About

Sunny Shin, Ph.D., is a Professor of Microbiology at the University of Pennsylvania Perelman School of Medicine. His research focuses on uncovering innate immune mechanisms used by the host to defend against bacterial pathogens and understanding how bacterial pathogens evade host immunity to cause disease. His laboratory studies innate immunity and host-pathogen interactions using various gram-negative bacteria, including Legionella pneumophila, Coxiella burnetii, Salmonella Typhimurium, and Yersinia pseudotuberculosis, employing mouse and human model systems. A major aspect of his work involves understanding how the immune system distinguishes between virulent and avirulent bacteria and tailors appropriate antimicrobial responses, with particular attention to the inflammasome pathway and its role in activating inflammatory responses critical for host defense. Dr. Shin's research also explores how the immune system overcomes pathogen strategies to suppress host functions. His team has identified mechanisms by which infected macrophages circumvent Legionella's ability to block host translation, facilitating cytokine production and immune crosstalk, and has studied dendritic cell responses to Legionella. His work aims to elucidate mechanisms that promote antimicrobial defense, which will advance understanding of bacterial pathogenesis and inform the development of antimicrobial therapies and vaccines. Dr. Shin's contributions include significant insights into inflammasome regulation, host cell death pathways, and host-pathogen interactions, with the goal of improving infectious disease interventions.

Research topics

• Immunology
• Cell biology
• Biology
• Biochemistry
• Microbiology
• Chemistry
• Genetics
• Pathology
• Virology
• Medicine

Selected publications

• Environmental Amino Acid Sensing Regulates the Rate of ASC Translation and NLRP3 Inflammasome Assembly

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-20 · 1 citations

  articleOpen accessCorresponding

  ABSTRACT The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein signaling complex that triggers pyroptotic cell death and interleukin (IL)-1 family cytokine release during infection and cell injury. Its assembly is driven by the adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), whose filamentation forms a supramolecular speck upon NLRP3 activation to amplify inflammasome signaling. While the NLRP3 inflammasome is well appreciated as a sensor of environmental danger and damage, little is known about how homeostatic environmental factors like dietary metabolites regulate its activity. Here, we find that environmental availability of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, controls NLRP3 inflammasome assembly. While ASC is typically viewed as a constitutively expressed, unregulated inflammasome component, we find that Toll-like receptor 4 (TLR4) activation triggers localization of ASC mRNA to the perinuclear space. Moreover, our data demonstrate that ASC undergoes TLR4-driven translational bursting from polyribosomes during inflammasome priming. This translational engagement is dependent on BCAA availability and mechanistic target of rapamycin (mTOR) activity, which regulate the kinetics of inflammasome assembly. In contrast, the translation of NLRP3 and caspase-1 is largely insensitive to these inputs. Furthermore, we find that BCAAs regulate NLRP3 inflammasome activation in both mouse and human macrophages, in the context of bacterial infection, and during lipopolysaccharide (LPS)-induced sepsis in vivo . Altogether, this work unveils a novel inflammasome priming event governed by the amino acid environment. These findings further highlight how the activity of proteins maintained in equilibrium like ASC can be dynamically regulated through rapid changes in mRNA translation.

  PublisherOA PDFDOI

• Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict <i>Legionella</i> infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-17 · 1 citations

  preprintOpen accessSenior authorCorresponding

  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 PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways 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 its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restricts Legionella replication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1 β early during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.

  PublisherOA PDFDOI

• TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral <i>Yersinia</i> infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-26 · 2 citations

  preprintOpen access

  Abstract Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a Gram-negative enteric pathogen, closely related to the plague agent Y. pestis, that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer’s patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination, and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate, using Sequence Tag-based Analysis of Microbial Populations in R (STAMPR), that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, populations of Yersinia are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both tissue colonization and lymphatic dissemination of intestinal bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens. Importance Bacterial escape from the intestine can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.

  PublisherOA PDFDOI

• TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral <i>Yersinia</i> infection

  mBio · 2025-09-09 · 6 citations

  articleOpen access

  ABSTRACT Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a gram-negative enteric pathogen closely related to the plague agent Y. pestis that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer’s patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the host factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate using sequence tag-based analysis of microbial populations in R (STAMPR) that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, Yersinia populations are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both initial colonization and subsequent dissemination of orally acquired bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens. IMPORTANCE Dissemination of bacteria following intestinal infection can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.

  PublisherDOI

• Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

  Nature Nanotechnology · 2025-08-11 · 42 citations

  articleOpen access
  PublisherOA PDFDOI

• Author response: Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages

  2025-03-27

  peer-reviewOpen accessSenior author
  PublisherDOI

• Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-23 · 1 citations

  articleOpen access

  Abstract The distal small intestine plays vital roles in host physiology by regulating nutrient and fluid homeostasis. Despite being impacted in Crohn’s disease and a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell-cell communication in the ileum during infection. Single cell and spatial transcriptomics have emerged as powerful technologies to study tissue heterogeneity in the gut, but these tools have focused on the large intestine, in part due to the accessibility of this tissue for biopsies and its importance in cancer. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a novel enterocyte cell state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of the transcriptional diversity of cellular landscapes in the small intestine.

  PublisherDOI

• GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during <i>Legionella</i> infection

  Infection and Immunity · 2025-06-05 · 1 citations

  articleOpen accessSenior author

  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- <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="u1" overflow="scroll"> <mml:mi>κ</mml:mi> </mml:math> 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.

  PublisherDOI

• Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages

  eLife · 2025-03-27 · 1 citations

  articleOpen accessSenior author

  Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.

  PublisherDOI

• Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict <i>Legionella</i> infection

  mBio · 2025-06-18 · 2 citations

  articleOpen accessSenior author

  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. IMPORTANCE The 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.

  PublisherDOI

Recent grants

• Innate immune-mediated control of pulmonary Legionella pneumophila infection

  NIH · $4.6M · 2015–2026

• NIH Grant R00AI087963

  NIH · $496k · 2013

• Defining human noncanonical inflammasome responses to Legionella pneumophila

  NIH · $2.0M · 2016–2023

• NIH Grant K99AI087963

  NIH · $95k · 2011

• TNF and caspase-8-mediated control of Legionella pneumophila infection

  NIH · $447k · 2021–2024

Frequent coauthors

• Igor E. Brodsky

  University of Pennsylvania

  35 shared

• Marisa S. Egan

  University of Pennsylvania

  12 shared

• Craig R. Roy

  Yale University

  11 shared

• Cierra N. Casson

  Takeda (United States)

  10 shared

• Alan M. Copenhaver

  AstraZeneca (United States)

  9 shared

• Jenna Zhang

  University of Pennsylvania

  9 shared

• Andy J. Minn

  University of Pennsylvania

  8 shared

• Mark A. Boyer

  University of Pennsylvania

  8 shared

Labs

• Sunny Shin's LabPI

Education

• B.S., Biology

  Massachusetts Institute of Technology

  1998

• Ph.D., Microbiology and Immunology

  Stanford University School of Medicine

  2004

• Other, Unconscious Bias Training: Impact on Decision Making

  University of Pennsylvania Perelman School of Medicine

  2020

• Other, Inclusive and Equitable Teaching Seminar

  Center for Teaching and Learning, University of Pennsylvania

  2021

• Other, HHMI Gilliam Mentorship Training

  HHMI and CIMER

  2022