How does the Immune System Handle Viruses?

Viruses

Viruses cannot reproduce by itself, because of this, it relies on the host cellular machinery to do so; therefore, it is referred to as an intracellular parasite.

Viruses are typically an RNA or DNA genome surrounded by a protective protein coat. A complete virus particle is referred to as a virion. The simplest virions are composed of its genome and a protein coat, known as the capsid which protects the genetic material from nucleases.

Viruses typically have a small genome size, aside from coding for few structural proteins (in the capsid) and the regulatory genes involved in its replication.

On the other hand, other viruses possess an additional covering called the envelope, which is derived in part from modified host cell membranes. These modified membranes often have ‘spikes’ called peplomers formed of glycoproteins.

This allows for a resemblance to the target host cell, whereby the glycosylation pattern confers the antigenic specificity of the virus.

Virus

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Cytotoxic cells

Mammals have developed a refined immune system to handle various types of infections. This is true, particularly for the adaptive immune system where it has a crucial role in limiting the viral infection and the clearance of it.

Once the virus has infiltrated the host cell through binding to its receptors, the virus commandeers the host's protein synthesis machinery to replicate and synthesize its proteins.

During this process, the host cell can take advantage of the virus's vulnerability whereby some of the newly synthesized protein fragments can be degraded into specific peptides. If there is a sufficient binding capacity this peptide fragment will then bind to the major histocompatibility complex (MHC) -1.

These MHC-1 complexes allow the peptide fragment to be presented on the surface of the infected cell and activated cytotoxic T cells or CD8+ T cells can distinguish the specific peptide and induce apoptosis of the infected cell by cytotoxic granules.

The CD8+ cells are activated within our lymph nodes where antigen-presenting cells (APCs) such as dendritic cells encounter a naïve T cell (CD4+). During this process, CD4+ and dendritic cells provide co-stimulation necessitated for the activation of CD8+ cells.

Despite this, viruses are highly adaptable and therefore can overcome detection by T cells. In such cases, the MHC-1 molecule can be inhibited from displaying viral peptides on the surface.

When this takes place, the cell cannot let the surrounding cells ‘know’ that it has been infected. Thankfully, when this occurs, our immune system is well equipped to compensate for this.

Natural killer (NK) cells are the second type of immune cell; they are lymphocytes without a clonally specific receptor. Due to this, they do not have an antigen-specific receptor and so do not resemble T or B cells. Previous work has identified NK cells to target and destroys cancerous cells without prior sensitization to them via cytolysis.

Observations following this led to the development of the ‘missing self’ hypothesis whereby these NK cells can target tumor cells that do not display the MHC-1 complex.

The ‘missing self’ hypothesis predicts that the NK cell can destroy viral- infected cells that can inhibit the expression of MHC-1 molecules. Recent advances have suggested NK cells are activated and regulated through various receptors.

Indeed, there are receptors present on the NK cell, which can identify viral-derived products. The most common viral product is haemagglutinin of an influenza virus which binds to the NKp46 receptor.

In addition to direct viral recognition, NK cells have an unusual ability to identify cellular stress signals through the NKG2 family. The NKG2D family is a critical mediator of NK-cell activation. The ligands associated (ULBP and MIC in humans) have been extensively researched and highlighting their roles in possible viral mechanisms that can escape NKG2D recognition such as cytomegaloviruses (CMV).

Further to this, this ligand is also expressed on macrophages and dendritic cells; therefore mediating crosstalk of the immune system.

Upon entering their activation and recruitment to the site of infection, NK cells can utilize different strategies to kill virally infected cells:

  1. Production of interferon-gamma (IFN-y): IFN-y can exert its effects on the infected cell directly by making it less hospitable. It can also recruit cytotoxic T lymphocytes and CD4+ cells.
  2. Perforin and granzymes: perforin permeabilizes the cell membrane, while granzymes can disrupt the cell cycle progression by DNA damage upon entrance into the cell.
  3. Cell-mediated cytolysis: NK cells express ligands capable of activating the extrinsic apoptosis pathway by activating the death receptors present on the infected cell.

Natural Killer Cell

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Antibodies

Enveloped viruses ubiquitous across viral families and have the potential to cause some of the deadliest diseases known today. They share a common component of glycoproteins or ‘spike’ proteins which allow for both host- cell recognition entry into the cell and also exposure to the adaptive immune response- being a target for antibodies.

The antigens or ‘spike’ proteins are recognized by B-lymphocytes which rapidly undergo replication whereby the B-cells mature and differentiate leading to the production and secretion of antibodies with a high affinity towards to antigen that triggered the response.

The initial IgM antibody undergoes class switching to have a high affinity and a potent response to the viral infection. However, this response is not just restricted to antigens; following the initial infection, the virus particles can be broken down into their components which are then exposed to the immune system.

The exposure of the epitopes and cryotopes allows the production of antibodies with various specificities. This allows for the neutralization of the intact virus and the identification of its components.

B-Lymphocytes

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References

  • Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 6.3, Viruses: Structure, Function, and Uses. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21523/
  • Rosendahl Huber, S., van Beek, J., de Jonge, J., Luytjes, W., & van Baarle, D. (2014). T cell responses to viral infections - opportunities for Peptide vaccination. Frontiers in immunology, 5, 171. https://doi.org/10.3389/fimmu.2014.00171
  • Brandstadter, J. D., & Yang, Y. (2011). Natural killer cell responses to viral infection. Journal of innate immunity, 3(3), 274–279. https://doi.org/10.1159/000324176
  • Sanna, P. P., & Burton, D. R. (2000). Role of antibodies in controlling viral disease: lessons from experiments of nature and gene knockouts. Journal of virology, 74(21), 9813–9817. https://doi.org/10.1128/jvi.74.21.9813-9817.2000

Further Reading

Last Updated: Jun 2, 2020

Gemma North

Written by

Gemma North

Gemma has a BSc in Biological Sciences from the University of East Anglia and an MSc(Res) Translational Oncology from the University of Sheffield. Her master’s thesis explored drug redeployment in multiple myeloma specifically looking at the effects of niclosamide and valproate. The study has broader implications for myeloma patients where therapies are often aggressive and not always suitable due to the demographic of patients.

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