Immune System

Contents

Heterotrophs

		There are two types of living organisms in this world. The autotrophs (self-nourishment) live on inorganic materials, while the heterotrophs (different-nourishment) must make use of resource that comes from other organisms in the form of fats, carbohydrates and proteins (Figure 01). Thus, there is always an arm race going on for the latter type - it's a race between attack and defence (Figure 02). Such acts are all too obvious in the macroscopic setting, actually the same kind of struggle is on going all the time in the microscopic environment. The lower frame of Figure 02 shows a swarm of viruses (in blue) attacking an E. coli bacterium with the contractile sheath, which acts like a syringe to squirt the genetic material (DNA) into the host cell.
Figure 01 Heterotrophs [view large image]	Figure 02 Attack and Defence [view large image]	It responds by secreting enzyme to cleave or disable the foreign DNA or commits suicide to protect the rest of the population if worse comes to worst.

The subject on immune system in the followings is about the defence of an macroscopic being against the invasion of pathogenic microbes including bacteria, viruses, parasitic worms and fungi. Micro-organisms outnumber the human cells of our bodies by ten to one. Some of them are friendly (up to a point), doing us neither good nor harm, many are important to the functioning of the body, but there are nasty varieties that can cause all kinds of illness. The defence has to be able to tell friends from foes and also doesn't kill itself. The main lines of defence are the innate and adaptive immune systems (Figure 03) when the first line of defence crumbles under the assault.

Figure 03 Immune Systems [view large image]

First Line of Defence

The first line of defence recruits helps with physical, chemical, and biological components. The methods are rather primitive, but all animals use them in one form or the others. A few of these are illustrated in Figure 04 (left frame). In addition to the three levels of defence as shown in the right frame, human culture/science has added a top layer by sanitating the environment, and by regulating the foods and drinks.

Figure 04 First Line Defence

The three components of the first line defence :

1. Physical Component - It is the physical barrier that blocks the entry point for pathogenic invasion. It consists of dead skin cells on the external surface, and mucus on the cell wall within.

	Skin - It is actually the tough layers of dead cells on the outside of the skin, which are frequently replaced. Figure 05 (left frame) displays the seemingly impenetrable scale in Iguana's tail spine. However, the weak spots are in between especially in falling external temperature when they would open up slightly for easier entry.
Figure 05 Physical Component	Mucus - It snares foreign material and carries off dead cells from the mucous membrane. It also secrets chemicals and harbors friendly flora to ward off the invaders.



2. Chemical Component - It consists of a variety of proteins that bind to and damage the cell walls of bacteria. These wall structures are unique to bacteria, so they present a useful target that can be attacked without risking the health of tissue cells. There are essentially three kinds as shown in Figure 04 and explained briefly below.

   	Antibacterial Emzyme - Human saliva and tears contain antibacterial compounds such as secretory IgA and lysozyme (see Figure 06 for the secretory glands). These enzymes function by attacking peptidoglycans (found in the cell walls of bacteria). Beside saliva and tears lysozyme is abundant in a number of secretions, such as human milk, mucus, and egg
   Figure 06 Antibacterial Emzyme [view large image]	white. IgA (Immunoglobulin A) plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined.

   Pore-forming Peptide - Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores. Figure 07 illustrates the process of positively charged peptide poring hole into the negatively charged cell membrane (via the electrostatic force).

   Figure 07 Pore-forming Peptide [view large image]

   Gastric Acid - pH of less than 2.0 generally kills all bacteria, but this pH value is rarely maintained for any length of time, especially during food intake, which is when most bacteria enter the stomach. Experiment shows that many micro-organisms do not survive in an environment at pH 1.0 or 2.0, whereas all bacteria tested survived at pH 4.0 - a pH level inside the mucus layer (Figure 08). In the acidic conditions of the stomach bacteria can escape the assault by binding to the food, neutralizing the acid, or preventing the secretion of more acid by the stomach. The H. pylori bacteria (the little bugs in

   Figure 08 Gastric Acid

   Figure 08) create diseases such as gastritis and ulcers by moving in a screw-like motion with the unique flagella and changing to a nonadherent state to avoid the adherence in the mucous layer.

