Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

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ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19

Clinical Science ◽

10.1042/cs20200363 ◽

2020 ◽

Vol 134 (7) ◽

pp. 747-750 ◽

Cited By ~ 20

Author(s):

Rhian M. Touyz ◽

Hongliang Li ◽

Christian Delles

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Basic Science ◽

Physiological Role ◽

Ang Ii ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Multifunctional Protein ◽

Angiotensin Converting Enzyme 2

Abstract Angiotensin converting enzyme 2 (ACE2) is the major enzyme responsible for conversion of Ang II into Ang-(1-7). It also acts as the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, which causes Coronavirus Disease (COVID)-19. In recognition of the importance of ACE2 and to celebrate 20 years since its discovery, the journal will publish a focused issue on the basic science and (patho)physiological role of this multifunctional protein.

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Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2

10.1101/2020.06.29.178459 ◽

2020 ◽

Cited By ~ 8

Author(s):

Huihui Mou ◽

Brian D. Quinlan ◽

Haiyong Peng ◽

Yan Guo ◽

Shoujiao Peng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Viral Receptor ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Binding Domains ◽

Protein Receptor ◽

Horseshoe Bat ◽

Horseshoe Bats

SUMMARYThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat (R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

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Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.732690 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keiji Kuba ◽

Tomokazu Yamaguchi ◽

Josef M. Penninger

Keyword(s):

Angiotensin Converting Enzyme ◽

Neutralizing Antibodies ◽

Cell Entry ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Angiotensin Converting Enzyme 2 ◽

Infected People ◽

Critical Attention ◽

Novel Coronavirus

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

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Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry

10.1101/2020.06.15.151779 ◽

2020 ◽

Cited By ~ 13

Author(s):

Seiya Ozono ◽

Yanzhao Zhang ◽

Hirotaka Ode ◽

Toong Seng Tan ◽

Kazuo Imai ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Causative Agent ◽

Cell Entry ◽

Viral Infectivity ◽

Converting Enzyme ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Naturally Occurring ◽

Spike Proteins

AbstractThe causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.

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Abstract MP62: Sars-cov-2 Spike Protein Regulation Of Angiotensin Converting Enzyme 2 And Tissue Renin-angiotensin Systems: Influence Of Biologic Sex

Hypertension ◽

10.1161/hyp.78.suppl_1.mp62 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Lisa A Cassis ◽

Christopher M Waters ◽

Robin C Shoemaker ◽

Jamie Sturgill ◽

Yasir AlSiraj ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Mrna Abundance ◽

Protein Regulation ◽

Converting Enzyme ◽

Alveolar Cells ◽

Male And Female ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Female Mice

Angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor and an enzyme of the renin-angiotensin system (RAS), is on the X chromosome and stimulated by estrogen. Male sex is a risk factor for SARS-CoV-2 severity. Previous investigators demonstrated that the SARs-CoV-2 Spike (S) protein decreases tissue ACE2 by protein internalization or shedding. This study defined sex differences in tissue ACE2 expression and their impact on SARS-CoV-2 S protein regulation of ACE2 activity and AngII levels. Male and female intact or gonadectomized (GDX) low density lipoprotein receptor deficient ( Ldlr -/- ) mice, and Four Core Genotype (FCG) male (XY or XX) or female (XX or XY) mice were fed a Western diet for 4 months. In lung, ACE2 mRNA abundance was similar in male and female mice and reduced by GDX (Male XY intact: 1.04 ± 0.15; Female XX intact: 1.13 ± 0.13; Male XY GDX: 0.11 ± 0.03; Female XX GDX: 0.18 ± 0.04 ΔΔCt; P<0.05). Lungs from XX mice had higher ACE2 mRNA abundance than XY mice regardless of gonadal sex (P<0.05), and GDX reduced ACE2 mRNA abundance in lungs of XX, but not XY females (XX Female GDX: 0.18 ± 0.04; XY Female GDX: 0.38 ± 0.09; P<0.05). In adipose, XX females had higher ACE2 mRNA abundance than XY males (XX female: 5.4 ± 0.7; XY male: 1.0 ± 0.1; P<0.05), regardless of gonadal sex (XY females: 3.3 ± 0.7; XX males: 1.5 ± 0.3; P<0.05). Male XY and female XX Ldlr -/- mice were administered vehicle or SARS-CoV-2 S protein (2 nmol/kg, ip, 3 doses) with tissue harvest six hours later. In lung, AngII levels were increased by S protein in male, but not female mice (Male, vehicle: 12.3 ± 2.3; Male, S protein: 33.6 ± 7.1; Female, vehicle: 16.1 ± 2.0; Female, S protein: 20.2 ± 1.3 pg/μg protein; P<0.05). In adipose, ACE2 activity was reduced by S protein in male, but not female mice (Male, vehicle: 63.6 ± 13.9; Male, S protein: 26.1 ± 1.9; Female, vehicle: 32.5 ± 1.9; Female, S protein: 25.1 ± 1.3 RFU/hr/mg tissue; P<0.05). SARS-CoV-2 S protein (35 nM) decreased ACE2 activity in type II lung alveolar cells (Vehicle: 2.0 x 10 4 ; S protein: 1.2 x 10 4 RFU/10 6 cells) and 3T3-L1 adipocytes (Vehicle: 2.1 x 10 4 ± 0.3 x 10 4 ; S protein: 1.1 x 10 4 ± 0.8 x 10 3 RFU/10 5 cells; P<0.05). Biologic sex regulation of ACE2 may protect females from SARS-CoV-2 S protein-mediated ACE2 reductions and activation of the local RAS.

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Severe Acute Respiratory Syndrome Coronavirus Infection of Mice Transgenic for the Human Angiotensin-Converting Enzyme 2 Virus Receptor

Journal of Virology ◽

10.1128/jvi.01702-06 ◽

2006 ◽

Vol 81 (3) ◽

pp. 1162-1173 ◽

Cited By ~ 122

Author(s):

Chien-Te K. Tseng ◽

Cheng Huang ◽

Patrick Newman ◽

Nan Wang ◽

Krishna Narayanan ◽

...

Keyword(s):

Weight Loss ◽

Severe Acute Respiratory Syndrome ◽

Transgenic Mice ◽

Angiotensin Converting Enzyme ◽

Virus Replication ◽

Clinical Manifestations ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Angiotensin Converting Enzyme 2 ◽

Coronavirus Infection

ABSTRACT Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg+) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg−) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg+ mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg+ AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice—AC70 in particular—makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.

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