Pulmonary Dipeptidyl Peptidase‐4 Expression in Lung: Relevance in Experimental Models and for Middle East Respiratory Syndrome Clinical Disease

Abstract

Dipeptidyl peptidase‐4 (DPP4, CD26) is a type II transmembrane exopeptidase and functions as a receptor for Middle East Respiratory Syndrome coronavirus (MERS‐CoV). Respiratory disease is a common presentation in people clinically affected by MERS‐CoV infection and likely contributes in a significant manner to MERS‐CoV morbidity and mortality. Unfortunately, the study of MERS‐CoV related pulmonary pathology is limited because of the lack of autopsy examination and leaves imaging technologies as the main evaluation of lung disease. Because of this constraint, we compared pulmonary distribution of DPP4 in humans to clinical MERS‐CoV disease in experimental animal models and to that reported in humans to evaluate for common features of disease pathogenesis. DPP4 is present in small amounts in airways – but is localized more extensively in cells of the pulmonary acinus in epithelial, immune cell and mesenchymal compartments. This anatomic distribution ostensibly correlates with ground‐glass and edematous changes seen by imaging in MERS‐CoV patients and in lung disease seen some, but not all animal models of MERS‐CoV infection. The putative lesions in humans and animal models with lung disease predominantly consist of diffuse alveolar disease‐like changes with a lack of airway centric disease suggesting that the receptor cellular distribution could be a relevant feature in MERS‐CoV pathogenesis. Furthermore, recent studies that show DPP4 expression levels might be influenced by comorbidities (concurrent lung disease, diabetes, etc.) that are known to predispose to severe disease make its relevance to pathogenesis and possible development of therapeutics even more compelling.