Air filtering respirators such as N95 masks can filtrate contaminants, bacteria and other matters from reaching nose and mouth. The research found avian flu virus passing through the N95 mask, but its transmission did not necessarily imply direct infection because many other factors involved Wiwanitkit, It is possible that a single virus particle can be transmitted from person to person Wiwanitkit, The most predominant filtration mechanisms for a high efficiency fibrous filter in capturing particles are interception, inertial impaction and diffusion TSI Incorporated, Interception occurs if a particle is captured by a fibre when it is in the vicinity.
Inertial impaction effects are observed typically on some large particles when they are captured by fibres due to particle inertia in the direction from their original paths. Diffusion mechanism is mainly identified for small particles in Brownian motion with diameters below 0. These small particles tend to move randomly and collide with each other frequently TSI Incorporated, Based on these mechanisms, particles near 0.
Hence the filtration capacity of 0. With different filtration capacities, the air filtering respirators can prevent airborne transmission in a wide size range of droplets, especially in the indoor areas with a high population density, poor ventilation and hence a greater chance of virus exposure. Research has also been recently carried out on the common materials for making masks.
Rengasamy et al. Konda et al. Wang et al. Zhao et al. They are considerably effective and economic in minimizing the chance of infection especially when the medical masks are not readily available to the majority of people. Mask effectiveness has been demonstrated in prevention of influenza and some other infectious diseases. Van der Sande et al.
Some observational results confirmed that frequently using masks in a community can prevent spread of infection from sick and infectious people Jensen et al. Sung et al. Masks and hand hygiene may reduce respiratory diseases in shared living environments and mitigate the impact of pandemic influenza A H1N1 Aiello et al. Wearing masks can also reduce the risk of avian influenza infection Wiwanitkit, Some studies explored the impact of mask use during influenza by establishing a population transmission model from an epidemiological perspective.
The results showed possibility of delaying the pandemic by wearing masks nationwide Brienen et al. Chan et al. The study focused on the effect of placing masks between cages. They then acquired the clinical score, viral load, histopathology and expression of viral nucleocapsid antigen. It is essential to wear masks correctly in order to effectively prevent epidemic diseases.
Surgical masks and respirators like N95 s are designed for only single use, because they work by trapping harmful particles inside the mesh of fibres of which they are made National Academies of Sciences, Reuse of the disposable filtering respirators may be needed during times of shortage to ensure continued availability, though there has been no any approved method for decontamination. The level of decontamination is determined by cumulative UV Hearn et al.
Vaporized hydrogen peroxide H 2 O 2 can remove infectious pathogens without affecting mask's function, fit or physical appearance. No H 2 O 2 has been tested after 3 h Cheng et al. Sodium hypochlorite, ethanol and isopropyl alcohol are not recommended Cheng et al. Moist heat incubation MHI , also called pasteurization, is using low temperature to disinfect masks in a humidity environment.
Disinfection may be able to extend the using time of respirators but if the shape or fabric structure change, this respirator should not be used again. Furthermore, once the mask is wet, soiled, damaged or difficult to breathe during wearing, it should be removed and discarded. If need to touch or adjust their masks, hand hygiene must be immediately followed Szarpak et al.
Cotton masks, which can be reused by washing, also need to be careful, since the virus may survive on the mask surfaces. Improper reuse of disposable cloth masks may increase the risk of infection Centers for Disease Control, There is a potential risk of airborne transmission in an indoor environment with poor ventilation.
The distance of droplet transmission can extend up to 4 m. Based on this data, the recommended social distancing range of 1—2 m CDC, ; WHO, may not necessarily guarantee the epidemic prevention. Therefore, wearing mask in public is essential as its effectiveness has already been well established by the current studies. For exhalation isolation, both surgical and N95 masks are shown to be effective in reducing the spread of respiratory diseases, but the former is more accessible and comfortable to wear compared to the latter.
For inhalation protection, air filtering respirators such as N95 masks can filtrate contaminants, bacteria and other matters from reaching nose and mouth, and are more efficient in virus penetration inhibition than surgical masks. Three major filtration mechanisms are identified, namely, interception, inertial impaction and diffusion.
