A Disintegrin and Metalloproteinase-Control Elements in Infectious Diseases

Abstract

Despite recent advances in treatment strategies, infectious diseases are still under the leading causes of death worldwide. Although the activation of the inflammatory cascade is one prerequisite of defense, persistent and exuberant immune response, however, may lead to chronicity of inflammation predisposing to a temporal or permanent tissue damage not only of the site of infection but also among different body organs. The initial response to invading pathogens is mediated by the recognition through various pattern-recognition receptors along with cellular engulfment resulting in a coordinated release of soluble effector molecules and cytokines aiming to terminate the external stimuli. Members of the 'a disintegrin and metalloproteinase' (ADAM) family have the capability to proteolytically cleave transmembrane molecules close to the plasma membrane, a process called ectodomain shedding. In fact, in infectious diseases dysregulation of numerous ADAM substrates such as junction molecules (e.g., E-cadherin, VE-cadherin, JAM-A), adhesion molecules (e.g., ICAM-1, VCAM-1, L-selectin), and chemokines and cytokines (e.g., CXCL16, TNF-α) has been observed. The alpha-cleavage by ADAM proteases represents a rate limiting step for downstream regulated intramembrane proteolysis (RIPing) of several substrates, which influence cellular differentiation, cell signaling pathways and immune modulation. Both the substrates mentioned above and RIPing crucially contribute to a systematic damage in cardiovascular, endocrine, and/or gastrointestinal systems. This review will summarize the current knowledge of ADAM function and the subsequent RIPing in infectious diseases (e.g., pathogen recognition and clearance) and discuss the potential long-term effect on pathophysiological changes such as cardiovascular diseases.

Keywords: SARS – CoV; cardiovascular; infection; metalloproteinase; regulated intramembrane proteolysis.

Figure 1

Exemplary illustration of ADAM function in infection. Pathogens like bacteria and their toxins may enter the body as exemplarily shown for the blood stream (left side) and the respiratory system (right side). The first line of defense for systemically entering pathogens is circulating monocytes and neutrophils and the endothelial barrier. ADAM proteases are involved in phagocytosis through, e.g., cleavage of scavenger receptors like CXCL16 or the cleavage of L-selectin (1), in the activation of the endothelium changing the recruitment of inflammatory cells through cleavage of adhesion and junction molecules like ICAM, VCAM, JAM-A and VE-cadherin (2), resulting in gap formation and disturbance of the barrier integrity (3). Thereby, not only inflammatory cells are able to enter the interstitial space but also pathogens (4). Mucus production and the ciliary movement are the natural barrier for pathogens entering via the airflow, which are influenced by the release of EGFR ligands (5). The epithelium expresses several receptors for pathogens, such as ADAM10 in the case of S. aureus HIa (6) or ACE2 in the case of SARS-CoV2 (7). Cleavage of ACE2 could limit the viral uptake through lack of receptor and the blocking of circulating virus particles. Pore formation and cleavage of junction molecules like E-cadherin (8) result in crossing of the pathogens and infection of the tissue. The infection is may be cleared by resident or newly recruited leukocytes and a beneficial systemic response, e.g., initiated by TNF-alpha release (9). However, systemic spread of the pathogens, e.g., amplified by the cleavage of syndecans and Notch-1, and enhanced release of pro-inflammatory mediators may cause systemic effects like sepsis or cardiovascular failure. These events are not only orchestrated by α-secretase cleavage but further regulated through RIPing processes mediated by γ-secretases (10). Furthermore, systemic effects may be based on changes in cytotoxic T cell expansion or viral release from central memory T cells (11), both involving L-selectin shedding. These are only a few examples of the ADAMs' impact in infection, which may differ in an organ- and site-specific manner. (VE-cadherin, vascular endothelial cadherin; JAM-A, junctional adhesion molecule A; ADAM, a disintegrin and metalloproteinase; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; TNF, tumor necrosis factor; NICD, Notch intracellular domain; NECD, Notch ectodomain; EGFR, epidermal growth factor; ACE2, angiotensin converting enzyme 2).