John-Demian (JD) Sauer · University of Wisconsin-Madison · PhdFit
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Dr. Sarah Chen
Stanford · NLP & interpretability
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John-Demian (JD) Sauer
· Professor of Medical Microbiology & ImmunologyVerified
University of Wisconsin-Madison · Medical Microbiology and Immunology
The focus of our lab revolves around understanding host pathogen interactions. Specifically we are interested in four separate but related questions: 1. How do intracellular pathogens parasitize their host cells? 2. How can we take advantage of pathogen virulence strategies to combat infectious diseases?
ABSTRACT Staphylococcus aureus bloodstream infections remain a major clinical challenge. A key knowledge gap is how S. aureus adapts to the hostile, nutrient-limited environment of human serum, where immune pressures, such as complement, antimicrobial peptides, and nutritional immunity, restrict bacterial survival. Recent investigations integrating transcriptomic, proteomic, and metabolomic data across five clinically relevant S. aureus lineages revealed coordinated serum-specific metabolic and stress-response adaptations (W. Mujchariyakul, C. J. Walsh, S. Giulieri, C. Cramond, et al., mSystems 11:e01183-25, 2026, https://doi.org/10.1128/msystems.01183-25 ). Serum triggered increased gluconeogenic and TCA-cycle activity, expanded carbohydrate, amino acid, and lipid utilization, and induction of iron-acquisition systems, nucleotide biosynthesis, and oxidative-stress defenses, while suppressing ribosome biogenesis. Functional validation confirmed key roles for carbon-metabolism genes ( gapdhB, sucA ), siderophore and iron-uptake systems ( sirA, sstD ), and the peroxide regulator perR . These findings highlight the metabolic resourcefulness and stress resilience that enable S. aureus survival and persistence despite antibiotic therapy. This work underscores the importance of multiomic approaches across pathogens and physiologic models to reveal new therapeutic targets for bloodstream infections.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-29
preprintOpen accessSenior authorCorresponding
ABSTRACT To survive within restrictive host niches, bacterial pathogens must possess finely tuned physiological adaptations. One such niche inhabited by Listeria monocytogenes ( L. monocytogenes ) is the host cell cytosol—a compartment characterized by significant barriers to entry, metabolic limitation, and immune surveillance. Previously, we identified L. monocytogenes transposon mutants defective for intracellular survival due to disruptions in key metabolic pathways, including cell wall biosynthesis, menaquinone production, and pyruvate metabolism. One of these mutants mapped to a central component of the pyruvate dehydrogenase (PDH) complex, pdhC ::Tn. Notably, this mutant exhibits pronounced survival defects during infection, despite retaining robust growth and survival in nutrient-rich media. We go on to show that disruption of pdhA ::Tn and pdhD ::Tn similarly led to virulence attenuation during intra-macrophage growth, plaquing assays, and murine infections. Respiro-fermentative metabolic profiling revealed that pdhC ::Tn mutants have an altered respiro-fermentative metabolism with more prominent secretion of lactate. Further, unbiased metabolomic profiling revealed a global starvation phenotype with lower levels of upper glycolytic intermediates and TCA cycle intermediates coupled with elevated intra-bacterial levels of pyruvate and lactate. We then demonstrate that PDH mutants are unable to efficiently utilize phosphotransferase (PTS)-dependent carbon sources and that their growth can be rescued using non-PTS-mediated carbon sources such as hexose phosphates. To identify genetic suppressors of PDH deficiency, we performed an EMS mutagenesis screen using fructose—a PTS-transported carbon source—as the sole carbon source. Five suppressors each contained a single independent mutation in the redox sensing regulator rex . Subsequently, we show that loss of rex restores pdhC ::Tn’s ability to consume PTS-mediated carbon sources through the alleviation of fermentative repression. Further, pdhC ::Tn suppressor mutants show restored intracellular growth, but not virulence in vivo . Together, these findings indicate that a key defect in PDH mutants is the inability to import and metabolize PTS-dependent carbon sources in the host cytosol. We posit this impairment leads to disruptions in redox balance and a shift in respiro-fermentative metabolism, ultimately contributing to the loss of intracellular fitness and virulence.
