This article was inspired by what we consider to be the best illustration of overall immune system functions that we have seen. More specifically, the illustration concerns the immune system reaction to a viral infection, and the article we found it in, by Dr. Gary Klimpel, was written about immune system defenses to infection by enveloped viruses such as coronaviruses. We wanted to share this awesome infographic with you (at the bottom of this article), but we then decided to summarize the entire old chapter for you in order that you be able to understand the infographic. After all, the immune system is very intricate. However, the original article is quite dated (more than 20 years now!) and the field of immunology has progressed much since. But this is precisely why we wanted to drill down into the basics of this complex topic.

We present the information with a flow that would be similar to a chronological progression of a virus infection along with the resulting changes in the immune system. We thought this might make it easier to try to start to understand how our immunity is working. Dive right in and enjoy!

Virus spread – How and Where?

Virus spread is best defined by keeping in mind both how an enveloped virus spreads as well as where the virus spreads.

Let’s start with where the virus spreads; this can be defined as how the virus enters the body and what the final target destination is based on a virus’ ability to move about in the body and this can be divided into the following categories:

• Local spread – Infection gets confined to a specific surface (such as mucosal surface of your respiratory tract) or organ.
• Primary hematogenous spread – Virus enters directly into the bloodstream (for example, through bite of an insect) and then to organs.
• Secondary hematogenous spread - Infection and replication (often relatively asymptomatic) occur on a mucosal surface, then enters bloodstream and then travels to organs.
• Nervous system spread – Virus spreads via the nervous system.

In terms of how an enveloped virus spreads during infection, the infected cells release the infectious virions by budding (pinching off) parts of their cell’s own cell membrane. This means two things:

• This type of budding virus infection results in destruction of the infected cell due to the disruption of its own membrane. This is referred to as acute cytolytic infection, and is the most common form of virus-host cell interaction.
• Before it lyses or is destroyed, virus-specific antigens (that are supposed to be part of the released new virions) have to be presented on the infected cell’s surface in order to end-up being part of the envelope surrounding the new virus.

Viral activation of immunity

When a virus infects the body, the following immune responses are effective against viruses:

1. Cell-mediated immunity involving T lymphocytes and cytotoxic effector T lymphocytes
2. Humoral immunity using antibodies, with and without their additional interaction with complement
3. Antibody-dependent cell-mediated cytotoxicity (ADCC)
4. Natural killer (NK) cells and macrophages
5. Lymphokines and monokines (cytokines)

Do not worry, everything is explained below!

*It is important to note that these immune responses are bigger during any re-infection of a host.

In addition, a host’s immune responses work synergistically with some nonimmune defense mechanisms to further enhance protection. Here is a chart that summarizes all of these bodily responses that can be generated to combat viral infections (with more detailed explanations below):

All these summarized multiple immune and nonimmune host defenses aim to achieve following:

• Stop viral infection
• Stop disease process

However, while these host immune responses are expected to be beneficial, they may also be detrimental, or maybe both (more about the detrimental, virus-induced immunopathology below).

The immune response can also be categorised by when it happens, in two stages:

• Early responses – Nonspecific responses that seek to limit viral multiplication during the acute phase of virus infections. These includes nonspecific inhibition, natural killer cell activity, and interferon cytokines.
• Later responses – Specific immune responses start to eliminate viruses at the end of the acute phase, and build specific resistance. These include humoral and cell-mediated immunity. Humoral and cell-mediated immunities are not independent of each other.

Immune functions during viral infections, in detail

Non-specific immune defenses

When encountering an infection for first time (host is non-immune), then early nonspecific defense mechanisms are activated first. These defenses are meant to stop the infection. If this fails, virus spread occurs (where it becomes disseminated). If the virus manages to spread to numerous organs, this results in a generalized infection.

These nonspecific responses that occur within hours and consist of:

1. Interferon production - alpha and gamma
   Viruses can stimulate alpha interferon production by macrophages; this alpha interferon stimulates natural killer cells as well as inhibiting virus multiplication in neighboring cells.
   There is also gamma interferon produced by activated T cells. Gamma interferon can activate macrophages to increase phagocytosis (virus destruction) and become cytotoxic toward virus-infected cells.
    