While interception takes place for nearby particles, inertial impaction is mainly dominated by some large particles. Diffusion mechanism primarily applies to small particles with diameters around 0.
A mask design needs to consider all these mechanisms in order to increase the filtration capacity for all particle sizes. In this regard, inhalation protection via masks is particularly important in order to reduce the transmission of viruses that are potentially carried by droplets and aerosols.
National Center for Biotechnology Information , U. Med Devices Sens. Author information Article notes Copyright and License information Disclaimer. Donglu Shi, Email: ude. Corresponding author. Email: ude. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
This article has been cited by other articles in PMC. Open in a separate window. Differences of droplet and droplet nuclei transmission a without and b with mask. Protective mechanism of a mask when in close contact with a patient. Author, year Materials Method Results Dato et al. Significantly higher aerosol penetration level than N95 respirator. Jung et al. Ma et al. Cases studies on protection effective of masks Mask effectiveness has been demonstrated in prevention of influenza and some other infectious diseases.
Disinfection and of Filtering Facepiece Respirators. Journal of Infectious Diseases , , — Aerosol Science and Technology , 54 , — Airborne or droplet precautions for health workers treating coronavirus disease ? JAMA , , — American Journal of Infection Control , 34 , 51— Influenza Other Respi Viruses , 14 , — Journal of Engineered Fibers and Fabrics , 5 , Environmental Research , , Violent expiratory events: On coughing and sneezing.
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Buy article Get time limited or full article access on ReadCube. References 1. Article Google Scholar 2. Article Google Scholar 6. Ethics declarations Competing interests The author declares no competing interests. Rights and permissions Reprints and Permissions. The mechanism of penetration of non-enveloped viruses remains poorly understood, although they are relatively small and simple in structure Fusion of the more complex enveloped viruses is better understood owing to the similarities between enveloped viruses and cells — both are surrounded by membranes and their fusion does not necessarily require a significant reorganization of the viral nucleoprotein complex.
By contrast, either the whole non-enveloped virus must cross the membrane, or it must undergo important conformational changes and transfer the genome through the membrane. In the latter case, the energy of the metastable state must be used not only to destabilize the cell membrane, but also to reorganize the nucleoprotein complex so that the genome can be released through the destabilized membrane either through pores or other structures.
Although the structures of several key intermediates in the conformational changes of viral entry proteins have now been solved to atomic resolution, it is clear that there is a great deal left to learn owing to the difficulties that are associated with studying the rapid conformational changes of only a few molecules of each virion against a background of large numbers of surface molecules on the virion that undergo no structural changes.
Viral proteins can destabilize not only plasma and endosomal membranes during entry, but can also destabilize other membranes inside cells to which the protein is in close proximity if there is a suitable trigger, such as a receptor, low pH or low calcium concentration.
For example, such conditions arise during transportation of viral proteins after synthesis in the host cell in acidic Golgi vesicles. It seems that viruses have developed strategies to cope with this problem. For example, the G protein of rhabdoviruses, such as rabies and VSV, can exist in native, activated and inactive conformations. It was proposed that the inactive state helps to avoid membrane fusion during the transport of the G protein However, the HIV-1 Env can induce cell lysis after interaction with receptors — probably through disruption of important intracellular membranes — so methods to cope with destabilization of cell functions are not universal The significance of membrane fusion effects in human pathogenesis is unclear.
Perhaps viruses that are well adapted to their hosts do not induce significant pathogenic effects that could lead to a reduction of virus production. Cell fusion — perhaps mediated by Envs — by endogenous retroviruses could contribute to cancer Entry is an attractive target for inhibition because the entry machinery is extracellular and it is therefore easier for drug molecules to reach than intracellular targets.
Any step s of the entry process can be targeted by an entry inhibitor. Various types of molecules, such as proteins, peptides, carbohydrates, small organic molecules, nucleic acids and supramolecular structures, including liposomes and phage, have been found to inhibit entry.