3. Biological Component - Each part of the gut creates a nurturing environment for precisely the type of bacteria that it needs. For example, the intestine cells would provide a special kind of sugar for a particular bacteria when a signal is received from them. In turn, the bacteria would break down hard-to-digest food, add capillary branches, secrete antibacterial molecules (with exemption for themselves), occupy the space to block out unwanted bacteria, make vitamin K and other goodies for the intestine cells. Figure 09a lists further detail of this symbiotic relationship. Figure 09b shows the presence and abundance of bacterial species in various

   		anatomical sites on and in the human body and a short description of their functions. The bacteria in each site compile a micro-ecosystem (called microbiome) with the members link together and interact with the environment on or in the host. The microbiome behaves very similar to the macroscopic ecosystem, which exists in equilibrium even under small
   Figure 09a Good Bugs [view large image]	Figure 09b Microbiome [view large image]	perturbation, except that it can respond quickly to change and different composition could perform the same funtion (to the host).

resistant. Common side effects include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection. Other antibiotics include Cephalosporins, Aminoglycosides, Tetracyclines, ... With advances in medicinal chemistry, most modern antibacterials are semisynthetic modifications of various natural compounds. These germ killing products, which are not produced by micro-organisms, such as proflavine, sulfonamide, ... are referred to as antibacterial drugs.

Figure 09c Penicillin [view large image]

It is found that antibiotic use (or mis-use) severely disrupts the microbiome (the micro-ecosystems on and in our body), causing extensive collateral damage. The indiscriminate killing of nonpathogenic members makes it easier for pathogens to invade otherwise stable, occupied environments.

Second Line of Defence (Innate Immune System)

		The white blood cells (leukocyte) are either amoeba-like single cells for devouring foreign substances or protista with granular chemicals on the surface for combating intruders (by releasing the chemicals). Figure 10 shows some of the different varieties. The upper frame in the image shows a macrophage in the process of devouring some E.coli bacteria, while the lower frame lists some of the various kinds of white blood cells. Essentially, there are two main types - phagocytes for the 2nd line of defence and lymphocytes for the 3rd line of defence. Both of them originate in the bone marrow.
Figure 10 Phagocytes [view large image]	Figure 11 2nd Line of Defence [view large image]

A short list of the white blood cell types (see Figure 10, the pink ovals in the background are red blood cells with their nucleus and other cellular organelles squeezed out and ingested or destroyed by the marcophages) :


• Phagocytes (eating-cell) in 2nd line of defence :
  
  • Monocytes - They leave the blood vessel and mature to macrophages and one type of dendritic cell (messengers between the innate and the adaptive immune systems).
  • Marcophages - They are large, motile, phagocytic cells that engulf foreign material, dead body cells, and cellular debris.
  • Neutrophils (neuter = neutral, phil = loving in Greek) - The most abundant white blood cells. They squeeze through the capillary walls into infected tissue where they kill and eat the invaders.
  • Eosinophils (eosin = red dye) - This type is rare but the number increases sharply in certain deseases, especially infections by parasitiic worms. They are cytotoxic, releasing the contents of their granules on the invaders.
  • Basophils - This type is also rare, the number also increases during infection. They leave the blood vessel to converge and accumulate at the site of infection or other inflammation, where they discharge the contents of their granules and other antibiotic chemicals, which play an important part in some allergic responses such as hay fever and swelling in insect stings.
  • Mast (masto = breast) Cells (Figure 11) - These cells with granular surface secrete histamine to increases blood vessel permeability. This leade to swelling, warmth, redness, and the attraction of other inflammatory cells to the site of release.
  
