About

Steven R. Blanke is a Professor of Microbiology and the Ralph S. Wolfe Professorial Scholar at the School of Molecular & Cellular Biology, Illinois College of Liberal Arts & Sciences. His research focuses on infection biology and cancer, particularly host-pathogen interactions, bacterial pathogenesis, and microbial physiology. His laboratory investigates how pathogenic bacteria modulate host cells and tissues through toxins, with a specific emphasis on bacterial toxins such as VacA from Helicobacter pylori, cytolethal distending toxins, and others. The research aims to understand cellular intoxication mechanisms, structure-function relationships of toxins, and how bacteria persist within hosts during chronic infections, especially in the context of H. pylori's role in gastric diseases and stomach cancer. Additionally, his work explores intracellular lifestyles of bacteria like Bacillus anthracis, mechanisms of bacterial manipulation of host cell cycles, and the complex interactions within microbiota ecosystems. His ultimate goal is to develop molecular countermeasures against pathogenic organisms. Dr. Blanke holds a B.A. in Biochemistry from Virginia Tech University and a Ph.D. in Biochemistry from the University of Illinois, with postdoctoral training at Harvard Medical School. He has received numerous awards for research, scholarship, and teaching, including being named the Ralph S. Wolfe Professorial Scholar and a Fellow of the American Academy of Microbiology. He has also held leadership roles in scientific conferences and societies, contributing significantly to the field of microbial pathogenesis.

Research topics

• Microbiology
• Immunology
• Biology
• Medicine
• Molecular biology
• Pharmacology
• Internal medicine
• Cell biology
• Biochemistry

Selected publications

• A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage

  iScience · 2025-02-27 · 1 citations

  articleOpen accessSenior author

  organoid model. Our data indicate that the suppression of autophagy, through a p53-proteasome-LC3 regulatory axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could provide a means for realigning proteostasis in cells undergoing DNA damage repair.

  PublisherDOI

• Autophagy suppression in DNA damaged cells occurs through a newly identified p53-proteasome-LC3 axis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-23

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that suppression of autophagy, through a newly identified p53-proteasome-LC3 axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could potentially be important for realigning proteostasis in cells undergoing DNA damage repair.

  PublisherOA PDFDOI

• Corrigendum: Revisiting bacterial cytolethal distending toxin structure and function

  Frontiers in Cellular and Infection Microbiology · 2024-01-16

  erratumOpen accessSenior authorCorresponding

  [This corrects the article DOI: 10.3389/fcimb.2023.1289359.].

  PublisherOA PDFDOI

• Restoration of mitochondrial structure and function within <i>Helicobacter pylori</i> VacA intoxicated cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-05-20

  preprintOpen accessSenior authorCorresponding

  ABSTRACT The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.

  PublisherOA PDFDOI

• Host cell sensing and restoration of mitochondrial function and metabolism within <i>Helicobacter pylori</i> VacA intoxicated cells

  mBio · 2023-10-10 · 16 citations

  articleOpen accessSenior author

  ABSTRACT Helicobacter pylori vacuolating cytotoxin A (VacA) is an intracellular-acting protein exotoxin that induces mitochondrial dysfunction and energy depletion within host cells. Although exposure to VacA results in mitochondrial dysfunction, one recent study revealed that, following limited exposure to VacA, mitochondrial function and cellular ATP levels were restored in a time-dependent manner. Studies performed to address the mechanism by which host cells detect and respond to intracellular VacA identified the adenosine monophosphate (AMP)-activated protein kinase (AMPK) as a sensor of toxin-dependent alterations in cellular energy status. Activation of AMPK in response to VacA was demonstrated to orchestrate alterations in mitochondrial dynamics which resulted in restoration of mitochondrial function. Specifically, upregulation of dynamin-related protein 1 (Drp-1)-dependent mitochondrial fission resulted in reversible fragmentation of filamentous mitochondria and time-dependent reduction in mitochondrial-associated VacA, suggesting that fragmentation is important for removal of VacA from mitochondria. Cells with reduced levels of Drp-1 were more susceptible to VacA-dependent cell death, suggesting that mitochondrial dynamics is important for maintaining cell viability through the reduction in mitochondrial-associated toxin. Collectively, these studies support a model that cellular recovery and survival in response to VacA-dependent mitochondrial dysfunction is linked to host cell modulation of mitochondrial dynamics. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies. IMPORTANCE Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.

