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by Christina Crowe

Dario Vitturi, Ph.D., Assistant Professor, Molecular and Cellular Pathology, has received grant funding to support his project “Kynurenine-dependent redox signaling at the interface between innate and adaptive immunity.” The five year, $2.82 million R01 is funded by the National Institute of Allergy and Infectious Diseases (NIAID).

 Dario 1

Upon recognizing the presence of bacterial or viral components, our cells activate potent inflammatory responses with the objective of removing the pathogenic threat. However, our immune system must precisely orchestrate these actions in order to minimize collateral tissue injury and develop a targeted response that will enable faster threat clearance upon pathogen re-exposure. Immune and non-immune cells use a variety of mechanisms to attain this delicate balance, with the upregulation of tryptophan metabolism via the kynurenine pathway recently coming into focus as an important immunosuppressive strategy.

The kynurenine pathway consumes more than 95 percent of all tryptophan, an essential amino acid that humans obtain through diet. In a paper published by Vitturi and collaborators in Science Advances in 2022, the team showed that kynurenine gives rise to the formation of kynurenine-carboxyketoalkene (Kyn-CKA), a new molecule that has ability to inhibit pro-inflammatory signaling and activate cyto-protective mechanisms. According to Vitturi, “the up-regulation of kynurenine synthesis and its metabolism to Kyn-CKA is an adaptive response that attenuates inflammation and protects tissues.”

This grant aims to define the formation and metabolism of Kyn-CKA in myeloid-lineage leukocytes. It also takes aim at elucidating the effects of Kyn-CKA on myeloid cell activation and T-cell polarization by defining the effects of Kyn-CKA metabolic and transcriptional programs involved in myeloid antigen-presenting cell activation and T-cell differentiation. A third aim of the work involves determining the impact of Kyn-CKA on endotoxin resistance and tolerance in vivo.

“We’re trying to uncover new mechanisms for the regulation of the immune response, particularly at the critical juncture between innate and adaptive responses,” Vitturi says.

Vitturi simplifies innate immunity as, “an immediate response to the presence of molecular patterns that are conserved among pathogens” whereas the adaptive response is, “subsequently developed to neutralize specific human pathogens and prevent future re-infections.”

In particular, Vitturi’s research focuses on the ability of Kyn-CKA to modify reactive cysteine residues in proteins that are involved in the regulation of the immune response.

“By chemically modifying these sites in proteins, Kyn‑CKA can simultaneously modulate different gene expression programs to promote coordinated immune cell responses and protect tissues from injury,” he says.

By elucidating the mechanisms the regulate Kyn-CKA formation and target engagement, Vitturi expects to uncover novel pharmacological strategies to treat dysregulated immune responses in the context of sepsis, autoimmunity, organ transplantation and cancer.

This is Vitturi’s first R01 grant. Originally from Montevideo, Uruguay, Vitturi obtained his Ph.D. at the University of Alabama at Birmingham under the direction of Rakesh Patel, Ph.D., Vice Chair of Research and Director of the Molecular and Cellular Pathology Division. Upon completion of his graduate studies, Vitturi joined the Department of Pharmacology and Chemical Biology at the University of Pittsburgh, first as a postdoctoral associate, and then as a faculty member. In August 2022 he returned to UAB as an assistant professor in the division where he completed graduate studies.