  
• Lymphocytes (sap-cell) with large nucleus in 3rd line of defence (Figure 12) :
  
  • B Cells - These cells originate in bone morrow (hence the "B"). They are responsible for making antibodies.
  • T Cells - These cells originate in bone morrow but migrate to the thymus where they mature (hence the "T"). They are messengers to recruit phagocytes, executioners for virus-infected and tumor cells by secreting lethal chemicals, and helpers to enhance the production of antibodies by B cells.
  • B and T Cells - Both of them reside in lymph nodes and the spleen where they would be trained to recognize antigens, continue to divide by mitosis, and mature into fully functional cells.

Action in 2nd Line of Defence (Figure 11) :


1. The phagocytes normally spread through the body in blood. They can choose to leave the blood vessels by squeezing through the gaps between the capillary cells. Once there, they can settle down or actively go on to patrol the tissue spaces.
2. The phagocytes' receptors can detect bacterial cell walls and waste products or molecules from stressed and dying human cells.
3. Once the signals for bacterial invasion are detected, the phagocytes would crawl to the source (much in common with the embryonic cell migration). Upon reaching the trouble spot, they would secrete more signalling molecules for reinforcements, release a cocktail of highly toxic chemicals, and endeavor to engulf and destroy the bacteria.
4. The chemicals are so lethal that considerable damage is also inflicted to the ordinary human tissue. The result is a local build-up of redness and heat, from the increased blood flow, swelling from the fluid and accumulating cells, and pain from injured nerve endings. In the middle of the inflammation is an area of whitish pus - essentially phagocytes, dead bacteria, and dead human tissue.
5. When the receptors detect signals from stressed and dead human tissue, e.g., from an injury, excessive violence is triggered. Every living thing in the general area is killed to make sure any disease is stopped in its tracks.

Third Line of Defence (Adaptive Immune System)

Since small unicellular organisms such as the viruses can alter their genes and appearance rapidly, no macroscopic animals can keep up with the pace correspondingly. Together with the innate immunity, the adaptive immune system has been evolved in vertebrates to deal with this problem. It is based on the "lock and key" mechanism that allows the generation of receptor that fit into the special feature on the pathogenic surface as illustrated in the left frame in Figure 13a. Fragments can also be manufactured by macrophage (and dendritic cell, ...) and presented to the B and T-helper cells (Figure 13a, right frame) for recognition. The helper (CD4+) T cells summon macrophages and neutrophils to the site of infection, while the cytotoxic (CD8+) T cells kill the pathogens directly.

Figure 12 T and B Cells

Vaccination is the administration of antigenic material (such as fragments of pathogenic protein, or a harmless or weakened strain - the vaccine) to stimulate the immune system for developing adaptive immunity with a pathogen. See lot more details in "Antibody".

Mechanism of the 3rd Line of Defence :


• Even though there are millions of different antigens, the T cells use just one basic gene to make countless receptors by deliberately rearranging the DNA sequence randomly. The upshot is millions slightly different T cells each bearing a different shape of receptor.


• T cells are born from stem cells, found in the bone marrow. These precursor cells then migrate to the thymus gland which is surrounded by fragments of protein on the cell surface. They mature into several distinct types of T cells in the thymus (Figure 12).

  The differentiation continues after they have left the thymus. Those T cells would commit suicide if the antigen receptor do not fit any cell surface protein because they will be useless. Those with strong binding also kill themselves because the fragments are certainly to be normal human material, this is the way the immune system avoids acting against its own body. Thus, only those with weak binding survive, finish the education, and eventually enter into service carrying a memory of previous infection. Any pathogen with that particular fragment would be recognized quickly and disposed of. Figure 13a shows the training with pathogenic antigen.

  Figure 13a 3rd Line of Defence [view large image]

  BTW, "specificity" means an unique fit (see Figure 13a lower left), and lymphokine is protein mediator carrying various kinds of messages (Figure 13a,left); and it is now realized that T cells cannot recognize (and therefore cannot respond to) "free" or soluble antigens.

