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21.3: Prevention and Treatment of Viral Infections - Biology

21.3: Prevention and Treatment of Viral Infections - Biology


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21.3: Prevention and Treatment of Viral Infections

Prevention and Treatment of Viral Infections

Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis (Figure). These diseases can be treated by antiviral drugs or by vaccines, but some viruses, such as HIV, are capable of both avoiding the immune response and mutating to become resistant to antiviral drugs.

Viruses can cause dozens of ailments in humans, ranging from mild illnesses to serious diseases. (credit: modification of work by Mikael Häggström)


TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS

Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 (tripartite motif-containing protein 21) interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes its K27-linked polyubiquitination, thereby promoting the recruitment of TBK1 to MAVS. Specifically, the PRY-SPRY domain of TRIM21 is the key domain for its interaction with MAVS, while the RING domain of TRIM21 facilitates the polyubiquitination chains of MAVS. In addition, the MAVS-mediated innate immune response is enhanced by both the PRY-SPRY and RING domains of TRIM21. Mutation analyses of all the lysine residues of MAVS further revealed that Lys325 of MAVS is catalyzed by TRIM21 for the K27-linked polyubiquitination. Overall, this study reveals a novel mechanism by which TRIM21 promotes the K27-linked polyubiquitination of MAVS to positively regulate innate immune response, thereby inhibiting viral infection.IMPORTANCE Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. MAVS plays a critical role in innate immune response to RNA viral infection. In this study, we demonstrated that TRIM21 targets MAVS to positively regulate innate immunity. Notably, TRIM21 targets and catalyzes K27-linked polyubiquitination of MAVS and then promotes the recruitment of TBK1 to MAVS, leading to upregulation of innate immunity. Our study outlines a novel mechanism by which the IFN signaling pathway blocks RNA virus to escape immune elimination.

Keywords: IL-28A IL-29 MAVS TRIM21 innate immunity interferon virus.

Copyright © 2018 American Society for Microbiology.

Figures

Viral infection induces the expression…

Viral infection induces the expression of TRIM21. (A and B) HLCZ01 cells were…

Induction of TRIM21 depends on…

Induction of TRIM21 depends on the JAK/STAT signaling pathway. (A) HLCZ01 cells were…

TRIM21 positively regulates innate immune…

TRIM21 positively regulates innate immune response to RNA nucleic acid mimics in HLCZ01…

TRIM21 positively regulates innate immune…

TRIM21 positively regulates innate immune response to RNA nucleic acid mimics in Huh7…

TRIM21 positively regulates innate immune…

TRIM21 positively regulates innate immune response to RNA viral infection in HLCZ01 cells.…

TRIM21 positively regulates innate immune…

TRIM21 positively regulates innate immune response to RNA viral infection in Huh7 cells.…

TRIM21 promotes the activation of…

TRIM21 promotes the activation of IRF3 and NF-κB signaling and suppresses viral infection.…

TRIM21 targets and interacts with…

TRIM21 targets and interacts with MAVS. (A to C) Luciferase activity of lysates…

TRIM21 promotes K27-linked ubiquitination of…

TRIM21 promotes K27-linked ubiquitination of MAVS. (A) TRIM21 promotes the K27-linked ubiquitination of…

TRIM21 promotes the K27-linked polyubiquitination…

TRIM21 promotes the K27-linked polyubiquitination of MAVS on Lys325 and the recruitment of…

Schematic model of TRIM21-mediated K27…

Schematic model of TRIM21-mediated K27 polyubiquitination of MAVS during viral infection. TRIM21 targets…


Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV

With the current trajectory of the 2019-nCoV outbreak unknown, public health and medicinal measures will both be needed to contain spreading of the virus and to optimize patient outcomes. Although little is known about the virus, an examination of the genome sequence shows strong homology with its better-studied cousin, SARS-CoV. The spike protein used for host cell infection shows key nonsynonymous mutations that might hamper the efficacy of previously developed therapeutics but remains a viable target for the development of biologics and macrocyclic peptides. Other key drug targets, including RNA-dependent RNA polymerase and coronavirus main proteinase (3CLpro), share a strikingly high (>95 %) homology to SARS-CoV. Herein, we suggest four potential drug candidates (an ACE2-based peptide, remdesivir, 3CLpro-1 and a novel vinylsulfone protease inhibitor) that could be used to treat patients suffering with the 2019-nCoV. We also summarize previous efforts into drugging these targets and hope to help in the development of broad-spectrum anti-coronaviral agents for future epidemics.