  PublisherDOI

• Revisiting bacterial cytolethal distending toxin structure and function

  Frontiers in Cellular and Infection Microbiology · 2023-11-14 · 3 citations

  articleOpen accessSenior authorCorresponding

  Cytolethal distending toxins (CDTs) are intracellular-acting bacterial genotoxins generated by a diverse group of mucocutaneous human pathogens. CDTs must successfully bind to the plasma membrane of host cells in order to exert their modulatory effects. Maximal toxin activity requires all three toxin subunits, CdtA, CdtB, and CdtC, which, based primarily on high-resolution structural data, are believed to preassemble into a tripartite complex necessary for toxin activity. However, biologically active toxin has not been experimentally demonstrated to require assembly of the three subunits into a heterotrimer. Here, we experimentally compared concentration-dependent subunit interactions and toxin cellular activity of the Campylobacter jejuni CDT ( Cj -CDT). Co-immunoprecipitation and dialysis retention experiments provided evidence for the presence of heterotrimeric toxin complexes, but only at concentrations of Cj- CdtA, Cj- CdtB, and Cj- CdtC several logs higher than required for Cj- CDT-mediated arrest of the host cell cycle at the G 2 /M interface, which is triggered by the endonuclease activity associated with the catalytic Cj- CdtB subunit. Microscale thermophoresis confirmed that Cj -CDT subunit interactions occur with low affinity. Collectively, our data suggest that at the lowest concentrations of toxin sufficient for arrest of cell cycle progression, mixtures of Cj- CdtA, Cj -CdtB, and Cj -CdtC consist primarily of non-interacting, subunit monomers. The lack of congruence between toxin tripartite structure and cellular activity suggests that the widely accepted model that CDTs principally intoxicate host cells as preassembled heterotrimeric structures should be revisited.

  PublisherOA PDFDOI

• Restoration of Mitochondrial Structure and Function within &amp;lt;i&amp;gt;Helicobacter pylori&amp;lt;/i&amp;gt; VacA Intoxicated Cells

  Advances in Microbiology · 2023-01-01 · 2 citations

  articleOpen accessSenior author

  The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.

  PublisherOA PDFDOI

• The Active Subunit of the Cytolethal Distending Toxin, CdtB, Derived From Both Haemophilus ducreyi and Campylobacter jejuni Exhibits Potent Phosphatidylinositol-3,4,5-Triphosphate Phosphatase Activity

  Frontiers in Cellular and Infection Microbiology · 2021 · 17 citations

  • Biology
  • Cell biology
  • Molecular biology

  was not involved in the ability of the three Cdts to induce cell cycle arrest. Finally, we demonstrate that, like AaCdt, HdCdt is dependent upon the host cell protein, cellugyrin, for its toxicity (and presumably internalization of CdtB); CjCdt was not dependent upon this protein. The implications of these findings as they relate to Cdt's molecular mode of action are discussed.

