scholarly journals Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

2021 ◽  
Author(s):  
Sarah M Roelle ◽  
Nidhi Shukla ◽  
Anh T Pham ◽  
Anna M Bruchez ◽  
Kenneth A Matreyek
Keyword(s):  
Receptor Binding ◽  
Mitigation Strategies ◽  
Receptor Protein ◽  
Pseudotyped Virus ◽  
Mixed Cell ◽  
Binding Domains ◽  
Horseshoe Bat ◽  
Clade 1 ◽  
The Right ◽  
Spike Proteins

Viral spillover from animal reservoirs can trigger public health crises and cripple the world economy. Knowing which viruses are primed for zoonotic transmission can focus surveillance efforts and mitigation strategies for future pandemics. Successful engagement of receptor protein orthologs is necessary during cross-species transmission. The clade 1 sarbecoviruses including SARS-CoV and SARS-CoV-2 enter cells via engagement of ACE2, while the receptor for clade 2 and clade 3 remains largely uncharacterized. We developed a mixed cell pseudotyped virus infection assay to determine whether various clade 2 and 3 sarbecovirus spike proteins can enter HEK 293T cells expressing human or Rhinolophus horseshoe bat ACE2 proteins. The receptor binding domains from BtKY72 and Khosta-2 used human ACE2 for entry, while BtKY72 and Khosta-1 exhibited widespread use of diverse rhinolophid ACE2s. A lysine at ACE2 position 31 appeared to be a major determinant of the inability of these RBDs to use a certain ACE2 sequence. The ACE2 protein from R. alcyone engaged all known clade 3 and clade 1 receptor binding domains. We observed little use of Rhinolophus ACE2 orthologs by the clade 2 viruses, supporting the likely use of a separate, unknown receptor. Our results suggest that clade 3 sarbecoviruses from Africa and Europe use Rhinolophus ACE2 for entry, and their spike proteins appear primed to contribute to zoonosis under the right conditions.

scholarly journals Class II Contact-Dependent growth Inhibition (CDI) systems allow for broad-range cross-species toxin delivery

2019 ◽  
Author(s):  
Petra Virtanen ◽  
Marcus Wäneskog ◽  
Sanna Koskiniemi
Keyword(s):  
Growth Inhibition ◽  
Receptor Binding ◽  
Class Ii ◽  
Receptor Protein ◽  
Bacterial Populations ◽  
Cognate Receptor ◽  
Binding Domains ◽  
Dependent Growth ◽  
Species Specific ◽  
Contact Dependent Growth Inhibition

AbstractContact-dependent growth inhibition (CDI) allows bacteria to recognize kin cells in mixed bacterial populations. In Escherichia coli, CDI mediated effector delivery has been shown to be species-specific, with a preference for the own strain over others. This specificity is achieved through an interaction between a receptor-binding domain in the CdiA protein and its cognate receptor protein on the target cell. But how conserved this specificity is has not previously been investigated in detail. Here we show that three different class II CdiA receptor-binding domains and their Enterobacter cloacae analog are highly promiscuous, allowing for efficient effector delivery into several different Enterobacteriaceae species, including Escherichia, Enterobacter, Klebsiella and Salmonella spp. In addition, although we observe a preference for some receptors over others, this did not limit cross-species effector delivery, suggesting that class II CdiA proteins can allow for broad-range and cross-species growth inhibition in mixed bacterial populations.

scholarly journals SARS-CoV-2 Prion-Like Domains in Spike Proteins Enables Higher Affinity to ACE2

2020 ◽  
Author(s):  
George Tetz ◽  
Victor Tetz
Keyword(s):  
Receptor Binding ◽  
Cell Receptor ◽  
Binding Domain ◽  
Spike Protein ◽  
Striking Difference ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Functional Roles ◽  
Binding Domains ◽  
Spike Proteins

Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion-like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of spike proteins is particularly interesting, since although SARS-CoV-2 and SARS-CoV S share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interacts with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interacts with RBD have important functional roles in viral adhesion and entry.

scholarly journals Distinct Roles for Sialoside and Protein Receptors in Coronavirus Infection

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Enya Qing ◽  
Michael Hantak ◽  
Stanley Perlman ◽  
Tom Gallagher
Keyword(s):  
Cell Membrane ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Sialic Acids ◽  
Zoonotic Transmission ◽  
Virus Spread ◽  
Binding Domains ◽  
Protein Receptors ◽  
Cell Cell ◽  
Spike Proteins

