 latency and reactivation by regulating both receptor engagement and immunomodulatory signaling in the corneal epithelium, immune cells, and neurons. The underlying mechanisms of these phenotypes remain poorly understood because no tools selectively block their interaction. To dissect the contributions of individual amino acids (aa) to HVEM binding, we co‑immunoprecipitated wild‑type (WT) and mutant (Q27P and Q27A‑L28A‑T29A) forms of gD that disrupt gD binding to HVEM. We found that gD aa Q27-T29 were critical for HVEM binding, with the triple mutant showing greater disruption of HVEM binding than the Q27P single mutation, as assessed by co-immunoprecipitation and immunostaining. To map gD binding to HVEM and assess functional relevance, we constructed two recombinant viruses: a single-amino-acid (aa) gD mutation (v27 virus) and a triple-aa mutation in gD (v27-29 virus). Replication of both mutant viruses was comparable to that of the WT virus in four mammalian cell lines, except in Neuro2a cells. However, using confocal microscopy, HVEM protein expression was reduced in v27-29-infected Neuro2a cells, with no gD colocalization observed. Although Neuro2a cells infected with the single gD v27 mutant also showed less HVEM-gD colocalization than Neuro2a cells infected with WT virus, gD protein levels were not affected. RT‑PCR analysis of Neuro2a cells infected with single and triple gD mutants showed significantly less expression of viral glycoproteins (gB, gC, gD), host receptors (HVEM, nectin‑1, 3‑O‑sulfated heparan sulfate), and HVEM ligands (BTLA, LIGHT, Ltα, CD160), with the most pronounced effects observed for the triple v27‑29 mutant virus. Together, these results show that aa Q27-T29, rather than aa Q27 alone, are essential to completely block gD binding to HVEM and, consequently, affect overall receptor homeostasis.
Porcine epidemic diarrhea virus (PEDV) represents a severe threat to the global swine industry. Its infection process involves intricate virus-host interactions and immune evasion mechanisms, but effective therapeutic targets remain elusive. In this study, we identified protein arginine methyltransferase 3 (PRMT3) as a novel regulatory factor that significantly modulates PEDV infection via genome-wide CRISPR/Cas9 knockout library screening. Knockout or inhibition of PRMT3 markedly enhanced PEDV infection in multiple cell lines, including LLC-PK1, IPEC-J2, and primary porcine intestinal epithelial cells. Mechanistic investigations revealed that PRMT3 can restrict PEDV infection by interacting with vesicle-associated membrane protein-associated protein A (VAPA). Further analysis revealed that VAPA facilitates cholesterol transport through binding to oxysterol-binding protein (OSBP) and inhibits the autophagic degradation of the viral nucleocapsid (N) protein, with both processes being critical for promoting PEDV infection in host cells. A detailed analysis revealed that K52 within its major sperm protein (MSP) domain interacts with D404 and D405 in the two phenylalanines in an acidic tract (FFAT)-like motifs of the N protein, and these interactions proved essential for PEDV infection. In summary, this is the first study to identify and validate the PRMT3-VAPA-N protein autophagic degradation axis as a key pathway through which PRMT3 suppresses PEDV infection, with VAPA acting as an essential host factor for PEDV pathogenesis. These findings uncover novel signaling pathways and molecular targets for the development of anti-PEDV therapeutics.
Gammaherpesviruses, including human Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma-associated Herpesvirus (KSHV), establish lifelong latent infections that contribute to multiple cancers and Multiple Sclerosis. These viruses colonize naïve B cells and drive a robust, polyclonal germinal center response to expand the latent viral reservoir and establish lifelong infection in memory B cells. Despite the clinical burden of these viruses, the host factors that support chronic infection remain poorly defined. Interleukin-22 (IL-22) is a critical cytokine traditionally recognized for its protective roles in bacterial and fungal defense; however, its involvement in gammaherpesvirus pathogenesis has not been explored. Using murine gammaherpesvirus 68 (MHV68) as a tractable in vivo model, we identify IL-22 as a host factor that promotes the establishment of chronic gammaherpesvirus infection. MHV68 infection triggers robust IL-22 production across multiple anatomical sites and immune cell populations. Although IL-22 deficiency did not affect acute viral replication, IL-22 -/- mice exhibited a sustained reduction in latent viral burden within both the spleen and peritoneal cavity. This phenotype was accompanied by impaired germinal center B cell and T follicular helper cell responses, reduced plasma-cell expansion, diminished virus-specific antibody responses, and attenuated polyclonal autoreactive antibody production. Furthermore, IL-22 deficiency was associated with reduced systemic BAFF levels, suggesting that IL-22 contributes to the establishment of a germinal center microenvironment that supports chronic infection. Together, these findings identify IL-22 as a previously unrecognized regulator of chronic gammaherpesvirus infection and reveal a role for this cytokine in coordinating germinal center responses, humoral immunity, and latent reservoir establishment, providing new insight into how host immune pathways contribute to lifelong gammaherpesvirus infection.
