Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

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Crystal Structure of Enteric Adenovirus Serotype 41 Short Fiber Head

Journal of Virology ◽

10.1128/jvi.79.22.14088-14094.2005 ◽

2005 ◽

Vol 79 (22) ◽

pp. 14088-14094 ◽

Cited By ~ 18

Author(s):

Elena Seiradake ◽

Stephen Cusack

Keyword(s):

Crystal Structure ◽

High Resolution ◽

Intestinal Tract ◽

Human Adenovirus ◽

Short Fiber ◽

Adenovirus Serotype ◽

Enteric Adenovirus ◽

Coxsackievirus And Adenovirus Receptor ◽

Adenovirus Receptor ◽

Enteric Adenoviruses

ABSTRACT Human enteric adenoviruses of species F contain two fibers in the same virion, a long fiber which binds to coxsackievirus and adenovirus receptor (CAR) and a short fiber of unknown function. We have determined the high-resolution crystal structure of the short fiber head of human adenovirus serotype 41 (Ad41). The short fiber head has the characteristic fold of other known fiber heads but has three unusual features. First, it has much shorter loops between the beta-strands. Second, one of the usually well-ordered beta-strands on the distal face of the fiber head is highly disordered and this same region is sensitive to digestion with pepsin, an enzyme occurring naturally in the intestinal tract, the physiological environment of Ad41. Third, the AB loop has a deletion giving it a distinct conformation incompatible with CAR binding.

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Adenovirus Type 11 Uses CD46 as a Cellular Receptor

Journal of Virology ◽

10.1128/jvi.77.17.9183-9191.2003 ◽

2003 ◽

Vol 77 (17) ◽

pp. 9183-9191 ◽

Cited By ~ 259

Author(s):

Anna Segerman ◽

John P. Atkinson ◽

Marko Marttila ◽

Veronica Dennerquist ◽

Göran Wadell ◽

...

Keyword(s):

Cho Cells ◽

Chinese Hamster ◽

Human Adenovirus ◽

Adenovirus Type ◽

Host Cells ◽

Cellular Receptor ◽

Transfected Cells ◽

Coxsackie Adenovirus Receptor ◽

Adenovirus Receptor

ABSTRACT The 51 human adenovirus serotypes are divided into six species (A to F). Many adenoviruses use the coxsackie-adenovirus receptor (CAR) for attachment to host cells in vitro. Species B adenoviruses do not compete with CAR-binding serotypes for binding to host cells, and it has been suggested that species B adenoviruses use a receptor other than CAR. Species B adenoviruses mainly cause disease in the respiratory tract, the eyes, and in the urinary tract. Here we demonstrate that adenovirus type 11 (Ad11; of species B) binds to Chinese hamster ovary (CHO) cells transfected with CD46 (membrane cofactor protein)-cDNA at least 10 times more strongly than to CHO cells transfected with cDNAs encoding CAR or CD55 (decay accelerating factor). Nonpermissive CHO cells were rendered permissive to Ad11 infection upon transfection with CD46-cDNA. Soluble Ad11 fiber knob but not Ad7 or Ad5 knob inhibited binding of Ad11 virions to CD46-transfected cells, and anti-CD46 antibodies inhibited both binding of and infection by Ad11. From these results we conclude that CD46 is a cellular receptor for Ad11.

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Carbohydrate-Binding Agents: Potential of Repurposing for COVID-19 Therapy

Current Protein and Peptide Science ◽

10.2174/1389203721666200918153717 ◽

2020 ◽

Vol 21 (11) ◽

pp. 1085-1096 ◽

Cited By ~ 2

Author(s):

Rajesh Kumar Gupta ◽

Girish R. Apte ◽

Kiran Bharat Lokhande ◽

Satyendra Mishra ◽

Jayanta K. Pal

Keyword(s):

