Current Research Projects
1 Skin host defense and inflammation
Serezani lab members and others have shown that people and mice with diabetes and/or obesity are more susceptible to skin infections caused by different pathogens.
We have previously identified that an exaggerated inflammatory response in the skin leads to aberrant neutrophil migration and accumulation of macrophages, leading to larger wounds and increased bacterial loads. However, the drivers of exaggerated inflammatory response in the infected skin remain to be determined. Our preliminary data show an accumulation of apoptotic and necrotic cells in the infected skin of diabetic mice.
We are interested in understanding:
- The consequences of the accumulation of necrotic cells in the infected skin
- Whether the mechanism of clearance of dead cells is altered and whether modulating the abundance and actions of effector molecules involved in recognition and ingestion of dead cells could restore homeostasis, improve wound healing, and bolster host defense in models of metabolic dysfunction and infection.
This project is led by Ana Salina, PhD.
Efferocytosis assay
Cyclic AMP is a second messenger produced after gas-coupled receptor activation. The Serezani lab and others have shown that increased cAMP impairs macrophage and neutrophil antimicrobial effector function.
Using imaging mass spectrometry, we have previously shown that both obesity and hyperglycemia lead to increased cAMP in the skin, in areas near the abscess, which could be mechanisms of poor host defense observed in these animal models.
Using a variety of cAMP reporter mice and cell lines, CRISPR-Cas9 screening, and pharmacological approaches, we aim to dissect how changes in cAMP drive phagocyte host defense in diabetic conditions.
We are interested in:
- Identifying the ligands and receptors responsible for increased cAMP in the infected skin
- The role of downstream effectors PKA and Epac in skin host defense
- Whether different cAMP regulators that are FDA-approved drugs, such as PDE4 inhibitors, misoprostol (a prostaglandin analog), Treprostinil (prostacyclin analog) among others improves skin host defense during euglycemic and hyperglycemic conditions.
This is an open project.
Intravital imaging in the skin of cAMP reporter mice infected s.c. with S. aureus.
White = SGH
Yellow/Orange = cAMP production in phagocytes
Red = MRSA
Fungi, such as Candida albicans and Aspergillus fumigatus, are major causes of skin infections in both obese and diabetic conditions. The mechanisms underlying poor skin host defense during fungal infections are poorly understood.
We are interested in understanding:
- The role of skin resident vs. monocyte-derived macrophages during fungal infections
- The events that lead to poor phagocytosis and fungal ingestion during hyperglycemia
- Whether high glucose influences the activation of beta-glucan and mannan receptors
This project is led by graduate student Dante Reyna.
Even though recurrent infection is very debilitating, the cellular and molecular events that lead to infections in these individuals remain to be fully understood. Among the major limitations is the lack of animal models that mimic the human responses to recurrent infections. Here, we aim to perform a longitudinal collection of purulent abscesses of people infected with different pathogens, followed by single-cell RNAseq, metabolomics, and lipidomics to investigate prevalent alterations in these patients.
The ultimate goals are to:
- Understand the immunometabolic milieu in the infected skin of the patients
- Generate animal models that could help understand recurrent infections.
This is an open project.
In vivo efferocytosis in the infected skin of diabetic and nondiabetic mice
2 Sepsis and organ damage in euglycemic and hyperglycemic conditions
People and mice with diabetes are more prone to sepsis. In human patients, the inflammatory response is exaggerated, leading to more severe organ damage and mortality. We have previously shown that increased mortality in septic diabetic mice is due to excessive lipid mediator leukotriene B4 (LTB4) production and the Myeloid differentiation primary response 88 (MyD88).
The Serezani lab is currently interested in investigating the organ-specific transcriptional and epigenetic landscape in phagocytes from infected diabetic and nondiabetic mice. We are also testing if the same programs are present in PBMC from people with sepsis and metabolic dysfunction.
We aim to understand how metabolic changes influence the abundance of metabolites required for epigenetic enzyme activation and the aberrant inflammatory response observed in septic and diabetic mice and people.
PTEN is a protein and lipid phosphatase that inhibits tumor growth by controlling cell proliferation and metabolism. The role of PTEN in inflammatory responses and host defense is not well understood.
Serezani lab members and others have shown that PTEN deletion enhances macrophage antimicrobial effector functions. Furthermore, we have demonstrated that PTEN protects mice from sepsis by inhibiting MyD88 expression. We are currently investigating how PTEN regulates the intensity of the inflammatory response and protects from organ injury.
We are exploring:
- If PTEN enhances F-actin-dependent pathogen ingestion and phagosomal maturation in macrophages and
- The role of PTEN in the intersection between immunometabolism and epigenetics that controls exaggerated inflammatory responses and kidney injury during sepsis. Interestingly, using PBMCs from individuals with PTEN haploinsufficiency, we aim to understand how PTEN deficiency affects human cells.
To answer these questions, we are employing live microscopy, CRISPR screening (to modulate metabolic and epigenetic programs), and CUT&RUN/ATAC-seq analysis in different models of sepsis.
This project is led by graduate student Eden Faneuff.
PTEN expression in macrophages in the kidney of septic mice
SOCS1 is a classical inhibitor of the JAK/STAT pathway. SOCS1 has three different domains that are responsible for various functions:
- The kinase inhibitory region (KIR) is known to inhibit JAK1/2 activation
- The SOCS box domain that interacts with several ubiquitinating machinery enzymes exhibits ubiquitin-like activity and promotes protein degradation, and
- An SH2 (ESS) domain that interacts with GTPases, Ankyrin repeats, and SSB proteins.
The specific role of each domain in macrophage function remains to be determined. Besides the canonical role of SOCS1 in JAK/STAT1 signaling, we have shown that SOCS1 also influences macrophage function within minutes, such as increased macrophage antimicrobial effects. We also showed that SOCS1 deletion increases glycolysis by increasing the hypoxia-inducible factor (HIF) actions. We are investigating whether SOCS1 influences F-actin polymerization (leading to increased phagocytosis) and its consequences on mitochondrial function and host defense.