  
  
• The B cells follow the same development or education process in spleen and lymph nodes (not in thymus). They would inform the T cells of the presence of any foreign fragment encountered in the patrol. If the finding is confirmed, then the T cell multiplies itself and sends out signal to trigger the proliferation of that particular kind of B cells. Some of the daughter B cells become memory cells, while others secrete their receptor into the body fluid. These are called antibodies which bind to any thing that it recognizes, marking it for destruction via the mechanism of either the 1st or 2nd line of defence.


• As shown in Figure 13a (right frame), the phagocytes (a distinct type called dendritic cell) also present fragments to the T cells. However, the presentation has two different states - the usually aggressive state and a tolerant state which allows the co-existence with symbiotic bacteria (in the gut for example).


• Here's a summary of the antibody, which plays an important role in the variable part of the Adaptive Immune System :
  • Antibodies, aka Immunoglobulin (Ig) occur in two forms: one that is attached to a B cell or Helper T cell, and the other, a soluble form, that is unattached and found in extracellular fluids such as blood plasma (see Figure 13a). Formation of antibody starts from the presence of foreign object (antigen) such as virus which is ingested by Antigen Presenting Cell (APC), which attached the antigen to the surface of a B cell or Helper T cell (see Figure 16e). After binding to a B Cell Receptor (BCR), the B cell activates to proliferate and differentiate into either plasma cells, which secrete soluble antibodies with the same paratope, or memory B cells, which survive in the body to enable long-lasting immunity to the antigen. Soluble antibodies are released into the blood and tissue fluids, as well as many secretions. Because these fluids were traditionally known as humors, antibody-mediated immunity is sometimes known as, or considered a part of, humoral immunity. The soluble Y-shaped units can occur individually as monomers, or in complexes of two to five units.
  • The variable parts in the antibody are the antigen-binding sites at both tips of the antibody. In contrast, the remainder of the antibody is relatively constant (see Figure 13b,a). The constant region at the trunk of the antibody determines the function triggered by an antibody after binding to an antigen. They vary at different place in the body, e.g.,
    • IgA : It's found in the linings of the respiratory tract and digestive system, as well as in saliva, tears, and breast milk.
    • IgG : This is the most common antibody. It's in blood and other body fluids, and protects against bacterial and viral infections. IgG can take time to form after an infection or immunization.
    • IgM : Found mainly in blood and lymph fluid, this is the first antibody the body makes when it fights a new infection.
    • IgE : Normally found in small amounts in the blood. There may be higher amounts when the body overreacts to allergens or is fighting an infection from a parasite.
    • IgD : This is the least understood antibody, with only small amounts in the blood.
  • Antibody actions :
    
    • Antibodies are attached to pathogen marking it for destruction by killer cells. Effector cells (such as macrophages or natural killer cells) bind via their Fc receptors (FcR) to the Fc region of an antibody sticking out from the pathogen.
    • Antibodies block parts of the surface of a bacterial cell or virion to neutralize the attack.

    	Antibodies "glue together" (agglutination) foreign cells into clumps that are attractive targets for phagocytosis. Antibodies "glue together" (precipitation) serum-soluble antigens, forcing them to precipitate out of solution in clumps that are attractive targets for phagocytosis.
    Figure 13b Antibody [view large image]	See illustration and caption in Figure 13b,b.

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  Virus

  Most of the time the virus would just lay dormant as an inert crystal, lifeless as a rock and perhaps staying that way for centuries or millenniums. Yet, unlike a rock, it may wake up at any moment, when there is the warmth and moisture of some vulnerable cell that it can swiftly enter and infect. The structure of viruses consists of a protein capsule containing DNA or RNA with 1000 - 200000 base pairs. Figure 14a shows the virus known as T4 bacteriophage that preys exclusively on bacteria. The lower 69000X image reveals a swarm of viruses attacking an E. coli bacterium with the contractile sheath, which acts like a syringe to squirt the genetic material (DNA) into the host cell. In the spring of 2003 a new strain of coronavirus (Figure 15) causes the "Severe Acute Respiratory Syndrome" (SARS), which is much harder to control than influenza (Orthomyxovirus infection of the upper respiratory tract and lungs) or common cold (Rhinovirus infection of the upper respiratory tract). Viruses survive and reproduce by infecting a cell and commandeering the cellular synthetic machinery to make more viruses. Then the viruses lyse (destroy) the cell and start the cycle over again. DNA virus replication starts from

