About

Ileana M. Cristea is the Henry L. Hillman Professor of Molecular Biology and serves as the Director of Graduate Studies in the Department of Molecular Biology at Princeton University. Her research is at the interface between virology and proteomics, focusing on understanding cellular mechanisms used in defense against viruses and how viruses inhibit or hijack host cell processes. Her laboratory employs multidisciplinary approaches, integrating molecular virology, microscopy, mass spectrometry-based proteomics, and bioinformatics to develop proteomics-based methods for characterizing cellular processes during viral infections. Her work explores dynamic regulation of host-virus protein interactions, mechanisms of DNA sensing within infected cell nuclei, immune response initiation and propagation following infection with nuclear-replicating herpesviruses, and the roles of human deacetylases during viral infections. Dr. Cristea's research aims to elucidate how viruses modulate cellular pathways and how hosts respond to infection, with the goal of identifying key host proteins for therapeutic development. Her background includes graduate research at the University of Manchester and postdoctoral work at The Rockefeller University. She is actively involved in professional organizations, editorial boards, and educational initiatives related to proteomics and mass spectrometry.

Research topics

• Biology
• Genetics
• Computer Science
• Data science
• Internal medicine
• Endocrinology
• Bioinformatics
• Physiology
• Computational biology
• Engineering

Selected publications

• Targeting autocrine retinoic acid signaling by ALDH1A2 inhibition enhances antitumor dendritic cell vaccine efficacy

  Nature Immunology · 2026-01-05 · 4 citations

  article
  PublisherDOI

• Abstract 2856: Pks+ E. coli trigger intestinal stem cell plasticity and early onset colorectal cancer

  Cancer Research · 2025-04-21 · 2 citations

  article

  Escherichia coli (E.coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin associated with pathogenesis of colorectal cancer (CRC). The colibactin polyketide induces DNA damage through direct alkylation of DNA, which leads to characteristic mutational A-T rich signatures in the genome (SBS28 and SBS88) that can be identified by whole genome sequencing (WGS). Since WGS is not routinely used clinically, we developed an approach to specifically identify SBS-pks using a clinical targeted exon capture assay, MSK-IMPACT. In an institutional pan-cancer clinical cohort of 78,905 tumors we identified 15,967 samples with >20 mutations detected by MSK-IMPACT. We identified 149/1845 samples with microsatellite stable CRC with >10% mutations attributable to SBS-pks. Examining clinicopathologic and genomic features of SBS-pks+ compared to SBS-pks- CRC tumors, we find that SBS-pks+ signatures are significantly enriched in younger age of onset compared to SBS-pks- CRC patients (median age 52 vs 57, p=0.00059). While global genomic features and oncogenic pathways are similar, we find that the APC:c835-8A>G splice site mutation is overrepresented in SBS-pks+ tumors with 21.7% enrichment compared to 4.99% in SBS-pks- tumors, even further enriched in young onset SBS-pks+ CRC (27% <50 y, 31% <45 y, p<0.0001). To mechanistically investigate colibactin-associated damage we developed a novel long-term human colon organoid-microbe co-culture model system that takes advantage of reversal of polarity in suspension culture. WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E.coli NC101 confirmed induction of SBS-pks signatures, validating the model. 48h acute exposure to pks+ E.coli upregulates DNA replication and DNA damage repair (DDR) pathways coupled with cell cycle stalling in S phase with activation of ATM/ATR, indicative of replication stress. Strikingly, pks+ E.coli exposure drives a phenotypic shift of tumor and normal epithelial cells into an intestinal stem cell (ISC) state, with pks+ exposed cells demonstrating increased regeneration and proliferation, while thermal proximity coaggregation-MS analysis of protein complexes reveals global chromatin remodeling changes. Thus, our findings suggest that colibactin SBS signature is associated with young onset CRC and that the colibactin genotoxin phenotypically promotes cells to enter a proliferative intestinal stem cell states as precursors to CRC carcinogenesis. Correlating our clinicogenomic findings of an increased pks+ signature presence in young onset patients, we propose a model of colibactin injury in which younger, DNA replication and repair proficient cells are able to overcome colibactin-associated DDR stress, while aged colonic cells exit DDR stress through cell cycle arrest and apoptosis, resulting in the overall observed enriched genomic colibactin signature in young onset CRC. Citation Format: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Krystal Lum, Christopher Cowley, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Asha Saxena, Tavis J. Reed, Andrea Cercek, Rona Yaeger, Ileana Cristea, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh. Pks+ E. coli trigger intestinal stem cell plasticity and early onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2856.

  PublisherDOI

• Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures

  Molecular Systems Biology · 2025-04-01 · 4 citations

  articleOpen accessSenior author

  Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established an HTT association with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, we find HTT modulates the subcellular localization and assembly of the Mediator. We demonstrated striatal enriched and functional interactions with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology.