Malaria, caused by Plasmodium parasites, is a significant global health issue. CD4 + and CD8 + T cells are important for immunity against Plasmodium infections, but the specific roles of many immune-related effector molecules in T cells remain poorly defined. Here, we investigated the function of NK cell granule protein 7 (NKG7) in T cells during malaria, focusing on its role in CD4 + and CD8 + T cells in Plasmodium blood-stage responses. In a non-lethal malaria model, NKG7 regulated the development of pro-inflammatory T helper 1 (Th1), IL-10-producing type 1 regulatory (Tr1), and T follicular helper cell responses. In a model of cerebral malaria, NKG7had a cell-intrinsic role in regulating perforin and granzyme B expression, as well as Tr1 cell development. Human investigations involving peripheral blood mononuclear cells from volunteers participating in controlled human P. falciparum malaria infection studies, as well as endemic country patients with P. falciparum and P. vivax malaria, corroborated these findings. High NKG7 expression in T cells from Plasmodium -infected humans was observed, as well as differences in NKG7 expression based on the infecting Plasmodium species. NKG7 expression was associated with both cytotoxic and non-cytotoxic T cells, indicating varied functions following infection. These results advance our understanding about NKG7’s role in T cell-mediated malaria immunity and suggest potential for targeting NKG7 to improve outcomes following Plasmodium infection.
Malaria parasites must undergo complex developmental transitions to complete their life cycle and transmit between vertebrate and mosquito hosts. These transitions are tightly regulated by protein phosphorylation events, yet the specific kinases involved remain poorly characterized. Here, we investigate the role of a previously uncharacterized tyrosine kinase-like protein, TKL3, in the rodent malaria parasite Plasmodium berghei . We show that TKL3 is expressed in blood stages, schizonts, gametocytes, zygotes, and ookinetes and localizes to the cytoplasm. Targeted disruption of the TKL3 gene impairs asexual blood-stage growth, male gamete fertility, and consequently compromises ookinete development. Although oocyst numbers are significantly reduced in mosquitoes, the sporozoites that do form are morphologically normal, retain hepatocyte infectivity, and complete liver-stage development. However, TKL3 knockout sporozoites showed delayed blood-stage patency due to reduced asexual replication. These findings identify TKL3 as an important regulator of parasite growth and transmission, providing new insights into kinases involved in the Plasmodium life cycle.
Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment, but emerging resistance threatens their efficacy. The potential for the development of drug resistance against plasmepsin X (PMX)-selective inhibitors and dual plasmepsin IX/X (PMIX/X) inhibitors was investigated in Plasmodium falciparum. A series of PMX-selective (WM4, WM76, WM92) and PMIX/X dual inhibitors (WM382, WM09, WM42) were characterised for potency against parasite growth and enzyme inhibition. In vitro selection experiments showed that all compounds had a high barrier to resistance, although parasites with reduced sensitivity to PMX‑selective inhibitors could still be selected. Resistance mechanisms involved pmx gene amplification and point mutations (D245N, S315P, S359P, I363L) that alter inhibitor binding. Recombinant expression and Michaelis-Menten kinetics demonstrated that these mutations impair drug binding whilst preserving PMX catalytic function. Reverse genetics confirmed that introducing these mutations into the pmx gene resulted in decreased potency of the inhibitors. In this study, resistance to the PMIX/X dual inhibitors evaluated here could not be selected, despite prolonged selection pressure. Antimalarial Resistome Barcoding (AReBar) assays confirmed the absence of pre-existing resistance to either inhibitor class. Critically, PMIX/X dual inhibitors maintained efficacy against parasites with decreased sensitivity to PMX-selective compounds. These findings demonstrate that dual PMIX/X inhibitors present a substantially higher barrier to resistance than PMX-selective inhibitors, informing antimalarial drug development strategies and highlighting dual-target inhibition as a promising approach to mitigate resistance risks.