ABSTRACT Coronaviruses (CoVs) are common human and animal pathogens that can transmit zoonotically and cause severe respiratory disease syndromes. CoV infection requires spike proteins, which bind viruses to host cell receptors and catalyze virus-cell membrane fusion. Several CoV strains have spike proteins with two receptor-binding domains, an S1A that engages host sialic acids and an S1B that recognizes host transmembrane proteins. As this bivalent binding may enable broad zoonotic CoV infection, we aimed to identify roles for each receptor in distinct infection stages. Focusing on two betacoronaviruses, murine JHM-CoV and human Middle East respiratory syndrome coronavirus (MERS-CoV), we found that virus particle binding to cells was mediated by sialic acids; however, the transmembrane protein receptors were required for a subsequent virus infection. These results favored a two-step process in which viruses first adhere to sialic acids and then require subsequent engagement with protein receptors during infectious cell entry. However, sialic acids sufficiently facilitated the later stages of virus spread through cell-cell membrane fusion, without requiring protein receptors. This virus spread in the absence of the prototype protein receptors was increased by adaptive S1A mutations. Overall, these findings reveal roles for sialic acids in virus-cell binding, viral spike protein-directed cell-cell fusion, and resultant spread of CoV infections. IMPORTANCE CoVs can transmit from animals to humans to cause serious disease. This zoonotic transmission uses spike proteins, which bind CoVs to cells with two receptor-binding domains. Here, we identified the roles for the two binding processes in the CoV infection process. Binding to sialic acids promoted infection and also supported the intercellular expansion of CoV infections through syncytial development. Adaptive mutations in the sialic acid-binding spike domains increased the intercellular expansion process. These findings raise the possibility that the lectin-like properties of many CoVs contribute to facile zoonotic transmission and intercellular spread within infected organisms.

scholarly journals Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

Science ◽  
2021 ◽  
Vol 371 (6531) ◽  
pp. 823-829 ◽  
Author(s):  
C. Garrett Rappazzo ◽  
Longping V. Tse ◽  
Chengzi I. Kaku ◽  
Daniel Wrapp ◽  
Mrunal Sakharkar ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Human Monoclonal Antibody ◽  
Binding Activity ◽  
Lung Pathology ◽  
Receptor Binding Site ◽  
Binding Domains ◽  
Large Panel ◽  
Clade 1 ◽  
Conserved Epitope ◽  
Strong Binding Activity

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

scholarly journals Meningitis as a recurrent manifestation of anti-AQP4/anti-MOG negative neuromyelitis optica spectrum disorder: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chenyang Zhang ◽  
Kang Zhang ◽  
Bing Chen ◽  
Jiao Yin ◽  
Miaomiao Dong ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
Area Postrema ◽  
Neurological Diseases ◽  
Brain Magnetic Resonance Imaging ◽  
Transverse Myelitis ◽  
Corticosteroid Treatment ◽  
Neck Stiffness ◽  
Mixed Cell ◽  
Glucose Levels ◽  
The Right

Abstract Background Neuromyelitis optica spectrum disorders (NMOSD), a group of autoimmune neurological diseases, involve the optic nerve, spinal cord, and brain. Meningitis is rarely reported as the primary clinical manifestation of both anti-aquaporin-4 (AQP4)/ anti-myelin oligodendrocyte glycoprotein (MOG) antibody-negative NMOSD (NMOSDneg). Case presentation A 30-year-old man initially presented with fever, headache, and neck stiffness. Lumbar puncture revealed mixed cell reaction and decreased glucose levels. As a result, tuberculous meningitis was suspected. After 1 month, the patient developed longitudinally extensive transverse myelitis and area postrema syndrome. This was followed by the presentation of meningitis-like symptoms once again in the third attack, but his condition eventually improved after corticosteroid treatment without relapse for 2 years. However, he was readmitted to our hospital owing to symptoms of diplopia, hiccup, and numbness in the right hand. Brain magnetic resonance imaging (MRI) revealed that the area postrema still contained lesions. Spinal MRI revealed several segmental enhancements at the C4–C5, T1, and T5 levels. Anti-AQP4 and anti-MOG antibodies were persistently absent in the serum and cerebrospinal fluid (CSF). The patient was finally diagnosed with NMOSDneg. Conclusions Meningitis could be a recurrent manifestation of NMOSDneg and requires more careful evaluation.

scholarly journals Use of influenza C virus glycoprotein HEF for generation of vesicular stomatitis virus pseudotypes

2005 ◽  
Vol 86 (5) ◽  
pp. 1455-1465 ◽  
Author(s):  
Andrea Hanika ◽  
Birthe Larisch ◽  
Eike Steinmann ◽  
Christel Schwegmann-Weßels ◽  
Georg Herrler ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Receptor Binding ◽  
Viral Vectors ◽  
Basolateral Membrane ◽  
Apical Plasma Membrane ◽  
Pseudotyped Virus ◽  
Proteolytic Activation ◽  
Multifunctional Protein ◽  
Influenza C Virus ◽  
Vesicular Stomatitis

Influenza C virus contains two envelope glycoproteins: CM2, a putative ion channel protein; and HEF, a unique multifunctional protein that performs receptor-binding, receptor-destroying and fusion activities. Here, it is demonstrated that expression of HEF is sufficient to pseudotype replication-incompetent vesicular stomatitis virus (VSV) that lacks the VSV glycoprotein (G) gene. The pseudotyped virus showed characteristic features of influenza C virus with respect to proteolytic activation, receptor usage and cell tropism. Chimeric glycoproteins composed of HEF ectodomain and VSV-G C-terminal domains were efficiently incorporated into VSV particles and showed receptor-binding and receptor-destroying activities but, unlike authentic HEF, did not mediate efficient infection, probably because of impaired fusion activity. HEF-pseudotyped VSV efficiently infected polarized Madin–Darby canine kidney cells via the apical plasma membrane, whereas entry of VSV-G-complemented virus was restricted to the basolateral membrane. These findings suggest that pseudotyping of viral vectors with HEF might be useful for efficient apical gene transfer into polarized epithelial cells and for targeting cells that express 9-O-acetylated sialic acids.

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