Vaccine Development ◽

Host Cells ◽

Carbohydrate Binding ◽

Atypical Pneumonia ◽

The Novel ◽

High Infection ◽

Binding Agents ◽

Current Scenario ◽

Antiviral Activities ◽

Novel Drug

: With the emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the whole world is suffering from atypical pneumonia, which resulted in more than 559,047 deaths worldwide. In this time of crisis and urgency, the only hope comes from new candidate vaccines and potential antivirals. However, formulating new vaccines and synthesizing new antivirals are a laborious task. Therefore, considering the high infection rate and mortality due to COVID-19, utilization of previous information, and repurposing of existing drugs against valid viral targets have emerged as a novel drug discovery approach in this challenging time. The transmembrane spike (S) glycoprotein of coronaviruses (CoVs), which facilitates the virus’s entry into the host cells, exists in a homotrimeric form and is covered with N-linked glycans. S glycoprotein is known as the main target of antibodies having neutralizing potency and is also considered as an attractive target for therapeutic or vaccine development. Similarly, targeting of N-linked glycans of S glycoprotein envelope of CoV via carbohydrate-binding agents (CBAs) could serve as an attractive therapeutic approach for developing novel antivirals. CBAs from natural sources like lectins from plants, marine algae and prokaryotes and lectin mimics like Pradimicin-A (PRM-A) have shown antiviral activities against CoV and other enveloped viruses. However, the potential use of CBAs specifically lectins was limited due to unfavorable responses like immunogenicity, mitogenicity, hemagglutination, inflammatory activity, cellular toxicity, etc. Here, we reviewed the current scenario of CBAs as antivirals against CoVs, presented strategies to improve the efficacy of CBAs against CoVs; and studied the molecular interactions between CBAs (lectins and PRM-A) with Man9 by molecular docking for potential repurposing against CoVs in general, and SARSCoV- 2, in particular.

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SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

10.2196/preprints.21599 ◽

2020 ◽

Author(s):

Laura Lafon-Hughes

Keyword(s):

Viral Infection ◽

Viral Entry ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Whooping Cough ◽

Common Knowledge ◽

Herd Immunity ◽

Life Quality ◽

Host Cells ◽

System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

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Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

International Journal of Molecular Sciences ◽

10.3390/ijms22041617 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1617

Author(s):

Jimin Xu ◽

Judith Berastegui-Cabrera ◽

Marta Carretero-Ledesma ◽

Haiying Chen ◽

Yu Xue ◽

...

Keyword(s):

Potent Inhibitor ◽

Antiviral Drug ◽

Human Adenovirus ◽

Yield Reduction ◽

Respiratory Illnesses ◽

Molecule Inhibitor ◽

Wide Range ◽

Ic50 Values ◽

Life Threatening ◽

Salicylamide Derivatives

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

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Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

Molecules ◽

10.3390/molecules26082157 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2157

Author(s):

Norbert Odolczyk ◽

Ewa Marzec ◽

Maria Winiewska-Szajewska ◽

Jarosław Poznański ◽

Piotr Zielenkiewicz

Keyword(s):

Drug Development ◽

Protein Interactions ◽

Rna Virus ◽

Antiviral Drug ◽

Host Protein ◽

Host Cells ◽

Cell Surface Receptor ◽

Short Peptides ◽

Virus Protein ◽

Positive Strand Rna

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases reported to the beginning of December 2020, including over 1.5 million deaths. Unfortunately, currently, there is no specific and effective treatment for COVID-19. As SARS-CoV-2 relies on its spike proteins (S) to bind to a host cell-surface receptor angiotensin-converting enzyme-2(ACE2), and this interaction is proved to be responsible for entering a virus into host cells, it makes an ideal target for antiviral drug development. In this work, we design three very short peptides based on the ACE2 sequence/structure fragments, which may effectively bind to the receptor-binding domain (RBD) of S protein and may, in turn, disrupt the important virus-host protein–protein interactions, blocking early steps of SARS-CoV-2 infection. Two of our peptides bind to virus protein with affinity in nanomolar range, and as very short peptides have great potential for drug development.

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The Listeria monocytogenes hemolysin has an acidic pH optimum to compartmentalize activity and prevent damage to infected host cells

The Journal of Cell Biology ◽

10.1083/jcb.200201081 ◽

2002 ◽

Vol 156 (6) ◽

pp. 1029-1038 ◽

Cited By ~ 190

Author(s):

Ian J. Glomski ◽

Margaret M. Gedde ◽

Albert W. Tsang ◽

Joel A. Swanson ◽

Daniel A. Portnoy

Keyword(s):

Listeria Monocytogenes ◽

Bacterial Pathogen ◽

Cytolytic Activity ◽

Host Cells ◽

Adaptive Mutation ◽

Acidic Ph ◽

Listeriolysin O ◽

Lysosomal Hydrolases ◽

Ph Optimum ◽

Neutral Ph

Listeria monocytogenes is a facultative intracellular bacterial pathogen that escapes from a phagosome and grows in the host cell cytosol. The pore-forming cholesterol-dependent cytolysin, listeriolysin O (LLO), mediates bacterial escape from vesicles and is ∼10-fold more active at an acidic than neutral pH. By swapping dissimilar residues from a pH-insensitive orthologue, perfringolysin O (PFO), we identified leucine 461 as unique to pathogenic Listeria and responsible for the acidic pH optimum of LLO. Conversion of leucine 461 to the threonine present in PFO increased the hemolytic activity of LLO almost 10-fold at a neutral pH. L. monocytogenes synthesizing LLO L461T, expressed from its endogenous site on the bacterial chromosome, resulted in a 100-fold virulence defect in the mouse listeriosis model. These bacteria escaped from acidic phagosomes and initially grew normally in cells and spread cell to cell, but prematurely permeabilized the host membrane and killed the cell. These data show that the acidic pH optimum of LLO results from an adaptive mutation that acts to limit cytolytic activity to acidic vesicles and prevent damage in the host cytosol, a strategy also used by host cells to compartmentalize lysosomal hydrolases.