Tripartite motif-containing 21 (TRIM21) is an E3 ubiquitin ligase that binds viral and host proteins to mediate antiviral defense. Its role in Mycobacterium tuberculosis ( Mtb ) infection, however, is unclear. Here, our analysis of human TB transcriptomic datasets showed that TRIM21 expression levels correlate with TB progression in human patients. We further demonstrated that TRIM21 deficiency suppresses Mtb growth in both macrophages and a murine model of tuberculosis (TB). Mechanistically, TRIM21 limits host resistance to Mtb through a non-canonical pathway distinct with its E3 ligase activity. It physically interacts with the RNA helicase DEAD-box helicase family member DDX3X and disrupts phase separation dynamics required for stress granule (SG) assembly. Impaired SG formation compromises innate immune responses, thereby facilitating intracellular bacterial growth and creating a permissive cellular environment for Mtb growth. Consistent with these genetic findings, pharmacological inhibition of TRIM21 restricted Mtb growth in experimental macrophage and murine models. Together, these findings uncover a non-canonical role of TRIM21 in Mtb infection and highlight its potential as a therapeutic target for host-directed therapy against TB.
The E3 ubiquitin ligase TRIM23 is involved in diverse cellular processes, however, its function in antiviral defense against adenovirus remains unclear. Here, we identify a novel mechanism by which TRIM23 restricts human adenovirus type 5 (HAdV-C5) replication. TRIM23 expression was upregulated upon HAdV-C5 infection, and functional studies showed that its overexpression inhibited viral replication, while knockdown enhanced it. Mechanistically, TRIM23 interacts with the viral E1A protein and promotes its degradation through a mechanism dependent of its canonical E3 ligase activity. Moreover, TRIM23 recruits the selective autophagy receptor p62 promotes E1A degradation in a E1A ubiquitination-independent manner. Our results unveil a novel host defense pathway-the TRIM23-E1A-p62 axis-that highlights the role of selective autophagy in antiviral immunity.
Approximately 90 million American adults are hypercholesterolemic, with an estimated 43 million individuals either already using or eligible to receive cholesterol-lowering medications, such as bile acid sequestrants. Although bile acid sequestrants have demonstrated therapeutic efficacy in lowering cholesterol levels in individuals with hypercholesterolemia, their impact on intestinal homeostasis in healthy individuals and those with enteric microbial infections remains unclear. We set out to investigate the potential effects of bile acid sequestration on mucosal immune responses and to evaluate how enteric microbial pathogens colonize the small intestine of mice in vivo . We also examined how bile acid sequestration affected intestinal microbial ecosystems before and during enteric infection. We found that bile acid sequestration increased resistance to enteric infection, and this phenotype required farnesoid X receptor (FXR) in myeloid cells. We observed significantly increased diversity and richness in the gut microbiome of mice that were administered a bile acid sequestrant that correlated with enhanced resistance to enteric infection, suggesting that bile acids may function as limiting factors for the diversity and richness of the gut microbiome in health and disease. Notably, the antibiotic-driven depletion of the gut microbiome led to significantly increased susceptibility to infection with both Giardia duodenalis and Giardia muris . Our findings reveal a previously overlooked role for bile acid sequestrants in the regulation of the gut microbiome as well as host resistance to enteric infections. Bile acid sequestration and the subsequent blockade of pathways downstream of bile acid signaling may modulate host immunity during enteric infections, potentially leading to an altered gut microbiome in individuals taking bile acid sequestrants to lower blood cholesterol.