Yet, out of more than 30 antiviral drugs 76 , there are only two entry inhibitors — Synagis 77 and T Ref. Only T which is marketed as enfuvirtide is used for the treatment of ongoing viral HIV-1 infection. The humanized monoclonal antibody Synagis which is also known as palivizumab is used for the prevention of RSV infections in neonates and immunocompromised individuals. T is not a small molecule — regarded as the 'gold standard' for a drug — but is a peptide that cannot be taken orally.
A small organic molecule entry inhibitor pleconaril showed promising results for the treatment of infections caused by the picornaviruses that cause the common cold 80 , but was not approved by the FDA owing to concerns about potential interactions with other drugs — although different formulations are presently being evaluated for use in life-threatening disease.
At present, a number of compounds are in clinical trials, including small organic molecules that bind to the HIV-1 co-receptor CCR5, and entry inhibitors are also being tested for efficacy as microbicides. Challenges in the development of virus entry inhibitors. Major problems in the development of effective entry inhibitors include the generation of virus mutants that are resistant to such drugs, a low potency in vivo and toxic side effects.
Although these problems are common to the development of other antiviral and cancer drugs and limit their efficacy, the development of entry inhibitors might also face specific challenges.
Viruses have evolved to recognize cellular receptors and enter cells despite the presence of the host immune system. Antibodies that exhibit inhibitory effects on virus entry must bind viruses that have already developed a number of strategies for immune evasion, including the use of immunodominant variable loops and incomplete complementary binding surfaces, oligomeric occlusion, glycosylation 81 , conformational masking 82 and multivalent interactions. Some problems that are inherent to the design of any inhibitor are especially challenging for those targeted to virus entry, such as the inhibition of high-affinity protein—protein interactions by small molecules.
Another strategy used by viruses to counteract the action of antibodies and other entry inhibitors is the direct cell-to-cell transmission of viruses, which avoids or reduces the exposure of the virus to inhibitors that are not designed to penetrate through membranes or other barriers. This could be one important reason for the low efficacy that is observed in vivo of otherwise potent in vitro inhibitors.
Low inhibitor potency combined with a high virus mutation rate is perhaps the most challenging problem in the development of entry inhibitors. Although the rapid progress in our understanding of the structural mechanisms of virus entry promises new approaches that could 'outsmart' the virus, no entry inhibitors or treatment protocols in clinical use have so far been developed on the basis of predictions made by structural models, and the main source of new inhibitors is still from screening large libraries of small organic molecules, natural products, peptides and antibodies.
However, structures of entry proteins have been invaluable for the development of our understanding of the mechanisms of inhibition and should allow further improvement of the inhibitors. It seems likely that sooner or later structure-based design will yield entry inhibitors that will be in clinical use. Conserved entry intermediates as targets for inhibitors; multivalent inhibitors and other approaches.
One direction of research that could hasten the arrival of entry inhibitors to the clinics is the development of compounds that interact with conserved intermediates of the entry process or with the protein structures that, on binding to receptors, trigger the conformational changes that lead to the formation of these entry intermediates.
Typically, such intermediates are only transiently exposed, so viruses might not have evolved strategies to avoid inhibitors targeted to these structures.
In addition, conserved intermediates are usually important for virus entry and presumably cannot easily be substituted by other structures after mutation. An example of the successful design of an entry inhibitor that shows proof of the concept is the 5-Helix protein, which interferes with a conserved intermediate in the entry of HIV-1 Ref.
A related example is a class of peptides that could have broad applications to several viruses containing class I fusion proteins. The peptides are derived from regions of fusion proteins heptad repeats that have a propensity to form coiled-coils and which serve as fusion intermediates and enable oligomerization of proteins.
T also known as DP is derived from the carboxy-terminal heptad region of the HIV-1 gp41 and showed potent inhibitory activity in vivo Bossart and C. Broder, personal communication , perhaps owing to the endocytic entry route of these viruses. Although peptides have certain promising features, including a relatively small size that might ensure good penetration combined with high binding affinity, the lack of oral formulations, short half-life, possible toxicity and immunogenicity might limit their application.
