Victor Vazquez Marrero

All Publications

• Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict <i>Legionella</i> infection MBIO Vazquez Marrero, V. R., Doerner, J., Wodzanowski, K. A., Zhang, J., Lu, A., Boyer, F. D., Vargas, I., Hossain, S., Kammann, K. B., Dresler, M. V., Shin, S. 2025; 16 (7): e0125725

  Abstract

  The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRRs and guard proteins to respond to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) distinctly respond to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate robust intracellular replication. In contrast, T4SS activity triggers rapid death of DCs, which potently restricts Legionella replication. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single-cell level. Initially, some DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis early during infection. At later time points, other DCs undergo apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our findings suggest a model where Mcl-1 and cFLIP guard host translation in DCs. Furthermore, our work shows that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.IMPORTANCEThe innate immune system senses bacterial pathogens by employing pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) and guard proteins that monitor pathogen disruption of host cell processes. How different immune cell types engage pattern recognition receptors (PRRs) and guard proteins to respond to infection is poorly understood. Here, we reveal how dendritic cells (DCs) detect and restrict the intracellular bacterial pathogen Legionella pneumophila. At the single-cell level, we find that early during infection, some DCs activate caspase-11 pyroptosis. At later time points, other DCs undergo apoptosis driven by type IV secretion system (T4SS) effectors that block host protein synthesis, which depletes levels of the pro-survival proteins Mcl-1 and cFLIP. Our findings suggest Mcl-1 and cFLIP safeguard mRNA translation in DCs and highlight differences in how macrophages and DCs employ PRRs and guard proteins to respond to bacterial infection.

  View details for DOI 10.1128/mbio.01257-25

  View details for Web of Science ID 001510647000001

  View details for PubMedID 40530878

  View details for PubMedCentralID PMC12239575

• GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during <i>Legionella</i> infection INFECTION AND IMMUNITY Vazquez Marrero, V. R., Dresler, M., Haggadone, M. D., Lu, A., Shin, S. 2025; 93 (7): e0056524

  Abstract

  The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for host defense against a wide range of pathogens. During infection with the intracellular bacterial pathogen Legionella pneumophila, we previously found that GM-CSF enhances inflammatory cytokine production in murine monocytes and is required for in vivo control of Legionella. It is unclear whether GM-CSF similarly augments cytokine production in human monocytes during bacterial infection. Here, we find that GM-CSF enhances inflammatory cytokine expression in Legionella-infected human monocytes by engaging multiple signaling pathways. Legionella- and Toll-like receptor-dependent NF-[Formula: see text]B signaling is a prerequisite signal for GM-CSF to promote cytokine expression. Then, GM-CSF-driven Janus kinase 2/signal transducer and activator of transcription 5 signaling is required to augment cytokine expression in Legionella-infected human monocytes. We also found a role for phosphatidylinositol-3-kinase/Akt/mTORC1 signaling in GM-CSF-dependent upregulation of cytokine expression. Finally, glycolysis and amino acid metabolism are also critical for GM-CSF to boost cytokine gene expression. Our findings show that GM-CSF-mediated enhancement of cytokine expression in infected human monocytes is regulated by multiple signaling pathways, thereby allowing the host to fine-tune antibacterial immunity.

  View details for DOI 10.1128/iai.00565-24

  View details for Web of Science ID 001502440200001

  View details for PubMedID 40470942

  View details for PubMedCentralID PMC12234439

• CT imaging of and therapy for inflammatory bowel disease via low molecular weight dextran coated ceria nanoparticles. Nanoscale Rosario-Berríos, D. N., Pang, A. Y., Mossburg, K. J., Kim, J., Vázquez Marrero, V. R., Yoon, S., Gupta, M., Lenz, O. C., Liu, L. P., Kian, A. C., La Luz Rivera, K., Shin, S., Noël, P. B., Lennon, E. M., Cormode, D. P. 2025; 17 (16): 10356-10370

  Abstract

  Inflammatory bowel disease (IBD) affects approximately 3.1 million individuals in the U.S., causing deleterious symptoms such as bloody diarrhea and leading to an increased risk of colorectal cancer. Effective imaging is crucial for diagnosing and managing IBD, as it allows for accurate assessment of disease severity, guides treatment decisions, and monitors therapeutic responses. Computed tomography (CT) with contrast agents is the gold standard for imaging the gastrointestinal tract (GIT). However, current agents are less effective in obese patients and lack specificity for inflamed regions associated with IBD. Moreover, IBD treatments often have limited efficacy and do not address the role of oxidative stress in IBD progression. This study explores dextran-coated cerium oxide nanoparticles (Dex-CeNP) as a CT contrast agent and therapeutic for IBD, leveraging cerium's superior K-edge energy profile, dextran's inflammation-specific targeting, and cerium oxide's antioxidant properties. Herein, we synthesized Dex-CeNP formulations using 5, 10, 25, and 40 kDa dextran to explore the effect of dextran coating molecular weight. In vitro assays showed formulation biocompatibility and demonstrated that 5 kDa Dex-CeNP had the highest catalytic activity, which translated into improved suppression of inflammation. As a result, this formulation was selected for in vivo use. In vivo CT imaging of mice subjected to dextran sodium sulfate (DSS) colitis showed that Dex-CeNP provided better contrast in the GIT of mice with colitis compared to iopamidol (ISO), with pronounced attenuation in the large intestine and disease- specific retention at 24 h. Additionally, Dex-CeNP significantly decreased Disease Activity Index (DAI) scores, and diminished gastrointestinal bleeding when compared with a currently approved drug, indicating that it is an effective treatment for colitis. Studies also revealed that the Dex-CeNPs were safe and well-excreted following administration. In summary, Dex-CeNP has significant promise as a dual-purpose agent for CT imaging and treatment of IBD.