Keywords: 2019-nCoV 3CLpro RdRp SARS antiviral agents coronavirus spike proteins.


Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

Keywords: Antiviral Hepatitis Immunodeficiency virus Influenza Virus Type I IFN classes Viral infection.


Prevention & Treatment

About how much of its fish and seafood does the United States import?

The United States imports more than 80 percent of its fish and seafood. About 20 percent of its fresh vegetables and 50 percent of its fresh fruits are imported. As wealthy nations demand such foods year-round, the increasing reliance on producers abroad means that food may be contaminated during harvesting, storage, processing, and transport&mdashlong before it reaches overseas markets.

The United States imports more than 80 percent of its fish and seafood. About 20 percent of its fresh vegetables and 50 percent of its fresh fruits are imported. As wealthy nations demand such foods year-round, the increasing reliance on producers abroad means that food may be contaminated during harvesting, storage, processing, and transport&mdashlong before it reaches overseas markets.

The United States imports more than 80 percent of its fish and seafood. About 20 percent of its fresh vegetables and 50 percent of its fresh fruits are imported. As wealthy nations demand such foods year-round, the increasing reliance on producers abroad means that food may be contaminated during harvesting, storage, processing, and transport&mdashlong before it reaches overseas markets.

Infectious Disease Defined

A broad group of microscopic fungi that includes harmless forms of yeast used in baking and alcoholic fermentation as well as pathogenic species that can cause disease.

National Academies Press

Search the National Academies Press website by selecting one of these related terms.


Living With

When should I call my doctor concerning an infectious disease?

Let your doctor know if you have any symptoms of an infectious disease, especially if they are unusual or don’t go away over time. Symptoms like fever, vomiting and diarrhea may lead to more serious complications, including dehydration.

Your doctor should also know if you plan to travel to foreign countries. You may need to be vaccinated against common infectious diseases occurring at your destination.

If you have an ongoing infection, frequent follow-ups with your doctor help ensure your condition does not worsen.

Last reviewed by a Cleveland Clinic medical professional on 02/27/2018.

References

  • World Health Organization. Infectious Diseases. Accessed 3/6/2018.
  • United States Department of Labor. Infectious Diseases. Accessed 3/6/2018.
  • National Institute of Allergy and Infectious Diseases. Diseases & Conditions: Infectious Diseases. Accessed 3/6/2018.
  • National Foundation for Infectious Diseases. Influenza (Flu). Accessed 3/6/2018.
  • Merck Manual Consumer Version. Diagnosis of Infectious Disease. Accessed 3/6/2018.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Related Institutes & Services

Respiratory Institute

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy


21.3: Prevention and Treatment of Viral Infections - Biology

Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis (Figure 1). These diseases can be treated by antiviral drugs or by vaccines, but some viruses, such as HIV, are capable of both avoiding the immune response and mutating to become resistant to antiviral drugs.

Figure 1. Viruses can cause dozens of ailments in humans, ranging from mild illnesses to serious diseases. (credit: modification of work by Mikael Häggström)


Vaccines for Prevention

While we do have limited numbers of effective antiviral drugs, such as those used to treat HIV and influenza, the primary method of controlling viral disease is by vaccination, which is intended to prevent outbreaks by building immunity to a virus or virus family (Figure). Vaccines may be prepared using live viruses, killed viruses, or molecular subunits of the virus. The killed viral vaccines and subunit viruses are both incapable of causing disease.

Live viral vaccines are designed in the laboratory to cause few symptoms in recipients while giving them protective immunity against future infections. Polio was one disease that represented a milestone in the use of vaccines. Mass immunization campaigns in the 1950s (killed vaccine) and 1960s (live vaccine) significantly reduced the incidence of the disease, which caused muscle paralysis in children and generated a great amount of fear in the general population when regional epidemics occurred. The success of the polio vaccine paved the way for the routine dispensation of childhood vaccines against measles, mumps, rubella, chickenpox, and other diseases.