Recently, a small molecule, BMS, was identified that inhibits the entry of a broad range of HIV-1 isolates by a mechanism which was attributed to competition with the CD4 receptor for binding to gp Ref. So, at inhibitory concentrations, BMS does not interfere with CD4 binding, indicating a different inhibitory mechanism.
By analogy with inhibitors of picornavirus entry, such as pleconaril, BMS might inhibit the entry of HIV-1 by binding to conserved structures that are important for the conformational changes which gp must undergo for viral entry Potent virus-specific inhibitors of the viral-membrane-merging step have not been identified yet. Another promising direction is the development of multivalent inhibitors that can overcome problems caused by mutation of viral proteins to escape inhibition because multivalent inhibitors bind to several regions of the same or different protein s on the viral surface.
One example of a multivalent inhibitor is the multimeric soluble receptors of influenza and HIV-1 Ref. The use of entry inhibitors in combination or as fusion proteins could also result in increased efficiency. Finally, improvement of current methods for structure-based design by accounting for protein flexibility and dynamics in binding to ligands 85 , and screening methods for inhibitors 86 , 87 would certainly expand the range of possible inhibitors that can be tested.
Neutralizing antibodies and vaccine immunogen design. Neutralizing antibodies usually inhibit virus entry by preventing attachment of the virus to the cell or by binding to entry intermediates 88 , 89 , Human immunoglobulin composed of concentrated antibodies collected from pooled human plasma has been successfully used as a preventative treatment for virus infections, including rabies, hepatitis A and B, measles, mumps, varicella, cytomegalovirus and arenaviruses.
Antibodies can completely prevent infection, but once infection is established they are a much less efficient treatment. The only monoclonal antibody in clinical use today to treat a viral disease — Synagis MEDI — is more potent than the polyclonal immunoglobulin that is presently in use, and is broadly active against numerous RSV type A and B clinical isolates It binds to the F protein of RSV with high affinity 3 nM and inhibits virus entry and cell fusion in vitro with an IC 50 of approximately 0.
It seems that the efficacy of Synagis in vivo is correlated with the high affinity of binding and potency of this antibody in vitro The X-ray crystal structures of rhinovirus 21 and poliovirus 22 indicate a possible mechanism by which picornaviruses can avoid neutralization by antibodies through the mutation of non-conserved amino acid residues surrounding the receptor-binding site — a 2 nm deep and 2 nm wide canyon Fig. It was initially hypothesized that the conserved amino acid residues of the canyon are not accessible by antibodies; however, it was later shown that a strongly neutralizing antibody, Fab17, can penetrate deep within the receptor-binding canyon by undergoing a large conformational change without inducing conformational changes in the virus 90 , Unusually, not only the hypervariable residues but also residues from the framework region of Fab17 contact the canyon.
Yet another remarkable mechanism of immune recognition of viruses is the recently discovered receptor mimicry by post-translational modification tyrosine sulphation of antibodies Ref. It seems that any accessible viral surface can be recognized by antibodies. Rapidly mutating viruses can escape neutralizing antibodies even if they bind to structures that are essential for virus replication, such as receptor-binding sites, unless they bind with energetically identical profiles Whether a virus will escape neutralization by antibodies depends on the interplay between the antibody affinity avidity and kinetics of binding, generation rate, concentration and the viral mutation rate and fitness.
Mutations of immunodominant structural loops that form antibody-binding sites and mutations leading to changes in oligosaccharide attachment to viral entry proteins are common mechanisms by which viruses avoid neutralization 90 , Mutations of conserved residues that have a role in the entry mechanism typically result in reduction or loss of infectivity. Antibodies or their derivatives that bind to epitopes where residues contribute most of the binding energy could have potential as entry inhibitors.
Epitopes that are exposed after virus binding to receptors are typically well conserved — for example, the 17b 39 and X5 Ref. One potential problem with using antibodies as entry inhibitors in this case could be limited access to the post-receptor-binding state of the viral entry protein due to the relatively large size of the whole antibody.