2. Inflammation
   (Not discussed in the reviewed science article, so this is a bonus independent summary.) Inflammation is the body's immunovascular response to protect tissues from injury. It is initiated by resident immune cells already present in the involved tissue which recognise a change in molecular patterns in either the affected host cells or invading pathogens, and then release molecules that trigger inflammation. They trigger vasodilation which increases blood flow and heat to the inflamed site. Other factors increase the permeability of the blood vessels, meaning the blood vessels cells are spread further apart, allowing plasma proteins and fluid to leak into the surrounding tissue, resulting in swelling (edema). The increased permeability of the blood vessels also allows the migration of various white blood cells (leukocytes) into the surrounding tissue to travel to the injured cells.
   The article being reviewed did mention that once virus infection reaches target organs, control of the infection becomes more difficult. Inflammation in target organs then becomes an important initial defense mechanism, as does fever and use of interferons.
    
3. Fever
   (Not discussed in the reviewed science article, so this is also a bonus independent summary.) Fever, the outcome of which is to raise the body temperature, helps defend against infection in following ways:
   • Negatively affects the reproduction of pathogens by increasing the body’s temperature to one outside of the strict temperature requirements for the pathogen’s replication
   • Increases the rate of important immunological reactions. For example:
     • Increases mobility of effector leukocytes cells (see below)
     • Increases leukocyte phagocytosis (see immediately below)
     • Increases T cells proliferation (see below)
   
    
4. Phagocytosis
   This is the process whereby leukocyte cells directly dispose of virions by purposefully engulfing the virion to destroy it once it is inside the leukocyte. Macrophages are important phagocytes that recognise virus-infected cells in a non-specific manner. Macrophage phagocytosis decreases virus levels in body fluids and thus slows down viral spread. To slow down viral spread, viruses must be destroyed by macrophages once engulfed. However, a virus can escape this process and instead replicate inside macrophages! In such instances, the infected macrophages may actually help the virus infect other body cells (this is referred to as antibody dependent enhancement). Whether macrophages will fail and allow the virus replication instead of its destruction may depend on the specific condition of the macrophages but could also be influenced by the host’s age and genetics. Phagocytic cells are also important for cytokine production (ex. alpha and gamma interferon).
    
5. Natural killer cell activity
   Natural killer cells can destroy tumor cells, but are especially good against virus-infected or virus-transformed cells (referred to as their cytotoxic activity). Furthermore:
   • Natural killer (NK) cell killing is not dependent on human leukocyte antigen (or HLA, a receptor which presents a specific piece of the virus on the outside of the infected cell for recognition by other nearby immune cells) and thus NK cells do not exhibit immunologic specificity and their killing is broad in nature (non-specific). HLA is commonly referred to as major histocompatibility complex.
   • Natural killer cell killing is increased by interferon and interleukin-2 (IL-2), important early cytokines.
   • They can produce different cytokines (including interferon) when stimulated by a virus or virus-infected cells.
   • In later stages, they can mediate ADCC as natural killer cells possess Fc receptors (see below).

Specific immune defenses

These represent specific immune responses to a specific pathogen. These responses are triggered almost immediately after viral exposure but the end result happens later and takes 3 to 10 days for cell-mediated immunity and activated humoral immunity (the production of antiviral antibodies).

Cell-mediated immunity:

Virus-infected cells activate strong cell-mediated immunity responses.

Cell-mediated immunity means an array of cells called cytotoxic effector cells (or killer leukocytes) which, when stimulated by a virus or virus-infected cells execute the following:

• Destroy the virus as well as virus-infected cells.
• Produce soluble factors called cytokines to either enhance already activated responses or influence additional arms of the immune system.

Cell-mediated immunity processes are essential for recovery from a viral infection. But they can also be crucial in control of the virus spread, especially infections with viruses that spread directly from cell to the next cell. This is because enveloped viruses, which fuse with cellular membranes, can actually travel from cell to cell without any antibody being able to come near the virus.

