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Identifying Pathophysiological Bases of Disease in COVID-19 Carla J

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Identifying Pathophysiological Bases of Disease in COVID-19 Carla J Goldin et al. Translational Medicine Communications (2020) 5:15 Translational Medicine https://doi.org/10.1186/s41231-020-00067-w Communications REVIEW Open Access Identifying pathophysiological bases of disease in COVID-19 Carla J. Goldin1,2, Ramiro Vázquez3,4, Fernando P. Polack1 and Damian Alvarez-Paggi1,2* Abstract COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that can affect lung physiology encompassing a wide spectrum of severities, ranging from asymptomatic and mild symptoms to severe and fatal cases; the latter including massive neutrophil infiltration, stroke and multiple organ failure. Despite many recents findings, a clear mechanistic description underlying symptomatology is lacking. In this article, we thoroughly review the available data involving risk factors, age, gender, comorbidities, symptoms of disease, cellular and molecular mechanisms and the details behind host/pathogen interaction that hints at the existence of different pathophysiological mechanisms of disease. There is clear evidence that, by targeting the angiotensin-converting enzyme II (ACE2) –its natural receptor–, SARS-CoV-2 would mainly affect the renin- angiotensin-aldosterone system (RAAS), whose imbalance triggers diverse symptomatology-associated pathological processes. Downstream actors of the RAAS cascade are identified, and their interaction with risk factors and comorbidities are presented, rationalizing why a specific subgroup of individuals that present already lower ACE2 levels is particularly more susceptible to severe forms of disease. Finally, the notion of endotype discovery in the context of COVID-19 is introduced. We hypothesize that COVID-19, and its associated spectrum of severities, is an umbrella term covering different pathophysiological mechanisms (endotypes). This approach should dramatically accelerate our understanding and treatment of disease(s), enabling further discovery of pathophysiological mechanisms and leading to the identification of specific groups of patients that may benefit from personalized treatments. Keywords: SARS-CoV-2, COVID-19, Pathophysiology, RAAS, Risk factors, Comorbidities, Endotypes Introduction belonging to the betacoronavirus genus. While the usual The recently described SARS-CoV-2 virus is the latest HCoV are normally associated with common cold symp- addition into the group of pathogenic human corona- toms, these last pathogens may elicit infections that range viruses (HCoV). The Coronavirinae subfamily encom- from asymptomatic carrier to severe pneumonia, leading passes four different genera: alpha, beta, gamma and to acute respiratory distress syndrome (ARDS). A com- deltacoronavirus. The genetic and serologic groups alfa- mon feature of SARS-CoV and SARS-CoV-2 is that viral and betacoronavirus includes pathogens that mainly infect attachment occurs via interaction of the viral spike (S) mammals (except pigs) [1]. The normally circulating 229E protein —which is primed by the Transmembrane Serine and NL63 are alphacoronaviruses whereas OC43 and Protease 2 (TMPRSS2)— to the host angiotensin- HKU1 are betacoronaviruses. During the last twenty years, converting enzyme 2 (ACE2), allowing viral entry [2, 3]. three additional HCoVs from zoonotic origin have sur- Interestingly, this feature is shared with the NL63 HCoV, faced: SARS-CoV, MERS-CoV and SARS-CoV-2,all while the other HCoVs employ different receptors such as dipeptidyl peptidase 4 and aminopeptidase N [4]. The S/ * Correspondence: [email protected] ACE2 interaction gives place to a cross-talk point between 1INFANT Foundation, Buenos Aires, Argentina 2CONICET, Buenos Aires, Argentina viral infection and the renin-angiotensin-aldosterone Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Goldin et al. Translational Medicine Communications (2020) 5:15 Page 2 of 12 system (RAAS), and there is mounting evidence that this HEXXH zinc-binding metalloprotease domain [20–22]. interplay may crucially affect disease severity (see below). ACE2 is a member of the RAAS, that involves a var- SARS-CoV-2 causes COVID-19, a disease that pre- iety of hormones and enzymatic reactions whose pri- sents a wide range of clinical manifestations, from mary role consists of regulating the homeostasis