Non-tailed phages remain underexplored in marine environments, as tailed phages have long dominated sequence and culture collections. Yet recent surveys suggest that non-tailed phages may be more abundant and have distinct impacts on microbial mortality and gene transfer. Here, we solve the structure of Vibrio anguillarum bacteriophage NO16, one of the simplest members of the Varidnaviria realm. Mass spectrometry detected at least nine different proteins in the virion, which has a pseudoT = 21 capsid similar to that of related double jelly roll (DJR) phages, but differs in the organization of minor capsid proteins, particularly those mediating membrane-capsid contacts. The DJR major capsid protein GP19 is stabilized by strong electrostatic interactions between monomers, and possibly by a cation at its base, as seen in corticovirus PM2. Localized reconstruction revealed a symmetry mismatch at the vertex, where two trimeric GP13 spikes attach to the pentameric GP14 penton base. GP13 carbohydrate-binding sites and predicted glycosylase activity point to a role in host entry. Using structural and functional predictions for its entire proteome, we propose a complete atlas of the NO16 infectious cycle.
Flaviviruses are enveloped, positive-strand RNA viruses that cause millions of infections in the human population annually. Although Zika virus (ZIKV) had been detected in humans as early as the 1950s, its reemergence in South America in 2015 resulted in a global health crisis. While flaviviruses encode 10 proteins that can be post-translationally modified by host enzymes, little is known regarding post-translational modifications (PTMs) of the flavivirus proteome. We used mass spectrometry to comprehensively identify host-driven PTMs on the ZIKV proteome. This approach allowed us to identify 43 PTMs across 8 ZIKV proteins, including several that are highly conserved within the Flavivirus genus. Notably, we found two phosphosites on the ZIKV envelope protein that are functionally important for viral propagation. Both appear to regulate viral particle release, while one also impacts ZIKV cytopathogenicity. Additionally, we discovered host kinases that interact with ZIKV proteins and determined that Bosutinib-an FDA-approved tyrosine kinase inhibitor that targets some of these host kinases-impairs ZIKV growth, in part by blocking phosphorylation of a tyrosine residue on the envelope protein. Thus, we have defined a high-resolution map of host-driven PTMs on ZIKV proteins as well as cellular interacting kinases, uncovered novel mechanisms of host driven-regulation of ZIKV particle release and cytopathogenicity, and identified an FDA-approved inhibitor of ZIKV growth.
Citrobacter rodentium (CR) is a murine-specific enteric pathogen widely used to model infections of the attaching and effacing pathogens enteropathogenic and enterohaemorrhagic Escherichia coli. Infection induces colonic epithelial damage and inflammation that are resolved in resistant mice but result in severe disease and mortality in mice lacking interleukin-22 (IL-22). While IL-22-deficient (Il22-/-) mice succumb to CR infection due to dehydration, in part mediated by disruption of the barrier integrity by the type III secretion system (T3SS) effector EspF, the contribution of immunopathology to infection outcomes is not known. Here, using CR we tested whether dysregulated neutrophil responses drive disease progression in Il22-/- mice. We show that IL-22 deficiency is associated with progressive colonic pathology and increased neutrophil accumulation and activity in the colonic mucosa. Infection of mice with CR lacking the T3SS effector EspO, which is implicated in neutrophil recruitment, resulted in markedly reduced neutrophil accumulation and activity in Il22-/- mice without altering bacterial burden. Notably, CRΔespO infection led to reduced colonic inflammation and complete survival of Il22-/- mice. Consistent with these findings, CXCR2 antagonist treated Il22-/- mice displayed attenuated disease severity and delayed mortality. Together, we identified EspO as the second effector, alongside EspF, whose deletion results in survival of CR-infected Il22-/- mice. Moreover, these findings suggest that excessive neutrophil accumulation and activity are key drivers of lethality during CR infection in Il22-/- mice and that EspO amplifies neutrophil-dependent pathology within a vulnerable epithelial environment.