  PublisherOA PDFDOI

• Lineage memory shapes viral resistance barriers in human skin

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-27

  preprintOpen access

  Abstract Individual cells within a given population exhibit striking variability in viral susceptibility, but it remains unknown whether this heterogeneity reflects memories encoded into the cellular lineage or true probabilistic variability. We used multi-color lineage tracing in a human primary organotypic skin model to reveal that viral resistance is encoded within specific cellular lineages. These lineages create distinct boundaries that block viral spread. Our lineage analyses in vitro confirmed that viral susceptibility exhibits strong heritability across cell generations, with siblings and cousins displaying remarkably similar infection outcomes. ATAC and proteomics profiling of resistant and susceptible clones revealed distinct epigenomic and proteomic states, with the transcription factor AP-1 emerging as a potential central regulator of lineage-encoded viral resistance. Inducing AP-1 activity with PMA rendered cells resistant to viral infection, suggesting a causative role in mediating resistance memory. Our findings demonstrate that antiviral resistance in human skin cells is encoded within cellular lineages and preserved through cell divisions, revealing how cell memory may shape infection dynamics and viral containment in tissues.

  PublisherOA PDFDOI

• Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3

  iScience · 2025-10-04 · 2 citations

  articleOpen access

  and high-throughput screening approach followed by medicinal optimization to identify first-in-class, oral and safe antagonists of ALDH1A3 with potent anti-tumor immunotherapeutic activity and an optimized drug development profile.

  PublisherDOI

• Infection-induced lysine lactylation enables herpesvirus immune evasion

  Science Advances · 2025-01-08 · 23 citations

  articleOpen accessSenior authorCorresponding

  Aerobic glycolysis is a hallmark of many viral infections, leading to substantial accumulation of lactate. However, the regulatory roles of lactate during viral infections remain poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. We establish that lactyllysine is enriched in intrinsically disordered regions, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune factors suppresses immunity, a feature we show to be shared for HCMV and herpes simplex virus 1 infections, through regulation of RNA binding protein 14 and interferon-γ-inducible protein 16 (IFI16). K90 lactylation of the viral DNA sensor IFI16 inhibits recruitment of the DNA damage response kinase DNA-PK, preventing IFI16-driven virus gene repression and cytokine induction. Together, we characterize global protein lactylation dynamics during virus infection, finding that virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.

  PublisherDOI

• Ribosomal protein S25 promotes cell cycle entry for a productive BK polyomavirus infection

  Philosophical Transactions of the Royal Society B Biological Sciences · 2025-03-06 · 4 citations

  articleOpen access

  Many viruses use alternate mechanisms to initiate protein translation owing to their limited coding capacity. The ribosomal protein S25 (RPS25/eS25) is required for efficient non-canonical mechanisms of translation initiation, such as internal ribosomal entry site (IRES) initiation or ribosomal shunting, but eS25 is not required for efficient cap-dependent initiation. Thus, eS25 knockdown can be used to evaluate whether a virus relies on alternative mechanisms of initiation. Since earlier studies suggest that simian virus 40 (SV40) uses an IRES to translate a minor capsid protein VP3, which is translated from the same transcript as VP2, we sought to test if BK polyomavirus (BKPyV) also used an IRES by examining viral production with and without eS25. Instead, we found that BKPyV required eS25 for robust viral production prior to gene expression, suggesting that it affected an early step in the viral life cycle. These studies revealed a role for eS25 in cell cycle control. When eS25 was knocked down in primary kidney cells, it decreased the proportion of cycling cells, causing arrest at both G0/G1 and G2/M. These data suggest that the timing of BKPyV infection depends on the initial cell cycle state of the host cell.This article is part of the discussion meeting issue 'Ribosome diversity and its impact on protein synthesis, development and disease'.

  PublisherOA PDFDOI

• Sequestration of ribosome biogenesis factors in HSV-1 nuclear aggregates revealed by spatially resolved thermal profiling

  Science Advances · 2025-06-27 · 4 citations

  articleOpen accessSenior authorCorresponding

  Viruses exploit host cell reliance on compartmentalization to facilitate their replication. Herpes simplex virus type 1 (HSV-1) modulates the subcellular localization of host proteins to suppress immune activation, license viral gene expression, and achieve translational shutoff. To spatially resolve dynamic protein-protein interaction (PPI) networks during infection with an immunostimulatory HSV-1 strain, we integrated nuclear/cytoplasmic fractionation with thermal proximity coaggregation analysis (N/C-TPCA). The resulting expanded depth and spatial resolution of PPIs charted compartment-specific assemblies of protein complexes throughout infection. We find that a broader suite of host chaperones than previously anticipated exhibits nuclear recruitment to form condensates known as virus-induced chaperone-enriched (VICE) domains. Monitoring protein and RNA constituents and ribosome activity, we establish that VICE domains sequester ribosome biogenesis factors from ribosomal RNA, accompanying a cell-wide defect in ribosome supply. These findings highlight infection-driven VICE domains as nodes of translational remodeling and demonstrate the utility of N/C-TPCA to study dynamic biological contexts.