But remember virus infected cells exhibit viral antigens (fragments of virus proteins) on their surface. These cells exhibiting virus antigen can then be recognized by different effector cells and this helps to fight the local spread of this type of infection through destruction of these virus infected cells. To effectively halt this acute spread, infected cells have to be destroyed quickly before virus particles inside those infected cells can be assembled into complete mature virions. Macrophages are also central to the induction of T cell and B cell lymphocyte responses by presenting the initial viral antigen to them. It is especially the T cells (called T lymphocytes) that are important in recovery from viral infections.

Note: macrophages, natural killer cells and cytotoxic T cells can all recognize and kill virus-infected cells and are the primary cytotoxic effector cells (killer leukocytes).

There are also important non-cytotoxic T cells called helper T cells that recognize the virus-infected cells but only produce cytokines. However, helper T cells are actually required for the generation of cytotoxic T cells, as well as optimal antibody production (see below), and they influence other immune and inflammatory responses through their cytokine production.

However, there are differences in how cytotoxic T cells, natural killer cells and macrophages recognize virus-infected cells. Natural killer cells and macrophages recognize virus-infected cells in a non-specific manner, whereas the cytotoxic T cells will only recognize those infected cells for which they are configured to recognize.

Cytotoxic T lymphocytes only recognize and destroy virus-infected cells that present specific virus antigens on their cell surface using major histocompatibility complex (MHC). In other words, cytotoxic T cells are restricted to recognizing and attacking specific cells that showcase specific antigens, but it also means that these cytotoxic T cells are restricted by what major histocompatibility complex infected cells are using with which to present the virus antigen. Hence, T cells are said to be MHC restricted. For macrophages and natural killer cells, the recognition of virus-infected cells is not restricted by the major histocompatibility complex of the infected cells and therefore they can act broadly on virus-infected cells. This also means, macrophages and natural killer cells effector functions can begin very soon after the infection.

T-cell effector functions on the other hand begin 3–4 days after the start of a viral infection, and decrease rapidly, within 5–10 days of stopping the infection (until a virus is no longer present). Another form of T cell called virus-specific memory T cells are then maintained for a long time in case of future reinfection.

Humoral immunity:

This immunity is based on the production of specific antibodies against the virus. Antibodies take part later in a viral infection (7 days after infection start) but in contrast to cytotoxic T cells, antibodies’ high levels can be maintained for long periods of time, even years at a time.

Antibodies binding to a virus can neutralize viruses in the following ways:

1. Blocking the virus from interacting with and infecting host cells by interfering with:
   • Direct attachment of virus to a cell surface (most often interfered with)
   • Penetration of virus into the cell
   • Uncoating of the virus inside the cell (more rarely for last two points)
2. Recognizing viral antigens on virus-infected cells which can lead to decreasing number of infectious particles in one of two ways:
   • Lysis of virus-infected cells by various effector leukocyte killer cells via antibody-dependent cytotoxic cells (ADCC) mechanism
     The effector cells that destroy virus infected cells via ADCC have surface receptors called Fc receptors. These receptors recognize and bind to a specific portion of IgG antibodies (the Fc portion of IgG), one of the subcomponents of what makes up the antibody. Thus first, IgG antibodies bind to virus antigens presented on the surface of an infected cell, then the Fc portion of the IgG antibody is exposed and can be targeted by the Fc receptor of the effector cells. When this effector cell binds to the Fc portion of an IgG antibody that is itself is bound to an infected cell, the mechanism signals the effector cells to disrupt (lyse) the infected cell.
     ADCC is a very efficient way of destroying virus-infected cells because the amount of antibodies needed is far less than the antibody-complement lysis mechanism (immediately below).
     All cells with Fc receptors can mediate ADCC activity and that includes macrophages, neutrophils , natural killer cells and lymphocytes. Importantly, this is how macrophages and natural killer cells can be involved in both specific and non-specific responses to viral infections.
   • Lysis of virus-infected cells by the complement system
     Antibodies can activate a complement system which once activated is a series of chain-like reactions of activated proteins that result in constructing a structure that attacks and ruptures the cell membrane of a pathogen. This complement cascade of activated proteins can also promote phagocytosis with or without the antibody by binding to virions directly. Coating of the virions by complement system with or without antibody participation is called opsonization. Finally, the complement system can promote inflammation.
3. Enhance phagocytosis in one of three ways:
   • Antibody directly binding to the surface of the phagocytic cells
   • Antigen-antibody complexes binding Fc receptors to be engulfed by cells for destruction (ex. IgG described above)
   • Antigen-antibody-complement complexes binding the C3b receptor (recognizes part of the complement complex) signaling it is to be engulfed by cells for destruction
4. Causing virus aggregations thus decreasing numbers of circulating, functioning virions.

