Coronaviruses Immune Evasion

• Immune Evasion Mechanisms
  • Overcome Phagocytosis
  • Avoid Being Targeted
• Adaption of Immune Evasion
  • Genetic Adaption
  • Change the Way of Life
  • Adaption of Immune Evasion Mechanisms
• Overcome Innate Immunity
  • Overcome Physical Barriers
  • Overcome Chemical Barriers
  • Overcome Intra Cellular Immunity
• Overcome Acquired Immunity
  • Overcome Spike Binding Antibodies
• References

Immune Evasion Mechanisms

Overcome Phagocytosis

Phagocyte <- exploit phagocytosis by infecting the cell

• SARS-2 can replicate in macrophages (in vitro and in vivo detected by biopsies of severe cases.)
• In many immune cells no replication takes place e.g. since immediate/early apoptosis is triggered (dendritic cells) or no space in cytoplasm (T/B Cells) [to confirm]. By cell death the immune cell is still knocked out, though usually at the cost of triggering immune system alarms.

Costs: If phagocytes are infected at some point usually apoptosis is induced and thereby they ring the immune system bells (e.g. by releasing cytokines).

Avoid Being Targeted

Change the Appearance

Changing the appearance:

• By mutation: Mutating changes the appearance for future generations. This requires the hosts frequently need to learn new targets.
• By masking: Temporary change of the appearance during life-time. This requires the host to know multiple targets.

Shield

Most life forms place their core parts in the center shielded from other life forms and the environment. There are different structures which can shield:

• Parts with variable appearance e.g. by mutating often.
• Substances which are hard to recognize: E.g. unpolarized substances such as glycans or fatty acids.
• Host acquired substances.
  • The host cell acquired envelope.
  • During the metabolic phase the coronaviruses not only use the hosts ribosomes but also other structures e.g. they rearrange the membranes of the endoplasmic reticulum to have a protected space for genome expression and replication [to check and cite].

  When a hosts targets its own substances it is an autoimmune disease

Costs: Building shields requires time and resources.

Mask

Functional regions are often shielded until used: The receptor binding domains are buried within the spike until primed.

Benefits:

• Different priming steps in different locations can give different appearances at different locations in a host -> enabling intra-host spread [to check/confirm]
• Immunogenic parts have only a short exposure time

Costs: Masking requires an unmasking mechanism and doing so at the right time and place.

Adaption of Immune Evasion

Genetic Adaption

Mutating the genome changes the characteristics of the coming generations. This can be the way of life or just the appearance:

1. Change the Way of Life: A profound and very effective change to escape a certain immune mechanism.
2. Adapt Immune Evasion Mechanisms: Use a new or increase the effectiveness of an existing immune escape mechanism.
3. Change the Appearance: Escape host recognition mechanisms.

Costs: Most mutations reduce the fitness.

Change the Way of Life

Changing the way of life to circumvent certain immune mechanisms.

• For RNA viruses changing the way of life is often achieved by genetic adaption since their genome mutates fast and is very close to enzymes.
• Changing the habitat both within a host or to other hosts. In many larger organisms the immune system is localized, so if the protection is strong in place is still can be low in another.

Adaption of Immune Evasion Mechanisms

Existing evasion mechanisms can be strengthened or new mechanisms can be used. Especially if a host has a single sided immune response, mechanisms to escape this response can evolve.

This is a concern for the current Covid vaccines. All available vaccines produce a single sided immune response, namely targeting only spike epitopes: Mainly through IgG antibodies and systemic T cells.

Overcome Innate Immunity

Overcome Physical Barriers

• skin <- circumvention by human coronaviruses: enter via breathing
• mucus <- less mucus in the lungs and nasal cavity
• cell membranes <- fuse membranes with the spikes

Overcome Chemical Barriers

• stomach acid <- circumvented by coronaviruses
  • replicate to high numbers in the lungs and pass through the thin alveolar single cell layer to the blood
  • replicate to high numbers in the upper respiratory tract and hope some virions sneak through when drinking (fluids usually don’t stay long in the stomach)

Overcome Intra Cellular Immunity

A common way the over come intracellular immunity is by letting the cells produce replication sites which shield the viral metabolism from the cell intern immune mechanisms.