  PublisherDOI

• Shaping Viral Infection Outcomes via Organelle Remodeling

  Annual Review of Virology · 2025-06-24 · 1 citations

  reviewOpen accessSenior author

  Subcellular organelles are dynamic structures that tune their functions in conjunction with changes to their shapes and compositions. Each organelle has distinct structure-function relationships that change in response to diverse stimuli. Such remodeling events further affect organelle-organelle interaction networks facilitated by membrane contact sites, thereby activating rapid intra- and intercellular communication cascades. As viruses rely on repurposing the host cell machinery during infections, organelle remodeling is a fundamental facet and outcome of all viral infections. Some organelle remodeling events are unique to particular viruses, while others are shared by an array of viruses. Here, we review knowledge derived from this expanding yet still underexplored research area of infection-induced organelle remodeling. We focus on the molecular mechanisms used by viruses to temporally control organelle structure-function relationships. We highlight how organelle remodeling can inhibit host defenses or facilitate specific stages of a virus replication cycle, i.e., entry, replication, assembly, and spread.

  PublisherDOI

• Effect of host telomerase inhibition on human cytomegalovirus

  Journal of Virology · 2025-02-05 · 2 citations

  articleOpen access

  ABSTRACT Treatment options remain limited for human cytomegalovirus (HCMV). Host telomerase has been implicated in the pathogenesis and oncogenesis of multiple herpesviruses, most recently including HCMV. In this study, we investigated the effect of telomerase inhibition on HCMV replication, as well as the mechanism of the interaction between HCMV and host telomerase in vitro . We found that lytic HCMV infection increases host telomerase activity, at least in part, through modulation of hTERT expression during earlier phases of the HCMV replication cycle. We found telomerase inhibition strongly reduced viral titer for two HCMV strains in a dose-specific manner. Both post-translational pharmaceutical telomerase inhibition and siRNA-mediated knockdown of hTERT reduce HCMV yield. Telomerase inhibition results in both reduction of viral gene and protein expression across the HCMV replication cycle, and suppressed viral genome replication and viral infectivity, suggesting interference with at least early steps of the HCMV viral life cycle. Altogether, our findings indicate telomerase plays an important, perhaps non-canonical role in lytic HCMV infection which includes the support of viral replication and infectivity. IMPORTANCE Human cytomegalovirus (HCMV) seroprevalence and morbidity in immunocompromised patients and neonates infected in utero remain high globally. Host telomerase has been implicated in the success of multiple infection-induced pathologies, including the success of both lytic infection and oncogenesis in certain herpesviruses. The results of this study suggest a similar biologically important role for host telomerase in lytic HCMV infection. Furthermore, these results may provide the potential for a novel, adjunctive anti-viral treatment for HCMV infection as well as insight into the viral products likely to be involved with HCMV regulation of telomerase.

  PublisherDOI

Recent grants

• Gene Regulatory Networks for Cardiac Morphogenesis

  NIH · $2.5M · 2017–2021

• Cardiac interaction networks as determinants of transcriptional specificity

  NIH · $2.9M · 2017–2023

• NIH Grant R01HL127640

  NIH · $2.5M · 2020

• Predoctoral Training in Genetics and Molecular Biology

  NIH · $31.9M · 1977–2023

• Mechanisms mediating immune response upon sensing of nuclear viral DNA

  NIH · $2.6M · 2015–2025

Frequent coauthors

• Todd M. Greco

  73 shared

• Simon J. Gaskell

  30 shared

• Frank L. Conlon

  University of North Carolina at Chapel Hill

  29 shared

• Brian T. Chait

  27 shared

• Krystal K. Lum

  Princeton University

  26 shared

• Michael P. Rout

  20 shared

• Joel D. Federspiel

  Pfizer (United States)

  19 shared

• Anthony D. Whetton

  University of Surrey

  18 shared

Awards & honors

• Mallinckrodt Scholar Award, Edward Mallinckrodt, Jr. Foundat…
• American Society for Mass Spectrometry Research Award (2012)
• Early Career Award in Mass Spectrometry from the American Ch…
• Human Frontiers Science Program Young Investigator Award (20…
• NIDA Avant-Garde Director Pioneer Award for HIV/AIDS Researc…