Solving this, and other problems, could lead to the development of potent broadly neutralizing antibodies which could limit the generation of resistant viruses, especially if these inhibitors are used in combination with other antibodies or inhibitory molecules.
Many viruses, especially RNA viruses such as HIV-1, exist as swarms of virions inside an infected individual, and might significantly differ in sequence between isolates. So, elicitation of potent, broadly neutralizing antibodies is an important goal for vaccine development.
However, elicitation of these antibodies in vivo has not been successful. Identification of broadly neutralizing antibodies and the characterization of their epitopes could help to design vaccine immunogens that would be able to elicit these neutralizing antibodies in vivo — so-called retrovaccinology At present, all vaccines that elicit antibodies against entry proteins have been developed empirically using an antigen, rather than by designing an immunogen on the basis of the antibodies produced.
The important advantages of human antibodies as therapeutics are low or negligible toxicity combined with high potency and a long half-life. However, drawbacks include the generation of neutralization-resistant virus mutants, limited access of the large antibody molecules to the site of virus replication, lack of oral formulations and the high cost of production and storage.
Viruses are usually associated with disease. However, some viruses can be beneficial. The HERV-W Env, known as syncytin, is fusogenic and has a role in human trophoblast cell fusion and differentiation Retroviral particles have been observed in the placenta, along with fused placental cells, which are morphologically reminiscent of virally induced syncytia. These studies led to the proposal that an ancient retroviral infection might have been a pivotal event in mammalian evolution Viruses have long been used to transfer genes into cells.
During the last decade, another important application has been the viral delivery of genes and drugs to treat cancer. A major challenge has been to develop virus entry proteins to deliver molecules to specific cells with high efficiency.
To achieve this goal it is often desirable to engineer viruses that do not infect cells expressing the native receptor, but instead target a cell of choice. Engineering of entry proteins in this way is known as transductional retargeting A conceptually simple approach to transductional retargeting is to incorporate the protein that determines cell tropism into the infecting virion of choice — known as virus 'pseudotyping'.
This has been used in both retroviruses and adenoviruses, and does not require prior knowledge of specific virus—receptor interactions. In a related approach, viral entry proteins are used to produce drug and gene delivery vehicles, for example, the F protein of Sendai virus has been incorporated into liposomes to form virosomes and the L protein of hepatitis B has been incorporated into yeast-derived lipid vesicles Retargeting of retroviruses, adenoviruses and AAVs has been achieved by conjugation of entry proteins with molecular adaptors, such as bi-specific antibodies that have particular receptor-binding properties.
Modification of the entry proteins so that the normal receptor-binding property is abolished, or a ligand for alternative receptor binding is incorporated has also been successful at redirecting adenovirus tropism in cell culture, but is unlikely to work for the entry of viruses that require receptor-induced conformational changes, such as retroviruses, unless detailed molecular mechanisms of those conformational changes are better understood.
A related approach is based on screening libraries of chimaeric Envs from different strains of MLV , or randomized peptides inserted at tolerant sites in viral proteins, such as VP3 of AAV This approach seems promising for the selection of specific retargeting vectors. Understanding the structure of AAV and other viruses could help to further improve the specificity and efficiency of retargeting.
Retargeting viruses with complex entry mechanisms that involve several proteins, such as those of herpes viruses and poxviruses, remains challenging. Elucidation of the molecular mechanisms and the dynamics of the conformational changes driving virus entry remains a significant challenge.
It requires the development of new approaches to study the rapid conformational changes of a small number of membrane-interacting protein molecules that are surrounded by many more non-interacting molecules.
A more realistic goal is the determination of the structures of proteins that mediate the entry of all human viruses and the identification of the cognate cellular receptors.
If research continues at the present pace, this goal could be accomplished within the next decade. Identification of all the cellular receptors for human viruses would be an important contribution to our understanding of virus tropism and pathogenesis. The various, and in many cases unexpected, ways that entry proteins can affect pathogenesis could offer new opportunities for intervention.
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