BACKGROUND:The rapid global spread of hypervirulence in Enterobacteriaceae, particularly in carbapenem-resistant Klebsiella pneumoniae, poses a significant public health threat. However, the key genetic vehicles and mechanisms driving horizontal transfer of hypervirulence-associated genes (iucA, iroB, rmpA, rmpA2, and peg-344) remain poorly defined, limiting effective surveillance. METHODS:We performed a large-scale genomic survey of 2,869 virulence-associated plasmid sequences and 2,337 complete Enterobacteriaceae chromosomes. Using comparative genomics and evolutionary analyses, we systematically identified and characterized Hypervirulence-associated Pseudo-Compound Transposons (Hva-PCTs), defined as structured mobile elements in which hypervirulence-associated genes are flanked by insertion sequences. RESULTS:Our results demonstrate that hypervirulence-associated genes are transmitted primarily as discrete IS-bounded units, which we term Hva-PCTs. We identified 29 distinct plasmid-borne Hva-PCTs (pHva-PCTs) and 30 chromosomal Hva-PCTs (cHva-PCTs). These modules show clear species-specific patterns: iucA/iroB-associated Hva-PCTs mainly originate in Escherichia coli and spread through IncFIB-containing multi-replicon plasmids (commonly combined with IncFIC(FII) and/or IncFII, while rmpA/rmpA2/peg-344-containing modules originate in K. pneumoniae and are disseminated via IncHI1B/repB plasmids. Three Hva-PCTs were detected on both plasmids and chromosomes (xHva-PCTs). In one clinical K. pneumoniae isolate (LS356), the identical composite module was present on both replicons. Simpler sub-modules, such as ISKqu3-rmpA2-iucA_1-IS102 and IS102-rmpA-peg-344-iroB_1-IS1A, frequently co-occur on the same plasmid; when positioned in tandem, they reconstitute the full composite structure. This assembly pattern is further supported by a partial duplication event in plasmid pP901. CD-HIT clustering (80% nucleotide identity and 90% coverage) showed that 13 of 22 major clusters contained both plasmid and chromosomal copies, with intra-cluster identities >80% across multiple sequence types and host species. CONCLUSION:Hypervirulence-associated genes in Enterobacteriaceae are disseminated mainly as IS-flanked Hva-PCTs rather than solely through intact virulence plasmids. These modules exhibit strong but not absolute host specificity. The presence of identical Hva-PCTs on plasmids and chromosomes suggests inter-replicon mobility, while their stepwise assembly from simpler sub-modules highlights modular accretion as a key evolutionary process. Tracking Hva-PCTs as distinct mobile units may complement existing plasmid- and gene-centric surveillance approaches for hypervirulent and convergent strains. Experimental validation of their transposition activity and phenotypic effects is still required.
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a bat-originated alphacoronavirus that causes devastating enteric disease in neonatal piglets and possesses significant potential for cross-species transmission. While the early stages of the coronavirus life cycle have been extensively characterized, the host factors indispensable for virion assembly and subsequent export remain largely enigmatic. Here, by performing a genome-wide CRISPR-Cas9 knockout screen using a recombinant icSADS-CoV-GFP reporter virus, we identified the small GTPase Rab10 as a critical host dependency factor for SADS-CoV infection. Viral life cycle analysis revealed that Rab10 is not required for viral attachment, entry, or initial genome replication, but is essential for the virion transport and non-lytic egress. Rab10 deficiency markedly reduced the extracellular release of viral RNA, viral proteins, and infectious progeny, as well as the secretion of SADS-CoV virus-like particles. Confocal imaging showed that Rab10 and viral protein-positive intracellular structures were associated with LMAN1, TGN46, and LAMP1 positive compartments. These findings support a model in which Rab10 coordinates a virus-containing vesicles trafficking pathway associated with ERGIC-TGN-lysosome compartments. Mechanistically, Rab10 facilitates the loading of the viral envelope (E) protein into transport vesicles derived from the ERGIC. Rab10 associates with the SADS-CoV E protein, and mapping analyses implicated the C-terminal PDZ-binding motif, particularly residue V75, in efficient Rab10 association and viral release. Collectively, our findings identify Rab10 as a host regulator of SADS-CoV non-lytic egress and highlight the E-Rab10 interaction and the vesicular trafficking mechinery as a potential target for developing antiviral strategies.
Staphylococcus aureus α-toxin (AT) is a potent pore-forming toxin that causes cell damage during infection. The structure and activity of AT have been studied extensively, but the environmental factors that modulate its toxicity remain unclear. Here, we demonstrate that the extracellular pH modulates AT cytotoxicity through two independent mechanisms in human cells. First, we show that acidic conditions enhance AT pore maturation, causing a toxin-intrinsic and ADAM10 independent increase in cytotoxicity after prolonged exposure to AT. Second, we demonstrate that both acidic and alkaline conditions impair the cellular capacity to internalize AT pores, resulting in toxin retention at the cell surface and increased cytotoxicity after pulse intoxication. The cell-intrinsic, pH-dependent sensitization to AT is observed in various human cell types but not for other pore forming toxins. Together, our findings indicate that the extracellular pH modulates AT activity and host cell susceptibility.