  View details for DOI 10.1039/d4nr04994b

  View details for PubMedID 40178819

  View details for PubMedCentralID PMC11967712

• Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS. eLife Akuma, D. C., Wodzanowski, K. A., Schwartz Wertman, R., Exconde, P. M., Vázquez Marrero, V. R., Odunze, C. E., Grubaugh, D., Shin, S., Taabazuing, C., Brodsky, I. E. 2024; 13

  Abstract

  Inflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammasomes. Inflammasomes recruit caspases to undergo proximity-induced autoprocessing into an enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high-molecular-weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. However, the cellular correlates of Casp11 oligomerization and whether Casp11 forms an LPS-induced SMOC within cells remain unknown. Expression of fluorescently labeled Casp11 in macrophages revealed that cytosolic LPS induced Casp11 speck formation. Unexpectedly, catalytic activity and autoprocessing were required for Casp11 to form LPS-induced specks in macrophages. Furthermore, both catalytic activity and autoprocessing were required for Casp11 speck formation in an ectopic expression system, and processing of Casp11 via ectopically expressed TEV protease was sufficient to induce Casp11 speck formation. These data reveal a previously undescribed role for Casp11 catalytic activity and autoprocessing in noncanonical inflammasome assembly, and shed new light on the molecular requirements for noncanonical inflammasome assembly in response to cytosolic LPS.

  View details for DOI 10.7554/eLife.83725

  View details for PubMedID 38231198

  View details for PubMedCentralID PMC10794067

• TNF licenses macrophages to undergo rapid caspase-1, -11, and -8-mediated cell death that restricts Legionella pneumophila infection. PLoS pathogens Pollock, T. Y., Vázquez Marrero, V. R., Brodsky, I. E., Shin, S. 2023; 19 (6): e1010767

  Abstract

  The inflammatory cytokine tumor necrosis factor (TNF) is necessary for host defense against many intracellular pathogens, including Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires' disease and predominantly affects individuals with a suppressed immune system, including those receiving therapeutic TNF blockade to treat autoinflammatory disorders. TNF induces pro-inflammatory gene expression, cellular proliferation, and survival signals in certain contexts, but can also trigger programmed cell death in others. It remains unclear, however, which of the pleiotropic functions of TNF mediate control of intracellular bacterial pathogens like Legionella. In this study, we demonstrate that TNF signaling licenses macrophages to die rapidly in response to Legionella infection. We find that TNF-licensed cells undergo rapid gasdermin-dependent, pyroptotic death downstream of inflammasome activation. We also find that TNF signaling upregulates components of the inflammasome response, and that the caspase-11-mediated non-canonical inflammasome is the first inflammasome to be activated, with caspase-1 and caspase-8 mediating delayed pyroptotic death. We find that all three caspases are collectively required for optimal TNF-mediated restriction of bacterial replication in macrophages. Furthermore, caspase-8 is required for control of pulmonary Legionella infection. These findings reveal a TNF-dependent mechanism in macrophages for activating rapid cell death that is collectively mediated by caspases-1, -8, and -11 and subsequent restriction of Legionella infection.

  View details for DOI 10.1371/journal.ppat.1010767

  View details for PubMedID 37279255

  View details for PubMedCentralID PMC10275475

• In the Context of Polymorphism: Accurate Measurement, and Validation of Solubility Data. Crystal growth & design Vázquez Marrero, V. R., Berríos, C. P., Dios Rodríguez, L. D., Stelzer, T., López-Mejías, V. 2019; 19 (7): 4101-4108

  Abstract

  Solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations. In this study, solubility measurements from undersaturated solutions are employed to investigate the solubility of the two most stable polymorphs of flufenamic acid (FFA forms I and III), tolfenamic acid (TA forms I and II), and the only known form of niflumic acid (NA). The solubility was measured from 278.15 to 333.15 K in four alcohols of a homologous series (methanol, ethanol, 1-propanol, n-butanol) using the polythermal method. It was established that the solubility of these compounds increases with increasing temperature. The solubility curves of FFA forms I and III intersect at ~315.15 K (42 °C) in all four solvents, which represents the transition temperature of the enantiotropic pair. In the case of TA, the solubility of form II could not be reliably obtained in any of the solvents because of the fast solvent-mediated phase transformation. The solubility of the only known form of NA was also determined, and no other polymorphs of NA were observed. The experimental solubility data of FFA (forms I and III), TA (form I), and NA in these four solvents was correlated using the modified Apelblat and λh model equations. The correlated and experimentally determined solubility data obtained serves to (i) guide the accurate determination of the solubility for polymorphic compounds, (ii) assess the role of the solvent in mediating transformations, and (iii) provide a route to engineer advanced crystallization processes for these pharmaceutical compounds.

  View details for DOI 10.1021/acs.cgd.9b00529

  View details for PubMedID 32863778

  View details for PubMedCentralID PMC7453630