Immune cell recruitment to the site of infection is an integral part of an effective immune response to both bacterial and viral pathogens. However excessive immune cell infiltration and production of pro-inflammatory cytokines in the lung can result in increased lung pathology and disease severity. We recently discovered a novel and previously unrecognised mechanism of immune cell recruitment to the infected lung, which can be targeted pharmacologically to improve respiratory infection outcomes.
We showed that infection with M. tuberculosis (Mtb), influenza A virus (IAV) and SARS-CoV-2 leads to production of the oxidised cholesterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol in the lung through upregulation of the oxysterol-producing enzymes CH25H and CYP7B1. 7α,25-dihydroxycholesterol is the endogenous high affinity ligand for the oxysterol-sensing receptor GPR183, which is expressed on cells of the innate and adaptive immune system. We demonstrated in a preclinical model of Mtb infection that both CYP7B1 and GPR183 are required for rapid macrophage infiltration into the lung. Mice genetically deficient in GPR183 (Gpr183-/-) and mice that were unable to upregulate CYP7B1 upon infection had delayed macrophage infiltration and higher mycobacterial burden during early infection.
Similarly, in Gpr183-/- mice infected with either IAV or a mouse-adapted SARS-CoV-2 the infiltration of macrophages was delayed compared to control animals. However, this was associated with a significant reduction in inflammatory cytokines and beneficial infection outcomes. Therefore, we next administered a GPR183 antagonist to C57BL/6J mice 24 hours after SARS-CoV-2 infection and found that the antagonist significantly reduced macrophage infiltration without affecting other immune cell subsets. Further, the antagonist attenuated the severity of SARS-CoV-2 infection and reduced viral loads.
Finally, analysis of single cell RNASeq data from bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed that CH25H, CYP7B1 and GPR183 are significantly upregulated in human macrophages during COVID-19.
Together this study demonstrates that oxysterols drive macrophage infiltration and inflammation in the lung via GPR183. We provide the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe COVID-19.