ACE and ACE2: insights from Drosophila and implications for COVID-19

Abstract

Angiotensin-converting enzyme (ACE) and its homologue ACE2 are key regulators of the renin-angiotensin system and thereby cardiovascular function through their zinc-metallopeptidase activity on vasoactive peptides. ACE2 also serves as the receptor for the cellular entry of various coronaviruses including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19). The unprecedented scale of the COVID-19 pandemic has spurred the use of mammalian models to investigate the SARS-ACE2 relationship and knowledge gained from such research has accelerated development of vaccines and therapeutics. Recent studies have just started to underscore the utility of the fruit fly Drosophila melanogaster as a model system to study virus-host interactions and pathogenicity. Notably, the remarkable existence of catalytically functional ACE and ACE2 orthologues in Drosophila, discovered more than two decades ago, provides a unique opportunity for further developing this model organism to better understand COVID-19 in addition to identifying coronavirus preventative and therapeutic interventions targeting ACE2. Here, we review the studies that revealed crucial insights on the biochemistry and physiology of Ance and Acer , two out of the six Drosophila ACE family members with the greatest homology to human ACE and ACE2. We highlight shared in vivo functions outside of the renin-angiotensin system, which is not conserved in flies. Importantly, we identify knowledge gaps that can be filled by further research and outline ways that can raise Drosophila to a powerful model system to combat SARS-CoV-2 and its threatening vaccine-evading variants.

Proof-of-Concept Preclinical Use of Drosophila melanogaster in the Initial Screening of Immunomodulators

“…To improve the animal welfare, replacing the high-order animal model with a loworder animal model is strongly recommended, whenever possible [42]. In this case, the use of fruit fly D. melanogaster has attracted numerous innovations and opened new horizons in the study of human diseases and drug discovery [6,9,10], including in the study of coronavirus disease (COVID-19) [43][44][45]. Invertebrate model organisms, such as the fruit fly, are deemed to feel less pain and distress than the mammalian models, as suggested by the National Centre for the Replacement Refinement & Reduction of Animals in Research (NC3R) [42,46,47].…”

The Drosophila melanogaster ACE2 ortholog genes are differently expressed in obesity/diabetes and aging models: Implications for COVID-19 pathology

“…After the first detection in Wuhan, China, it quickly spread worldwide and was declared a pandemic by the World Health Organization (WHO) [1] , [2] , [3] , [4] , [5] . The entry of the SARS-CoV-2 into the host cell is through its binding to the angiotensin-converting enzyme 2 (ACE2), similar to previous coronavirus SARS-CoV [5] , [6] , [7] , [8] , [9] . ACE2 and its angiotensin-converting enzyme (ACE) homologue perform as a significant component of the renin-angiotensin-aldosterone system (RAAS), a dynamic system in vascular function, blood pressure, and immune response regulation.…”

“…The enzymatic activity of ACE2 is associated with the degradation of Angiotensin II (Ang II) to Angiotensin 1-7 (Ang 1-7), stimulating vasodilation and anti-inflammatory effects and, to a lesser extent, cleaving Angiotensin I (Ang I) to Angiotensin 1-9 (Ang 1-9). Adversely, ACE converts Ang I to Ang II, a potent vasoconstrictor and pro-inflammatory agent [5] , [6] , [7] .…”

“…The fruit fly Drosophila melanogaster is a model organism with wide availability of genetic tools, high similarity of virus pathways compared to vertebrates, and the possibility of therapeutic drug discovery [6] , [14] , [15] . Remarkably, D. melanogaster expresses two catalytic orthologs of ACE and ACE2, the angiotensin-converting enzyme (Ance) and angiotensin-converting enzyme related (Acer) [6] , [16] .…”

“…The fruit fly Drosophila melanogaster is a model organism with wide availability of genetic tools, high similarity of virus pathways compared to vertebrates, and the possibility of therapeutic drug discovery [6] , [14] , [15] . Remarkably, D. melanogaster expresses two catalytic orthologs of ACE and ACE2, the angiotensin-converting enzyme (Ance) and angiotensin-converting enzyme related (Acer) [6] , [16] . For this reason, the fruit fly has been discussed in several reviews as a potential animal model for COVID-19 research [6] , [14] , [17] , although, it has been overlooked in experimental COVID-19 research so far.…”