The danger of using live vaccines, which are usually more effective than killed vaccines, is the low but significant danger that these viruses will revert to their disease-causing form by back mutations. Live vaccines are usually made by attenuating (weakening) the “wild-type” (disease-causing) virus by growing it in the laboratory in tissues or at temperatures different from what the virus is accustomed to in the host. Adaptations to these new cells or temperatures induce mutations in the genomes of the virus, allowing it to grow better in the laboratory while inhibiting its ability to cause disease when reintroduced into conditions found in the host. These attenuated viruses thus still cause infection, but they do not grow very well, allowing the immune response to develop in time to prevent major disease. Back mutations occur when the vaccine undergoes mutations in the host such that it readapts to the host and can again cause disease, which can then be spread to other humans in an epidemic. This type of scenario happened as recently as 2007 in Nigeria where mutations in a polio vaccine led to an epidemic of polio in that country.

Some vaccines are in continuous development because certain viruses, such as influenza and HIV, have a high mutation rate compared to other viruses and normal host cells. With influenza, mutations in the surface molecules of the virus help the organism evade the protective immunity that may have been obtained in a previous influenza season, making it necessary for individuals to get vaccinated every year. Other viruses, such as those that cause the childhood diseases measles, mumps, and rubella, mutate so infrequently that the same vaccine is used year after year.

Vaccinations are designed to boost immunity to a virus to prevent infection. (credit: USACE Europe District)


Microscopy deep learning predicts viral infections

In humans, adenoviruses can infect the cells of the respiratory tract, while herpes viruses can infect those of the skin and nervous system. In most cases, this does not lead to the production of new virus particles, as the viruses are suppressed by the immune system. However, adenoviruses and herpes viruses can cause persistent infections that the immune system is unable to completely suppress and that produce viral particles for years. These same viruses can also cause sudden, violent infections where affected cells release large amounts of viruses, such that the infection spreads rapidly. This can lead to serious acute diseases of the lungs or nervous system.

Automatic detection of virus-infected cells

The research group of Urs Greber, Professor at the Department of Molecular Life Sciences at the University of Zurich (UZH), has now shown for the first time that a machine-learning algorithm can recognize the cells infected with herpes or adenoviruses based solely on the fluorescence of the cell nucleus. "Our method not only reliably identifies virus-infected cells, but also accurately detects virulent infections in advance," Greber says. The study authors believe that their development has many applications - including predicting how human cells react to other viruses or microorganisms. "The method opens up new ways to better understand infections and to discover new active agents against pathogens such as viruses or bacteria," Greber adds.

The analysis method is based on combining fluorescence microscopy in living cells with deep-learning processes. The herpes and adenoviruses formed inside an infected cell change the organization of the nucleus, and these changes can be observed under a microscope. The group developed a deep-learning algorithm - an artificial neural network - to automatically detect these changes. The network is trained with a large set of microscopy images through which it learns to identify patterns that are characteristic of infected or uninfected cells. "After training and validation are complete, the neural network automatically detects virus-infected cells," explains Greber.

Reliably predicting severe acute infections

The research team has also demonstrated that the algorithm is capable of identifying acute and severe infections with 95 percent accuracy and up to 24 hours in advance. Images of living cells from lytic infections, in which the virus particles multiply rapidly and the cells dissolve, as well as images of persistent infections, in which viruses are produced continuously but only in small quantities, served as training material. Despite the great precision of the method, it is not yet clear which features of infected cell nuclei are recognized by the artificial neural network to distinguish the two phases of infection. However, even without this knowledge, the researchers are now able to study the biology of infected cells in greater detail.

The group has already discovered some differences: The internal pressure of the nucleus is greater during virulent infections than during persistent phases. Furthermore, in a cell with lytic infection, viral proteins accumulate more rapidly in the nucleus. "We suspect that distinct cellular processes determine whether or not a cell disintegrates after it is infected. We can now investigate these and other questions," says Greber.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Watch the video: Microbiology lecturesLaboratory Diagnosis of viral Diseasesvirology lectures (May 2022).


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