  entering the host cell by endocytosis. The DNA then replicates more of its kind and simultaneously making new coating proteins. These parts assemble to form more viruses, which exit from the host to infect more cells (Figure 14b). The RNA retrovirus (such as the coronavirus) does it somewhat differently because the genetic material is in the form of RNA. It has to undergo a reverse transcription to form cDNA (DNA copied off from the RNA), which is then integrated into the host DNA. It commandeers the host's replication mechanism to make more RNAs, which in turn make more coating proteins for the final assembly of new viruses. The followings provides further details on RNA virus replication in

  Figure 14 DNA Virus [view large image]

  7 steps. There are numerous kinds of viruses, this summary only considers the single-stranded, positive-sense (its RNA is the same as mRNA) RNA virus (such as the Coronaviridae), which replicates solely in cytoplasm of the host cell (Figure 15).

  • Adsorption - Actually, Viruses can infect only certain species of hosts and only certain cells within that host. Cells that a virus may use to replicate are called permissive. It is the special kind of membrane receptor that allows certain kind of virus to enter. The permissive cell must also possess the materials required by the virus to replication.
  • Entry - A channel forms across the cell membrane and the virus enters through invagination from which process it enters into the host encapsulated inside a vesicle. It is thus protected from the host's antibodies.

  Uncoating - Host cell enzymes (from lysosomes) strip off the virus protein coat (a mistake committed by the host). This releases or renders accessible the virus RNA. Replication - Viral RNA polymerase copies plus-sense genomic RNA into complementary minus-sense RNA, the whole thing becomes cDNA (complementary DNA). The cDNA is then integrated into the host DNA for replication using the host's replicating machinery. Synthesis of viral Proteins - For single-stranded, positive-sense RNA virus, the RNA itself is the mRNA, which uses the host's ribosome and tRNA (also aaRS by implication) to make the viral coating proteins and viral RNA polymerase. Assembly - When sufficient plus-sense progeny RNA and virion proteins have accumulated, self-assembly begins with the virions (newly formed viruses) enclosed inside a vesicle. Release - The viruses, now being mature are released by either sudden rupture of the cell, or gradual extrusion (budding) of enveloped viruses through the cell membrane. In the case of bacterial viruses, the release of progeny virions takes place by lysis (destruction) of the infected bacterium. However, in the case of animal viruses, release usually occurs without cell lysis.

  Figure 15 RNA Virus [view large image]

  There is a progressively deadly strain called coronavirus because it looks like the solar corona under magnification of electron microscope (see insert at lower right corner of Figure 16a). Its date of origin is estimated from 10000 to 3000 million years ago. It caught attention only in 1912 by the strange symptom of an infected cat. Since then the same kind of virus has killed different kind of animals without being identified until the 1960s when it is put under the electron microscope. The lethal effect on human started with the SARS in 2003 for a total of about 8000 cases, and now the SARS2 has progressed to a pandemic from December 2019 with no end in sight as of June 2020 with more than 7 million cases and counting. Here's some unusual properties for this particular strain of SARS2.
  
  
  • It is the largest among the RNA virus with a size of 1.25x10^-5 cm and a genome of 30000 genetic bases.
  • It has a genomic proof-reading mechanism to prevent weakening through mutations.
  • However, it does mutate by recombination with the RNA of other corona-viruses.
  • As shown in Figure 16a, its spike proteins are extremely efficient at latching onto the ACE2 receptors on human cell.