Overcome Acquired Immunity

For coronaviruses waiting until immunity wanes or even jumping generations is usually not an option, thus circumventing acquired immunity is an essential skill.

However overcoming immunity can be costly for coronaviruses, so immune mechanisms slow the down.

Overcome Spike Binding Antibodies

Spike Antibodies Effector Mechanisms

Spike binding antibodies can opsonize the virions for phagocytosis, neutralize the virions or mark the virions as dangerous. Often antibodies act by all three mechanisms, however the effectiveness of the mechanisms vary.

Neutralizing Antibody

Neutralizing antibodies block virions from entering cells.

The only coronavirus protein well accessible from the outside is the spike protein, so that’s the target. If a sufficient number of spikes have antibodies attached a virion cannot infect cells on its own anymore, since working spike proteins are needed for active cell entry.

Neutralizing antibodies are a useful tools to do in vitro experiments. In vivo the neutralizing effect seems to be not really relevant [argumentation in work].

Opsonize Antibody

An antibody can opsonize a virion for phagocytosis.

Upon phagocytosis, mostly the virions are digested but sometimes the virions infect the phagocyting cell (especially if the intracellular detection mechanisms are reduced).

Marking Antibodies

An antibody can mark a virions. Upon infecting or phagocytosis the cell detect the danger and starts an antiviral program e.g. by producing interferons.

Spike Binding Antibody Escape Mechanisms

Coronaviruses - like many enveloped viruses - are good at escaping neutralizing antibodies and they use nearly the entire arsenal of immune evasion mechanisms to do so:

AB circumvention by Change of Appearance

Methods to change appearance are mutating or masking.

• The most exposed part of the coronavirus spikes, the S1 part, mutates frequently.
• Functional parts of the spikes are buried until usage.

AB circumvention by Shields

Shields protect functional parts:

• Coronaviruses have a host acquired envelope which can’t be targeted by the host immune system.
• The only proteins extern of the envelope are the spikes. The spikes in turn are shielded by hard to recognize glycans and the outermost regions of the spikes changes the appearance.

AB circumvention by Masking

• sensitive regions e.g. receptor binding domains are shielded until primed.
• different priming steps in different locations can give a different appearance at different locations in a host -> enabling intra-host spread [to check/confirm]

AB circumvention by Exploitation

Exploiting antibody induced phagocytosis by infecting the phagocyte cell

Natural infections and vaccines also produce antibodies targeting internal parts of the spike and internal proteins (natural infections and vaccines which include internal proteins as antigens), these helps to fight infections: the intracellular virion assembly process gets disrupted. [to check and cite]

Besides antibodies, natural infections and to some extent vaccines induce also specific immune cells such as memory T cells targeting different antigens of viruses. T cells are effective at recognizing infected cells since cells present pieces of the proteins they produce.

Adaptions to Increase Neutralizing Antibody Escape

Coronaviruses can adapt to increase the resistance towards neutralizing antibodies:

• Reduce Exposure Time by shortening the Virion Phase
  • Coronavirus virions can adapt to infect cells quicker by having the spikes primed faster
    • Shortening the virion phase can yield more localized infections.
    • Infecting cells quicker usually means the priming steps are less elaborate and so more cells are infected.

    This can cause more damage to the hosts which is not beneficial for viruses since they rely on their hosts.

• Bypass the Virion Phase Coronaviruses can induce cell-cell fusion with their spikes. Thereby they circumvent the virion phase and thus they cannot be classically neutralized.

  To induce cell-cell fusion the spikes are still used, so antibodies targeting the spikes can prevent cell fusion in theory, but cell fusion can be initiated fast and between the cells the antibody concentration can be low [to confirm and cite].

References

[in work], the above text is not yet complete and many sections have missing citations. Additionally not all refs are used

kikkert

Marjolein Kikkert Innate Immune Evasion by Human Respiratory RNA Viruses J Innate Immun 2020;12:4–20 https://doi.org/10.1159/000503030

Bachmann

Bachmann, M.F., Mohsen, M.O., Zha, L. et al. SARS-CoV-2 structural features may explain limited neutralizing-antibody responses. npj Vaccines 6, 2 (2021). https://doi.org/10.1038/s41541-020-00264-6