The metabolism of bacterial pathogens is exquisitely evolved to support virulence in the nutrient-limiting host. Many bacterial pathogens utilize bipartite metabolism to support intracellular growth by splitting carbon utilization between two carbon sources and dividing flux to distinct metabolic needs. For example, previous studies suggest that the professional cytosolic pathogen Listeria monocytogenes (L. monocytogenes) utilizes glycerol and hexose phosphates (e.g., Glucose-6-Phosphate) as catabolic and anabolic carbon sources in the host cytosol, respectively. However, the role of this putative bipartite metabolism in L. monocytogenes virulence has not been fully assessed. Here, we demonstrate that when L. monocytogenes is unable to consume either glycerol (ΔglpD/ΔgolD), hexose phosphates (ΔuhpT), or both (ΔglpD/ΔgolD/ΔuhpT), it is still able to grow in the host cytosol and is 10- to 100-fold attenuated in vivo suggesting that L. monocytogenes consumes alternative carbon source(s) in the host. An in vitro metabolic screen using BioLog's phenotypic microarrays unexpectedly demonstrated that WT and PrfA* (G145S) L. monocytogenes, a strain with constitutive virulence gene expression, use phosphotransferase system (PTS) mediated carbon sources. These findings contrast with the existing metabolic model that cytosolic L. monocytogenes expressing PrfA does not use PTS mediated carbon sources. We next demonstrate that two independent and universal phosphocarrier proteins (PtsI [EI] and PtsH [HPr]), essential for the function of all PTS, are critical for intracellular growth and virulence in vivo. Constitutive virulence gene expression using a PrfA* (G145S) allele in ΔglpD/ΔgolD/ΔuhpT and ΔptsI failed to rescue in vivo virulence defects suggesting phenotypes are due to metabolic disruption and not virulence gene regulation. Finally, in vivo attenuation of ΔptsI and ΔptsH was additive to ΔglpD/ΔgolD/ΔuhpT, suggesting that hexose phosphates and glycerol and PTS mediated carbon source are relevant metabolites. Taken together, these studies indicate that PTS are critical virulence factors for the cytosolic growth and virulence of L. monocytogenes.
The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.
The Midwest Microbial Pathogenesis Conference (MMPC) is a longstanding annual meeting that brings together scientists from across the Midwest and across career stages to discuss the latest advances in infectious diseases and host-microbe interactions.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-18 · 1 citations
preprintOpen access
ABSTRACT C-di-AMP is an essential second messenger in many bacteria but its levels must be regulated. Unregulated c-di-AMP accumulation attenuates the virulence of many bacterial pathogens, including those that do not require c-di-AMP for growth. However, the mechanisms by which c-di-AMP regulates bacterial pathogenesis remain poorly understood. In Listeria monocytogenes , a mutant lacking both c-di-AMP phosphodiesterases, denoted as the ΔPDE mutant, accumulates a high c-di-AMP level and is significantly attenuated in the mouse model of systemic infection. All key L. monocytogenes virulence genes are transcriptionally upregulated by the master transcription factor PrfA, which is activated by reduced glutathione (GSH) during infection. Our transcriptomic analysis revealed that the ΔPDE mutant is significantly impaired for the expression of virulence genes within the PrfA core regulon. Subsequent quantitative gene expression analyses validated this phenotype both at the basal level and upon PrfA activation by GSH. A constitutively active PrfA * variant, PrfA G145S, which mimics the GSH-bound conformation, restores virulence gene expression in ΔPDE but only partially rescues virulence defect. Through GSH quantification and uptake assays, we found that the ΔPDE strain is significantly depleted for GSH, and that c-di-AMP inhibits GSH uptake. Constitutive expression of gshF (encoding a GSH synthetase) does not restore GSH levels in the ΔPDE strain, suggesting that c-di-AMP inhibits GSH synthesis activity or promotes GSH catabolism. Taken together, our data reveals GSH metabolism as another pathway that is regulated by c-di-AMP. C-di-AMP accumulation depletes cytoplasmic GSH levels within L. monocytogenes that leads to impaired virulence program expression. IMPORTANCE C-di-AMP regulates both bacterial pathogenesis and interactions with the host. Although c-di-AMP is essential in many bacteria, its accumulation also attenuates the virulence of many bacterial pathogens. Therefore, disrupting c-di-AMP homeostasis is a promising antibacterial treatment strategy, and has inspired several studies that screened for chemical inhibitors of c-di-AMP phosphodiesterases. However, the mechanisms by which c-di-AMP accumulation diminishes bacterial pathogenesis are poorly understood. Such understanding will reveal the molecular function of c-di-AMP, and inform therapeutic development strategies. Here, we identify GSH metabolism as a pathway regulated by c-di-AMP that is pertinent to L. monocytogenes replication in the host. Given the role of GSH as a virulence signal, nutrient, and antioxidant, GSH depletion impairs virulence program expression and likely diminishes host adaptation.
