A1 Adenosine Receptor Signaling Reduces Streptococcus pneumoniae Adherence to Pulmonary Epithelial Cells by Targeting Expression of Platelet-Activating Factor Receptor

Abstract

Extracellular adenosine production is crucial for host resistance against Streptococcus pneumoniae (pneumococcus) and is thought to primarily affect antibacterial immune responses by neutrophils. However, whether extracellular adenosine alters direct host-pathogen interaction remains unexplored. An important determinant for lung infection by S. pneumoniae is its ability to adhere to the pulmonary epithelium. Here we explored whether extracellular adenosine can directly impact bacterial adherence to lung epithelial cells. We found that treatment of cultured human pulmonary epithelial cells with adenosine significantly reduced the ability of pneumococci to bind to these cells. Extracellular adenosine reduced S. pneumoniae adherence by acting on the host. Inhibition of adenosine receptor signaling using a pan antagonist blocked adenosine’s ability to inhibit bacterial binding while treatment with a pan adenosine receptor agonist mimicked the effects of adenosine. Using specific receptor agonists, we found that signaling through the A1 adenosine receptor mediated the reduction in bacterial binding to pulmonary epithelial cells. A1 receptor signaling inhibited bacterial binding by reducing the expression of platelet-activating factor receptor, a host protein used by S. pneumoniae to adhere to host cells. In vivo, A1 was expressed in the lungs and was required for control of pneumococcal pneumonia as inhibiting it resulted in an increase in bacterial numbers and reduced host survival in mice. As S. pneumoniae remain a leading cause of community-acquired pneumonia in the elderly, we explored the role of A1 in the age-driven susceptibility to infection. We found no difference in A1 pulmonary expression in young versus old mice. Strikingly, triggering A1 signaling boosted the ability of old mice to control S. pneumoniae pulmonary infection. A1 agonist-treated old mice displayed lower bacterial loads, reduced clinical signs of disease and prolonged survival. This study demonstrates a novel mechanism by which extracellular adenosine modulates resistance to lung infection by targeting bacterial-host interactions. Author Summary Streptococcus pneumoniae (pneumococcus) can cause life-threatening invasive infections, such as pneumonia, bacteremia and meningitis worldwide, particularly in the elderly. Understanding the pathways governing bacterial-host interactions can help us design therapies to better fight infection. Extracellular adenosine, a signaling molecule produced by the host, is crucial for resistance against pneumococcal pneumonia. Extracellular adenosine is thought to control the host immune responses, however, whether it affects host-pathogen interaction remains unexplored. Here we found that extracellular adenosine signaling directly affects pneumococcal-epithelial cell interactions. The ability of S. pneumoniae to adhere to epithelial cells is important for establishing lung infection. Extracellular adenosine signaling through A1, one of its receptors expressed in the lungs, inhibited the ability of S. pneumoniae to adhere to lung epithelial cells. Extracellular adenosine acted by reducing the expression of a host protein used by S. pneumoniae to adhere to epithelial cells. Importantly, A1 signaling was crucial for controlling lung infection by S. pneumoniae in young mice and could be targeted to boost the ability of old mice to fight lung infection. This study may have future implications for using clinically available adenosine-based therapies to boost the resistance of vulnerable hosts like the elderly to pneumococcal pneumonia.