In mammals, adenosine assumes an essential role in regulating innate and acquired immune responses. Strong or excessive host inflammatory responses, e.g. in response to bacterial infection, exacerbate the tissue damage inflicted by invading pathogens. Successful immune clearance of microbes therefore involves the balancing of pro- and anti-inflammatory mediators. The cytokines IL-4, IL-10, IL-13, and TGF-β play a role in restricting excessive inflammation, but only adenosine is able to completely suppress immune responses. The immunoregulatory attributes of adenosine are mediated via four transmembrane adenosine receptors: A1, A2A, A2B, and A3. T lymphocytes express the high affinity A2A receptor as well as the low affinity A2B receptor. Depending on their activation state, macrophages and neutrophils express all four adenosine receptors, whereas B cells harbor only A2A. Engagement of A2A inhibits IL-12 production, increases IL-10 in monocytes and dendritic cells, and decreases cytotoxic attributes and chemokine production in neutrophils. Generation of adenosine at sites of inflammation, hypoxia, organ injury, and traumatic shock is mediated by two sequential enzymes.
Although extracellular adenosine is essential for the suppression of inflammation, build-up of excess adenosine is also detrimental. This is exemplified in patients with a deficiency in adenosine deaminase, an enzyme that converts adenosine to inosine. Adenosine deaminase deficiency causes severe compromised immunodeficiency syndrome, with impaired cellular immunity and severely decreased production of immunoglobulins. As the regulation of extracellular adenosine is critical in maintaining immune homeostasis, perturbation of adenosine levels is likely to affect host immune responses during infection.
Staphylococcus aureus infects hospitalized or healthy individuals and represents the most frequent cause of bacteremia, treatment of which is complicated by the emergence of methicillin-resistant S. aureus. Scientists examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall–anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen Bacillus anthracis, and adenosine synthesis also enabled escape of B. anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.