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New R01 Grant Awarded to Partha Biswas, BVSc, MVSc, PhD

January 21, 2020
University of Pittsburgh Division of Rheumatology and Clinical Immunology associate professor Partha Biswas, BVSc, MVSc, PhD, was awarded a new National Institutes of Health (NIH) R01 grant for his studies on the “Mechanisms of Neutrophil Dysfunction in Antifungal Immunity.”

Disseminated candidiasis is the third most common hospital-acquired fungal infection, and it causes high mortality rates in patients with predisposing factors, including kidney diseases. The lack of approved antifungal vaccines and sensitive early diagnostic tools act as major constraints in preventing death from disseminated candidiasis in these patients. The objective of this project is to understand in detail why patients with kidney disease are more susceptible to death from disseminated candidiasis in comparison to individuals with normal kidney function. The goal of this research is to develop better therapies for effective treatment of disseminated candidiasis in patients with kidney disease.

Grant Abstract

Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy individuals efficiently control C. albicans infection. However, in certain pre-disposing conditions such as immunosuppression, antibiotic therapy, abdominal surgery, the use of invasive medical interventions, or kidney diseases, C. albicans can cause life-threatening disseminated candidiasis (DC). Although hemodialysis is a major cause of bloodstream infection in patients with kidney disease, mortality due to DC is two times higher in patients with kidney impairment than in individuals without renal dysfunction. Thus, kidney disease is a separate and major risk factor for death from DC in these patients, which has largely been overlooked. It is unknown why patients with kidney disease are inept at fighting DC compared to individuals with normal kidney function. Using a clinically relevant mouse model of renal disease, Dr. Biswas and colleagues show that mice with kidney dysfunction are far more susceptible to DC than control animals. Nevertheless, the underlying mechanisms of defect in antifungal immunity in kidney disease are poorly defined. 

Interestingly, Dr. Biswas’s team discovered an unanticipated role for uremia, characterized by the accumulation of uremic toxin(s) in the blood in the absence of kidney function, in causing neutrophil dysfunction in DC. The data imply that uremia induces a defect in reactive oxygen species (ROS) generation by neutrophils, which is essential for the elimination of fungi. In part, Dr. Biswas’s lab has shown that this is due to a defect in glucose transporter1-mediated uptake of glucose by neutrophils, which is required for glycolytic pathways upstream of ROS generation. Dr. Biswas’s hypothesis is that neutrophil-intrinsic impairment in candidacidal function of neutrophils makes uremic patients more susceptible to death from DC. 

The first aim of the new study will employ a series of in vitro and in vivo approaches to define the underlying cellular and molecular mechanisms of defect in glucose uptake and subsequent impairment in ROS production and antifungal activity of neutrophils during uremia. Knowledge gained from these studies will be utilized to identify potential uremic toxin(s) with neutrophil inhibitory activity. The study also will devise novel therapeutic approaches to correct the abnormalities in cell metabolic pathways and neutrophil dysfunction in kidney diseases. The second aim of the study will translate and validate the mouse model findings in patients with kidney disease by collecting biospecimens from pre- and post-hemodialysis patients and compare antifungal activity of neutrophils to healthy subjects. 

The goal of this proposal is to define the mechanisms of defect in antifungal activity of neutrophils in kidney disease and eventually to exploit this information for therapeutic benefit. The long-term objective is to reduce the mortality associated with this devastating nosocomial infection in patients with kidney disease.

More About Dr. Biswas Research

The kidney is often subject to irreversible damage caused by infections and auto-inflammatory conditions. The incidence of end-stage kidney damage is increasing worldwide and represents a major clinical and economic burden and currently there are no effective treatments for this fatal condition. The complex inflammatory cytokine network and renal inflammatory events that drives the progression of kidney injury to irreversible damage is poorly understood. 

The research program in the Biswas laboratory is divided into several areas that are centered on cytokine Interleukin-17 (IL-17) signaling in the kidney. IL-17 is important for host defense against bacterial and fungal infections, but it also is implicated in tissue pathology if it is not regulated. Dr. Biswas’s laboratory takes advantage of multiple in vivo mouse models of acute and chronic kidney diseases and human biospecimens to:

  1. Determine how IL-17 drives irreversible kidney damage, with the ultimate goal of revealing effective therapeutic approaches to block IL-17 signaling in chronic kidney diseases.
  2. Delineate the mechanisms of IL-17-mediated renal immunity against disseminated candidiasis and uropathogenic E. coli infection. The data generated from these studies will inspire the development of effective vaccines against kidney infections caused by fungal and bacterial pathogens.
  3. Define the role of IL-17 signaling in renal fibrosis, the final outcome of acute or chronic kidney diseases leading to kidney dysfunction.
  4. Define the mechanisms of increased mortality in patients with kidney disease due to systemic bacterial and fungal infections.

The  long-term goal of Dr. Biswas’s research is to reduce the morbidity and mortality associated with end-stage renal diseases caused by infections and auto-inflammatory conditions in the kidney.