  PublisherOA PDFDOI

• Risk factors associated with gastric malignancy during chronic Helicobacter pylori infection

  Medical Research Archives · 2020-01-01 · 4 citations

  articleOpen accessSenior author

  Chronic Helicobacter pylori (Hp) infection is considered to be the single most important risk factor for the development of gastric adenocarcinoma in humans, which is a leading cause of cancer-related death worldwide. Nonetheless, Hp infection does not always progress to malignancy, and, gastric adenocarcinoma can occur in the absence of detectable Hp carriage, highlighting the complex and multifactorial nature of gastric cancer. Here we review known contributors to gastric malignancy, including Hp virulence factors, featuring the vacuolating cytotoxin (VacA), the cytotoxin-associated gene A (CagA), and other bacterial components that promote chemotaxis, colonization, and the establishment of chronic inflammation. In addition, we discuss host factors including sex, age, and genetic polymorphisms associated with host inflammation. Moreover, we consider environmental variables that influence cancer risk, such as nutritional status, socio-economic status, and smoking. In addition to these relatively well-studied contributors to gastric cancer risk, the resident gastric microflora in humans have more recently been proposed as an additional risk factor for disease progression in Hp-infected individuals. Molecular approaches for microbe identification have revealed differences in the gastric microbiota composition between cancer and non-cancerous patients, as well as infected and uninfected individuals. Although the reasons underlying differences in microbial community structures are not entirely understood, gastric atrophy and hypochlorhydria that accompany chronic Hp infection may be a critical driver of gastric dysbiosis that promote colonization of microbes that contribute to increased risk of malignancy. However, definitive evidence that the gastric microbiota influences the emergence of gastric cancer does not exist. In summary, while controversial and unresolved, the importance of the gastric microbiota as a risk factor for gastric malignancy is a vital area of current research.

  PublisherOA PDFDOI

• Chronic in vivo exposure to Helicobacter pylori VacA: Assessing the efficacy of automated and long-term intragastric toxin infusion

  Scientific Reports · 2020 · 16 citations

  Senior authorCorresponding
  • Medicine
  • Immunology
  • Pharmacology

  Helicobacter pylori (Hp) secrete VacA, a diffusible pore-forming exotoxin that is epidemiologically linked to gastric disease in humans. In vitro studies indicate that VacA modulates gastric epithelial and immune cells, but the in vivo contributions of VacA as an important determinant of Hp colonization and chronic infection remain poorly understood. To identify perturbations in the stomachs of C57BL/6 or BALB/C mice that result specifically from extended VacA exposure, we evaluated the efficacy of administering purified toxin using automated infusion via surgically-implanted, intragastric catheters. At 3 and 30 days of interrupted infusion, VacA was detected in association with gastric glands. In contrast to previously-reported tissue damage resulting from short term exposure to Hp extracts administered by oral gavage, extended infusion of VacA did not damage stomach, esophageal, intestinal, or liver tissue. However, several alterations previously reported during Hp infection were detected in animals infused with VacA, including reduction of the gastric mucus layer, and increased vacuolation of parietal cells. VacA infusion invoked an immune response, as indicated by the detection of circulating VacA antibodies. These foundational studies support the use of VacA infusion for identifying gastric alterations that are unambiguously attributable to long-term exposure to toxin.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI045928

  NIH · $1.9M · 2011

• NIH Grant R56AI045928

  NIH · $254k · 2012

• Intracellular trafficking of the mitochondrial targeting toxin VacA from Helicobacter pylori

  NIH · $418k · 2015–2017

• NIH Grant R21AI059095

  NIH · $528k · 2006

Frequent coauthors

• Robin L. Holland

  University of Illinois Urbana-Champaign

  19 shared

• R. John Collier

  16 shared

• Carlos W. Nossa

  New York University

  12 shared

• M. Ashley Spies

  University of Iowa

  11 shared

• Kenneth A. Bradley

  Roche (Switzerland)

  10 shared

• Lowell P. Hager

  9 shared

• Wilfred A. van der Donk

  Howard Hughes Medical Institute

  9 shared

• Brenda A. Wilson

  University of Illinois Urbana-Champaign

  8 shared

Awards & honors

• Named the Ralph S. Wolfe Professorial Scholar (2017)
• Fellow of the American Academy of Microbiology (2015)
• Faculty Excellence Award (2014)
• Award for Excellence in Research and Scholarship at the Asso…
• Award for Excellence in Research and Scholarship at the Assi…