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Abstract 110: The Separation of Serum Amyloid A from HDL is Mediated by Heparan Sulfate Through Histidine Dependent Interactions: HDL Function is Enhanced but Amyloid-Fibrils may be the “Price to Pay”¼

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.110 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

John B Ancsin ◽

Kim Munro ◽

Shui-Pang Tam ◽

Michael H Davidson

Keyword(s):

Heparan Sulfate ◽

Serum Amyloid A ◽

Amyloid Fibrils ◽

3D Structure ◽

Serum Amyloid ◽

Acidic Ph ◽

Heparin Binding ◽

Additional Time ◽

Amyloid A ◽

Hdl Function

Serum amyloid A (SAA) is an acute-phase protein that circulates bound to high density lipoprotein (HDL) and can influence HDL function as part of a poorly understood defense re-sponse to tissue trauma or infection. We have previously demonstrated that under mildly acidic pH the glycosaminoglycans, heparan sulfate (HS) and heparin can interact with HDL-SAA and cause SAA to dissociate from HDL. This remodeling improves HDL functionality but also predisposes SAA to form AA-amyloid fibrils. In this study we explore some potential pathophysiological conditions in vitro that could influence this HS/HDL-SAA remodeling process and the fate of SAA in vivo. SAA’s binding affinity for heparin was found to be enhanced by acidic pH and low concentrations of urea. The heparin dependent remodeling of HDL-SAA was promoted by the partial denaturation of HDL-SAA. Moreover, HDL-SAA remodeling was observed to follow a strict SAA:heparin stoichiometry and could be partially inhibited with a short heparin oligosaccharide of 8-sugar units. Evidence is also presented that once dissociated from HDL, SAA requires additional time to organize into Triton x-100 resistant amyloid-like structures. Circular dichroism spectroscopic analysis and in silico modeling of SAA’s ionizable residues highlights the importance of the histidine-36 within a highly conserved, pH-sensitive HS-binding site (HSBS-pH). A peptide containing the HSBS-pH sequence was demonstrated to have AA-amyloid seeding activity in a cell culture system. The recent determination of the 3D structure for human SAA1.1 has allowed the opportunity to re-assess and validate the HS/heparin binding sequences that had previously been identified biochemically with short synthetic peptides. We postulate that the dissociation of SAA from HDL takes place during the retro-endocytosis of HDL-SAA and is an important aspect of SAA function not previously appreciated.

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The endosomal epsilon-coatomer protein is involved in human adenovirus type 5 internalisation

Acta Veterinaria Hungarica ◽

10.1556/avet.50.2002.4.10 ◽

2002 ◽

Vol 50 (4) ◽

pp. 481-489 ◽

Cited By ~ 1

Author(s):

Cs. Jeney ◽

Boglárka Banizs ◽

Orsolya Dobay ◽

Keyword(s):

Chinese Hamster ◽

Human Adenovirus ◽

Adenovirus Type ◽

Inhibitory Effect ◽

Bafilomycin A1 ◽

Cho Cell ◽

Coxsackie Adenovirus Receptor ◽

Downstream Effector ◽

Adenovirus Receptor ◽

Adenovirus Type 5

The effects of bafilomycin A1 and of the reduced level of endosomal epsilon-COP (coatomer protein) on the infectivity of human adenovirus type 5 were investigated in Coxsackie adenovirus receptor- (CAR-) transfected Chinese hamster ovary (CHO) cells. The endosomal proton pump inhibitor bafilomycin A1 was able to cause only partial inhibition. Using ldlF cells (an epsilon-COP thermosensitive mutant CHO cell line) the reduction of epsilon-COP level also had partial inhibitory effect. Based on these results and comparing them to existing models of the adenovirus entry, we propose a refined model in which there are two pathways of adenoviral entry: the first one involves the epsilon-COP as the downstream effector of the acidification and can be blocked by bafilomycin A1 and the second one is a pH-independent pathway.

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