Pre-clinical studies to repurpose FDA-approved adenosine A2A receptor antagonists for lethal rickettsial infection

Rickettsial infections caused by obligately intracellular bacteria of the genus Rickettsia (R) are notoriously difficult to clinically diagnose early because of their nonspecific flu-like signs and symptoms. The delays lead to missed treatment windows that result in severe morbidity and mortality. It is forecasted that global climate change will lead to more widespread distribution of rickettsioses. It is crucial to develop therapeutics for severe infections, particularly for clinically delayed diagnosed cases. We reported cAMP-signaling plays a critical role during fatal rickettsioses. The adenosine receptors are a class of transmembrane receptors that can stimulate intracellular cAMP accumulation. The FDA approved A2AR antagonist istradefylline (Istra) for treatment of Parkinson’s disease in 2019. During project R21AI137785, we examined efficacies of Istra in mouse models of lethal R australis and R conorii infections. We observed that, similar to Doxy, initiating daily treatment with Istra up to 48 hrs post-infection (p.i.) conferred protection against lethality in mice. However, no protection was observed when Istra or Doxy was administered individually when treatments begin at 72 hrs p.i. We found that treatments beginning at 72 hrs p.i. using combinations of Doxy and Istra exhibit protection. Mechanistic studies suggest that the inhibition of A2AR enhances the host's innate immune response, resulting in improved bacterial clearance. Our central hypothesis is that A2AR signaling dampens anti-R immunity, and targeting A2AR with FDA- or FDA- Investigational New Drug (IND)-approved drugs may provide a potential avenue for novel therapeutics against severe R infections. During this multiple-PI project, we will perform a mechanistic study to determine the role of A2AR in R infection.