[R21] Recovering CD8 T cell memory during chronic infection by JAK-inhibitors

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2028-04-30

Importo max: 234.750 EUR

Paese: US

Descrizione

Vaccines are the most successful prophylactic measure against pathogens, and their protective capacity depends on the formation of long-lived immunological memory, e.g. memory T lymphocytes (TMEM). Coordination between B and T lymphocytes is required against intracellular pathogens to neutralize pathogens and eradicate infected cells, respectively, as recently highlighted with COVID19 vaccine responses. Individuals living with chronic infections were shown to exhibit inferior responses to subsequent infections and vaccination. Studies in animal models suggested the cause to be the inferior recall responses by the TMEM generated to acute stimuli in hosts with preexisting chronic infection (hereafter termed inflm-TMEM). However, epigenetic imprints of persistent inflammation on inflm-TMEM have not been examined, and interventions to restore efficient protective recall responses by inflm-TMEM are understudied. Previous studies and our preliminary data demonstrated arrested development of inflm-TMEM, especially the central memory subset (TCM). Previous transcriptional profiling and our chromatin-accessibility profiling revealed skewed transcriptional and epigenetic landscapes of antigen-specific inflm-TMEM compared to bona fide TMEM, with enrichment of signatures associated with inflammatory mediators including type I interferon (IFN-I) and interleukin-6 (IL-6), which signal downstream janus kinase 1/2 (JAK1/2). We hypothesize that JAK1/2 inhibition would recover normal TMEM differentiation in hosts with preexisting chronic infection. To investigate this, we will use the same mouse model utilized for our preliminary studies to examine the differentiation of antigen-specific T cells responding to acute infection in the presence of preexisting chronic infection with or without JAK1/2 inhibition (JAKi) treatment. We will dissect the profiles of inflm-TMEM using high- dimensional flowcytometry and combined scRNAseq/scATACseq (MultiOme) profiling. More importantly, we will investigate the functional impact of JAKi-treatment on enhanced pathogen clearance and protection upon rechallenge. Our team has expertise in immunology, mouse models, and MultiOme profiling tools. This puts us in a unique position to address our main objectives which are: (1) to examine the capacity of FDA-approved interventions (JAKi) to recover generation of efficient TMEM in hosts with preexisting chronic infection, and (2) to gain insights into the molecular mechanisms underlying the skewed differentiation of inflm-TMEM., and aspects recovered by JAKi treatment. These studies push the envelope of innovation where we will employ combined state-of-the-art high-dimension flowcytometry, functional assays, and MultiOme profiling, to decipher specific mechanisms associated with lower recall capacity of inflm-TMEM that is understudied to date. We will validate novel therapeutic approaches using FDA-approved medication(s) for enhancing TMEM formation in hosts with preexisting chronic infec Istituzione: EMORY UNIVERSITY PI: Mohamed Abdel Hakeem Progetto: 1R21AI194202-01A1

Settori: National Institute of Allergy and Infectious Diseases

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.