Antibody neutralization is most effective against:

• Viruses in large fluid spaces (such as blood)
• Viruses on moist surfaces (such as respiratory and gastrointestinal tracts)

This is where the virus is most exposed and susceptible to an antibody attack. Viremia for example, or presence of viruses in the circulation system, is easily eliminated by even low levels of circulating antibodies.

Steps in humoral immunity activation:

• Viral antigen binds to B cell immunoglobulin receptors
• B cells interact with macrophages and helper T cells
• B cells differentiate into one of 5 types of plasma cells secreting different antibodies: IgG, IgM, IgA, IgD, and IgE

IgG, IgM, and IgA can neutralize the infectivity of virtually all known viruses.

When the first infection takes place, viral antigens will typically first promote the production of IgM antibodies. This is referred to as early antibody response, and the reason why it is the first observed response is because the production of these antibodies by B cells is T cells independent, and thus B cells are activated faster. As a consequence of lacking activation of B cells by a specific viral antigen that matches that of activated T cell receptors, the B cells are activated instead by much more generic antigens confronted directly on the surface of the virus. IgA and IgG antibodies responses take place a few days later after the IgM.

The main difference between IgA and IgG antibodies is the location of their distribution. IgG antibody is predominantly used in serum (preceded by IgM) and provides protection against generalized infections when a virus spreads through the bloodstream (condition known as viremia). IgG antibodies can also leave the blood stream to reach the site of inflammation when the increased permeability of the blood vessels allow their migration into the surrounding tissue.

IgA antibodies on the other hand (as with some IgM) are used for the protection of the mucosal localized tissues, and are important in protecting against localized surface viral infections such as the common cold or influenza.

Viral infections that begin on a mucosal surface and then spread hematogenously (spreading from localized surface to target organs through blood) can be prevented at this early stage by local IgA antibody secretion, or alternatively finished by IgG antibodies if the infection progresses to the viremic stage.

Another notable difference is that IgA antibodies duration is much shorter (months) than the persistence of IgG antibodies in serum (which can last up to years).

Virus-induced immunopathology

An immune-mediated disease that develops as a consequence of viral infection is due to the persistent presence of viral antigens and an uncontrolled immune hypersensitivity to them.

Immune-mediated diseases can be started by both humoral and cell-mediated immune functions.

For example, if the immune-mediated disease is started by virus/virus antigen-antibody complexes, it is referred to as immune-complex syndrome. T cells (cytotoxic and helper) can also start immunopathologic injuries.

How immunopathology could start:

• Tissue/organ damage via cytotoxic T cells
• Inflammation via cytokines
• Antibody-complement complexes contributing to inflammation and tissue injury
• Antibody-antigen complexes and/or ADCC contributing to inflammation and tissue injury. Not discussed in the reviewed science chapter is the fact that this can also promote the original infection’s progression through antibody dependent enhancement.

Summary graph

Now that we have spelled everything out (actually the science publication we are summarizing here is just one chapter of a large book), it is time to summarize it all with an infographic. This was presented in the reviewed science paper and was the reason behind why this article was produced. It is because it looked like the best summary of virus activation of the immune system we have seen. However, the original copy that was uploaded is very poor, so we reproduced the original almost identically to showcase what we consider to be the best cheat sheet for immune response upon infection with a virus such as a coronavirus!

Adapted from G. R. Klimpel. 1996. “Chapter 50: Immune Defenses” in Medical Microbiology. 4th edition. S. Baron, editor. Galveston (TX): University of Texas Medical Branch at Galveston.

The above is almost identical to the original summary presented by Dr. Klimpel. If you got through this and feel like you have much better grasp of the immune system intricacies, we invite you to check out the original chapter by Dr. Kimpel, as there are more great explanatory illustrations. We just focused on the best one and wanted to share it and this great review. Hope you learned lots along with us!

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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