Increasing evidence suggests macrophages play a crucial role in fibrosis pathogenesis, including lung fibrosis. Understanding mechanisms that underly pro-fibrotic macrophage can help identify new drug targets for anti-fibrotic therapies. Lung fibrosis has been associated with oxidative stress. Here, we hypothesize that pro-fibrotic macrophages have distinct metabolic adaptations aiding their survival under conditions of oxidative stress. <i>In vitro</i> exposure of human primary macrophages to pro-fibrotic (IL4/IL13+TNFα) and pro-reparative (IL4/IL13) cytokine cocktails induced transcriptional phenotypes resembling those found in respective macrophage populations in lungs of patients with idiopathic pulmonary fibrosis (IPF). Multi-omics analysis revealed distinct expression patterns of redox balance-associated regulators involved in ferroptosis, in homeostatic and fibrotic primary human macrophages. Importantly, these metabolic pathways were also observed in fibrotic and reparative macrophages in fibrotic lungs. Inhibitors were used to test the relevance of these metabolic adaptations to cellular survival and ferroptosis sensitivity in pro-fibrotic and pro-reparative macrophages. Pro-fibrotic macrophages exhibited <i>a priori</i> protection from ferroptosis, in contrast to pro-reparative macrophages. Mechanistically, this protection could be linked to the expression of GPX4 and GCH1 pathways, known regulators of ferroptosis protection in cancer cells. We found that pro-fibrotic macrophages adapt metabolically to resist redox stress-related cell death. This reveals new metabolic regulators in pro-fibrotic macrophages offering potential drug targets for managing fibrosis.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-28
preprintOpen access
ABSTRACT Minocycline activity against Acinetobacter baumannii ( AB ) in vivo is underestimated by standard methods of susceptibility testing. We examined pharmacologic effects of minocycline on primary immunity that may be contributing to the in vivo vs. in vitro discrepancy of minocycline activity against AB. Minocycline MICs against 10 AB strains were compared in standard bacteriologic media (Mueller-Hinton broth, MHB) and physiologic (RPMI) media. Macrophages were pretreated with minocycline or comparator antibiotics before AB co-culture. Macrophage cytokine production and phagocytosis of AB were measured without and with pre-treatment with minocycline. Two to eight-fold reduction in minocycline MIC against 10 AB strains occurred in RPMI compared to MHB, which was more pronounced than other antibiotic classes. Macrophages pretreated with 1, 5, 10, 30, 50, and 100 μg/mL minocycline before bacterial co-cultures significantly decreased AB inoculum at 6 hours of co-culture in a dose-dependent manner, with no bacterial colonies observed from co-cultures with macrophages pretreated with 30 μg/mL or more of minocycline. Macrophages pretreated with minocycline for 24 hours before zymosan stimulation led to significantly higher levels of phagocytosis. Macrophages treated with minocycline for 24 hours significantly decreased production of IL-6, TNF-α, and MCP-1 in a dose dependent manner. The minocycline in vivo efficacy may be attributed to enhanced activity in nutrient-limited, physiologic medium combined with increased macrophage phagocyte efficiency. Incorporating novel assays that recapitulate the in vivo environment will be important for understanding the host-pathogen-antibiotic relationship toward a goal of improved future drug discovery and overall treatment strategies against AB and other drug-resistant pathogens.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-12 · 1 citations
preprintOpen accessSenior authorCorresponding
ABSTRACT The metabolism of bacterial pathogens is exquisitely evolved to support growth and survival in the nutrient-limiting host. Many bacterial pathogens utilize bipartite metabolism to support intracellular growth by splitting carbon utilization between two carbon sources and dividing flux to distinct metabolic needs. For example, previous studies suggest that the professional cytosolic pathogen Listeria monocytogenes ( L. monocytogenes ) utilizes glycerol and hexose phosphates (e.g. Glucose-6-Phosphate) as catabolic and anabolic carbon sources in the host cytosol, respectively. However, the role of this putative bipartite glycerol and hexose phosphate metabolism in L. monocytogenes virulence has not been fully assessed. Here, we demonstrate that when L. monocytogenes is unable to consume either glycerol (Δ glpD /Δ golD ), hexose phosphates (Δ uhpT ), or both (Δ glpD /Δ golD /Δ uhpT ), it is still able to grow in the host cytosol and is minimally attenuated in vivo suggesting that L. monocytogenes consumes alternative carbon source(s) in the host. An in vitro metabolic screen using BioLog’s phenotypic microarrays demonstrated that both WT and PrfA* L. monocytogenes, a strain with constitutive virulence gene expression mimicking cytosolic replication, use phosphotransferase system (PTS) mediated carbon sources. These findings contrast with the existing metabolic model that cytosolic L. monocytogenes expressing PrfA does not use PTS mediated carbon sources. We next demonstrate that two independent and universal phosphocarrier proteins (PtsI [EI] and PtsH [HPr]), essential for the function of all PTS, are critical for intracellular growth and virulence in vivo. Finally, virulence phenotypes of these mutants were additive to mutants unable to consume glycerol and hexose phosphates (Δ glpD /Δ golD /Δ uhpT ) in vivo , suggesting that hexose phosphates and glycerol are relevant metabolites in vivo in addition to those derived from PTS. Taken together, these studies indicate that PTS are critical virulence factors for the cytosolic growth and virulence of L. monocytogenes .
expression and blocking IL-1R signaling partially rescued wound healing in the presence of persistent infection. We found a critical window of microbial clearance necessary to limit persistent inflammation and enable efficient wound repair. Taken together, our findings suggest that the dynamics of microbe-induced tissue inflammation impacts repair in complex tissue damage independent of bacterial load, with a critical early window for efficient tissue repair.
