Quantum dots crack the influenza uncoating puzzle

Yamauchi, Yohei

doi:10.1073/pnas.1822089116

Cited by 10 publications

(6 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cell machinery is then hijacked to replicate and assemble new virus particles that eventually exit the cell, primarily through budding. Broadly speaking, this is the same pH-dependent endocytic path followed by the influenza virus (Qin et al, 2019;Yamauchi, 2019), and likely all other coronaviruses (including MERS-CoV). While infections by CoV1 and CoV2 are mediated by the ACE2 receptor, MERS-CoV (MERS) gains entry to cells through DPP4 (Raj et al, 2013).…”

Section: Introductionmentioning

confidence: 85%

Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

Camacho

Paris

Santiago

2020

Preprint

View full text Add to dashboard Cite

Cell surface receptor engagement is a critical aspect of viral infection. This paper compares the dynamics of virus-receptor interactions for SARS-CoV (CoV1) and CoV2. At low (endosomal) pH, the binding free energy landscape of CoV1 and CoV2 interactions with the angiotensinconverting enzyme 2 (ACE2) receptor is almost the same. However, at neutral pH the landscape is different due to the loss of a pH-switch (His445Lys) in the receptor binding domain (RBD) of CoV2 relative to CoV1. Namely, CoV1 stabilizes a transition state above the bound state. In situations where small external strains are applied by, say, shear flow in the respiratory system, the off rate of the viral particle is enhanced. As a result, CoV1 virions are expected to detach from cell surfaces in time scales that are much faster than the time needed for other receptors to reach out and stabilize virus attachment. On the other hand, the loss of this pH-switch, which sequence alignments show is unique to CoV2, eliminates the transition state and allows the virus to stay bound to the ACE2 receptor for time scales compatible with the recruitment of additional ACE2 receptors diffusing in the cell membrane. This has important implications for viral infection and its pathology. CoV1 does not trigger high infectivity in the nasal area because it either rapidly drifts down the respiratory tract or is exhaled. By contrast, this novel mutation in CoV2 should not only retain the infection in the nasal cavity until ACE2-rich cells are sufficiently depleted, but also require fewer particles for infection. This mechanism explains observed longer incubation times, extended period of viral shedding, and higher rate of transmission. These considerations governing viral entry suggest that number of ACE2-rich cells in human nasal mucosa, which should be significantly smaller for children (and females relative to males), should also correlate with onset of viral load that could be a determinant of higher virus susceptibility. Critical implications for the development of new vaccines to combat current and future pandemics that, like SARS-CoV2, export evolutionarily successful strains via higher transmission rates by viral retention in nasal epithelium are also discussed.

show abstract

Section: Introductionmentioning

confidence: 85%

Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

Camacho

Paris

Santiago

2020

Preprint

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 83%

On the molecular mechanism of SARS-CoV-2 retention in the upper respiratory tract

Paris

Santiago

Camacho

2020

Preprint

View full text Add to dashboard Cite

Cell surface receptor engagement is a critical aspect of viral infection. At low pH, binding of SARS-CoV and its ACE2 receptor has a tight interaction that catalyzes the fusion of the spike and endosomal membranes followed by genome release. Largely overlooked has been the role of neutral pH in the respiratory tract, where we find that SARS-CoV stabilizes a transition state that enhances the off-rate from its receptor. An alternative pH-switch is found in CoV-2-like coronaviruses of tropical pangolins, but with a reversed phenotype where the tight interaction with ACE2 is at neutral pH. We show that a single point mutation in pangolin-CoV, unique to CoV-2, that deletes the last His residue in their receptor binding domain perpetuates this tight interaction independent of pH. This tight bond, not present in previous respiratory syndromes, implies that CoV-2 stays bound to the highly expressed ACE2 receptors in the nasal cavity about 100 times longer than CoV. This finding supports the unfamiliar pathology of CoV-2, observed virus retention in upper respiratory tract1, longer incubation times and extended periods of shedding. Implications to combat pandemics that, like SARS-CoV-2, export evolutionarily successful strains via higher transmission rates due to retention in nasal epithelium and their evolutionary origin are discussed.

show abstract

“…Further, by utilizing smFISH probes that carry spectrally distinct fluorophores, more than one RNA species can be imaged simultaneously [27]. In virology, single viral genomes or gene segments can be detected by smFISH leading to new insights into the molecular mechanism of infection, replication and assembly of influenza viruses [28][29][30]. Similar studies have been performed in other viruses, e.g., rotavirus, bunyavirus and human leukaemia virus [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Viral detection and identification in 20 minutes by rapid single-particle fluorescence in-situ hybridization of viral RNA

Hepp

Shiaelis

Robb

et al. 2021

Preprint

View full text Add to dashboard Cite

The increasing risk from viral outbreaks such as the ongoing COVID-19 pandemic exacerbates the need for rapid, affordable and sensitive methods for virus detection, identification and quantification; however, existing methods for detecting virus particles in biological samples usually depend on multistep protocols that take considerable time to yield a result. Here, we introduce a rapid fluorescence in situ hybridization (FISH) protocol capable of detecting influenza virus, avian infectious bronchitis virus and SARS-CoV-2 specifically and quantitatively in approximately 20 minutes, in both virus cultures and combined throat and nasal swabs without previous purification. This fast and facile workflow is applicable to a wide range of enveloped viruses and can be adapted both as a lab technique and a future diagnostic tool.

show abstract

Quantum dots crack the influenza uncoating puzzle

Cited by 10 publications

References 33 publications

Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

On the molecular mechanism of SARS-CoV-2 retention in the upper respiratory tract

Viral detection and identification in 20 minutes by rapid single-particle fluorescence in-situ hybridization of viral RNA

Contact Info

Product

Resources

About