TRAF6 is traditionally recognized as an antiviral ubiquitin E3 ligase that positively regulates the production of type I interferon and inflammatory cytokines. However, our study reveals that TRAF6 also plays a crucial role in the lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV). Mechanistically, during KSHV lytic replication, TRAF6 mediates the K63-linked polyubiquitination and activation of Akt, which is required for the efficient viral replication. Disruption of TRAF6 or Akt expression through CRISPR-mediated knockout, or inhibition of TRAF6 or Akt with small molecule inhibitors, reduces KSHV replication efficiency. Conversely, expression of constitutively active Akt can rescue the impaired replication caused by TRAF6 deficiency. Notably, the TRAF6-Akt axis is also required for the lytic replication of Epstein-Barr virus but not for Human cytomegalovirus. These findings highlight the role of the TRAF6-Akt axis in the life cycle of oncogenic herpesviruses and suggest potential therapeutic targets for related diseases.
Two-component systems (TCSs) in Pseudomonas aeruginosa are essential for sensing and responding to diverse environmental cues, including those associated with ion homeostasis and virulence within the host. However, how specific TCSs discriminate between chemically similar metal signals to fine-tune adaptation remains unclear. Here, we identify the TCS ColRS, conserved across the Pseudomonas genus, as a critical sensor that distinguishes zinc (Zn2+) and copper (Cu2+) to drive divergent survival strategies. First, we establish that the response regulator ColR directly binds the promoters of lipid A modification genes (arnB, eptA), the metal responsive regulator czcR, and the alginate and motility regulator Z (amrZ), genetically linking metal sensing to resistance and virulence circuitry. Phenotypically, ColRS translates these inputs into context-dependent states: enhancing polymyxin tolerance and suppressing motility under copper stress, while sustaining type III secretion system (T3SS) virulence and motility under zinc stress. Mechanistically, this discrimination relies on the sensor kinase ColS, which utilizes a non-canonical E96-H105 interface as a specificity filter to recognize Cu2+ (Kd ≈ 1.11 μM) and distinguish it from Zn2+ (Kd ≈ 19.8 μM). Global proteomics confirms this bifurcation, revealing that Zn2+ triggers focused metabolic tuning, whereas Cu2+ induces broad envelope and motility rewiring. Collectively, our findings reveal ColRS as a pivotal molecular hub that decodes the duality of host metal immunity to optimize pathoadaptation.
Cancer hallmarks are characterized by wide-scale changes in gene expression programs. Pioneering studies showed how viral oncogenes target regulatory pathways, but little is known about tumorigenic mechanisms of non-viral pathogens. Theileria annulata is an intracellular parasite (related to apicomplexa parasites causing malaria) which remarkably transforms bovine leukocytes, hijacking host signaling pathways to induce cancer phenotypes, akin to human leukemias. While some host genes contribute to the proliferative or invasive hallmark phenotypes, there is still limited comprehensive understanding of the impact of Theileria infection on host transcription and transformation. We performed a multi-omics meta-analysis to investigate the effect of Theileria infection on cancer hallmarks in bovine B lymphocytes. Combining transcriptomic, proteomic and epigenomic analysis across multiple datasets, we show that Theileria infection suppresses host immune pathways. Specifically, genes encoding innate and adaptive immune mediators are repressed in T. annulata-infected B cells (and in T. parva infected T cells), including downregulation of genes for Toll-like receptors (TLR), inflammasome components of the guanylate binding protein (GBP) family and major histocompatibility complex class (MHC) II genes. Treatment with distinct theilericidal drugs could partially rescue immune gene expression. Mechanistically, we describe alterations in the host epigenome, including loss of activating histone modifications (e.g., H3K18ac, H3K4me3, H3K27ac) on the promoters of repressed immune genes, and enrichment of silencing marks (H3K27me3) on promoters of the BOLA genes and the gene encoding CIITA, the master transcriptional regulator of MHC class II gene expression. Our results suggest that intracellular T. annulata and T. parva parasites could drive an immune evasion cancer hallmark in host lymphocytes by epigenetic silencing of genes for innate and adaptive immunity.