of asymptomatic to severe ARDS and may result fatal due the cardiovascular and renal systems [23, 24], playing to respiratory insufficiency, stroke, thrombotic complica- also a critical function in inflammatory response [25]. tions [5] and, finally, multi organic failure [6]. Although This system consists of two main axes: the classic an accurate mechanistic description is lacking, it is pro- angiotensin-converting enzyme (ACE)-angiotensin II- posed that an uncontrolled and excessive release of pro- AT1 receptor, and the ACE2-angiotensin-(1–7)-Mas inflammatory cytokines (called “cytokine storm”) may receptor axis, that was discovered rather recently cause some of the symptoms, including shock and tissue (Fig. 1). damage, and massive neutrophil infiltration [7]. Current Both ACE and ACE2 are found in the cytoplasmic consensus is that older people, immunocompromised or membrane of arterial and venous endothelial cells, and patients with significant underlying conditions and co- arterial smooth muscle cells [26, 27]. ACE2 is expressed morbidities such as diabetes and hypertension are more in several organs such as the heart, kidney, lung and tes- likely to experience severe COVID-19 symptoms [8]. tes, among others [17, 19]. In particular, it is present in Assessment of the mechanisms underlying SARS- human nasal epithelium, alveolar and small intestinal CoV-2-induced disease and severity has focused mainly cells [28]. ACE and ACE2 have been largely studied as on the immunopathological features [7, 9, 10], and have pivotal members of the RAAS. As shown in Fig. 1, they resulted in some unexpected findings: the unusual sero- play antagonistic roles by processing the renin-cleaved conversion processes involving IgM and IgG titers decapeptide angiotensin both competitively or in an al- among infected patients [11], the age-dependent cyto- ternate fashion. The main role of ACE2 is countering kine storm-induced reduction and functional exhaustion ACE activity by reducing angiotensin 2 (AngII) —a po- of CD4+ and CD8+ T cells —both critical to eliminate tent vasopressor and sodium-and-water retaining octa- virus-infected cells and for achieving successful recovery peptide— bioavailability and increasing angiotensin-(1– [12]—, and the possible link between severity and gen- 7) (Ang-(1–7)) formation —a vasodilator and diuretic etic variations in chemokine receptors and blood group peptide—, although alternative catalytic pathways exist loci [13], among others. These findings clearly hint at [29–31]. In this context, an imbalance in ACE2/Ang-(1– the existence of distinct pathophysiological bases of dis- 7) and ACE/AngII axes may be critical in the develop- ease in COVID-19. In addition, other actors have been ment of cardiovascular diseases [32]. Activation of the identified or proposed, such as endocrine and metabolic ACE-mediated classic axis leads to deleterious effects: pathways [14] and the role of infected endothelial cells vasoconstriction, fibrosis, migration, fluid retention, [15] in disease severity. However, a comprehensive and thrombosis and inflammation; on the other hand, the cohesive evaluation of these factors is lacking. In the fol- ACE2-centered via exerts protective vasodilation, and an- lowing sections, we present a detailed review attempting tithrombotic, antiarrhythmic and anti-inflammatory ac- to identify molecular bases of disease severity based on tions [33, 34]. the specifics of host/pathogen interplay, with an em- phasis on the endocrine-immune interactions involved. S induces downregulation of ACE2 after complex Finally, we speculate that COVID-19 is actually an um- formation brella term that includes several pathophysiological The extracellular domain of ACE2 can be cleaved from mechanisms, known as endotypes, originated in the the transmembrane domain by at least two different en- individual-specific host/pathogen interactions, which zymes, ADAM metallopeptidase domain 17(ADAM17) simultaneously depend on the functional status of the and TMPRSS2, and the resulting soluble protein is re- RAAS. leased into the bloodstream and ultimately excreted into urine [3, 35]. TMPRSS2 is a type II transmembrane The entry point of SARS-CoV-2: ACE2 and TMPRSS2 serine protease expressed in the airway epithelial cells ACE2 is a central component of the RAAS and several tissues. It participates not only in SARS- The coronaviruses SARS-CoV, SARS-CoV-2 and NL63-
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