Many of the Category A, B and C priority pathogens and toxins lead to disease as a result of an excessive host response. Our group at the University of Virginia, in partnership with Adenosine Therapeutics LLC has created a multidisciplinary and collaborative team with expertise in infectious disease, biodefense, immunology, chemistry and pharmacology. Together, we have developed and tested synthetic adenosine receptor agonists as novel immunotherapies that attenuate inflammatory responses and protect a host from different infections that cause disease through immune-mediated injury. Studies suggest that adenosine is a naturally occurring autocoid that limits tissue damage associated with inflammation. The effects of adenosine are controlled by four receptors (A1, A2A, A2B, and A3), which are variably expressed depending on cell lineage and species. Activation of A2AAR on immune cells produces a series of responses that in general can be categorized as anti-inflammatory. Preliminary data suggest that A2AAR maintain a tone of immunological restraint that protects against disease caused by excessive inflammatory responses triggered by several different pathogens. Thus, the general hypothesis is that A2AAR agonists protect the host from the morbidity and mortality of immune-mediated injury triggered by a broad spectrum of Category A, B and C pathogens and toxins. The objective of this proposal is to develop A2AAR agonists as novel biodefense immunotherapies. The first product will be ready for clinical testing within 3 years and second-generation compounds that can be delivered more easily via mucosal (oral or inhaled) routes will be ready for clinical evaluation in 5 years. This will be achieved in the following Specific Aims:
Aim 1. Discovery and development of lead A2AAR agonists.
Aim 2 Evaluation of the efficacy of A2AAR agonists as an immunotherapy.
Aim 3. Define the mechanisms that can be used as correlates of protection in humans.
Aim 4. Translation of A2AAR agonist function from animal models to applications in humans. These studies extend preliminary data showing A2AAR agonists complement conventional treatments to augment protection against agents relevant to biodefense. The proposal describes a systematic approach to develop, synthesize and test A2AAR agonists in relevant animal models as well as human cells in vitro. This work will build on past basic research to support new applied research and advanced product development for use in future clinical trials. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (M2))
Program Officer
Sawyer, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Das, Soumita; Sarkar, Arup; Choudhury, Sarmistha Sinha et al. (2015) ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome. Cell Mol Gastroenterol Hepatol 1:311-324
Das, Soumita; Sarkar, Arup; Ryan, Kieran A et al. (2014) Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells. FASEB J 28:2214-24
Kurtz, Courtney C; Drygiannakis, Ioannis; Naganuma, Makoto et al. (2014) Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells. Am J Physiol Gastrointest Liver Physiol 307:G338-46
Warren, Cirle Alcantara; Calabrese, Gina M; Li, Yuesheng et al. (2012) Effects of adenosine AýýýA receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice. BMC Infect Dis 12:13
Luo, Yingqin; Kong, Qingke; Yang, Jiseon et al. (2012) Comparative genome analysis of the high pathogenicity Salmonella Typhimurium strain UK-1. PLoS One 7:e40645
Wilson, Jeffrey M; Kurtz, Courtney C; Black, Steven G et al. (2011) The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6. J Immunol 186:6746-52
Drygiannakis, Ioannis; Ernst, Peter B; Lowe, David et al. (2011) Immunological alterations mediated by adenosine during host-microbial interactions. Immunol Res 50:69-77
Das, Soumita; Owen, Katherine A; Ly, Kim T et al. (2011) Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. Proc Natl Acad Sci U S A 108:2136-41
Luo, Yingqin; Kong, Qingke; Yang, Jiseon et al. (2011) Complete genome sequence of the universal killer Salmonella enterica Serovar Typhimurium UK-1 (ATCC 68169). J Bacteriol 193:4035-6
Ernst, Peter B; Garrison, James C; Thompson, Linda F (2010) Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 185:1993-8

Showing the most recent 10 out of 14 publications