  Entry into the human cell is assisted by the Furin enzyme at the surface of the cell. It breaks the spike protein of the virus and fuses the viral membrane with the membrane of the host cell allowing the viral RNA to invade. Such mechanism gives SARS2 a 100 - 1000 times greater chance than SARS of getting deep into the lungs. This is the main reason for such nasty pandemic (see Figure 16a). The SARS-CoV-2 can readily attack human cells at multiple points, with the lungs and the throat being the main targets. It can infect the intestines, the heart, kidney, liver, spleen, the blood, sperm, eye, and possibly the brain. The infection can also trigger an excessive immune response known as cytokine storm, which can lead to multiple organ failure and death (see Covid-19 symptoms at lower right of Figure 16a).

  Figure 16a Covid-19, 2020 [view large image]

  See original article : "Profile of a Killer" in Nature, 7 May 2020.

  The race is on to find the vaccines for stopping the spread of the disease. Here's a copy of the "Coronavirus Vaccines" from Nature 30 April 2020 (click image to enlarge) for the various approaches without much success so far (as of June 11, 2020) :
  
  

  Figure 16b COVID-19 Vaccines (in progress) [view large image]

  
  
  The mRNA vaccine from Pfizer-BioNTech and Moderner have been approved for COVID-19 vaccination in December, 2020 (See "How Pfizer Makes Its Covid-19 Vaccine"). The following is a brief summary of the process (see Figure 16e,a).
  
  

  	The artificial mRNA to generate COVID-19 spike protein is obtained from the virus's plasmid DNA (plasmid) in vitro (in the lab) using bacteriophage RNA polymerase. Beside the coding sequence (CDS), it is enclosed by a cap and tail. In order to further increase both translation and stability, it requires 2 untranslated regions (UTRs) to flank the CDS (see Figure 16c).
  Figure 16c mRNA Structure	The mRNA is unstable against decomposition, it must be stored at ultra-low temperatures of -80°C to -60°C up to the end of its expiry date for a duration of 30 days. See more on the mRNA technology in "The promise of mRNA vaccines".

  
  

  The mRNA is protected and uptake enhanced by lipid coating. Pfizer delivers the vaccine in vial contains 6 doses of 0.3 mL (to be diluted with 0.9% Sodium Chloride Injection, USP - sold separately; Figure 16d). Administration of the vaccine is via intramuscular (IM) injection to the muscle in the arm for a series of two doses (0.3 mL each) 21 days apart. See " Guideline for the Pfizer vaccine in BC, Canada", and "Product Monograph, PFIZER-BIONTECH COVID-19 Vaccine" for details.

  Figure 16d

  Vaccine Dilution [view large image]

  • Once inside the cell, the mRNA is processed by the host's ribosome which translates the CDS to the corresponding protein. The immune system is activated to recognize the spike protein (in case of COVID-19 vaccine) as foreign and initiates an immune response. The mRNA and spike protein are then cleared by the immune system. Almost all cell types can present antigens in some way. They are found in a variety of tissue types. However, the cytotoxic (killer) T cells must be activated before they can divide and perform their function. This is achieved by sensing a chemical message (Interleukins-2, IL-2) from the helper T cell, which is in turn activated by the "professional" Antigen-Presenting-Cell (APC) (see the sequence in Figure 16e,b).
  
  
  • The mRNA becomes quickly degraded by extra and intracellular enzymes (RNAases) after injection into the body. Animal models using lipid-coating mRNA vaccines against the virus show that virus neutralising antibody production falls off

    markedly ~ 21 days after a first injection, suggesting limited survival and stimulation by the vaccine mRNA and its' encoded Spike protein beyond such time interval. However, the specific anti-viral immune response was strongly boosted with a 2nd injection of vaccine. This raises concerns that extending a second injection out to beyond ~ 21 days could compromise vaccine efficacy. The time interval for a mRNA booster may be very critical for getting the best sustained immune response.

    Figure 16e mRNA Vaccine and T Cell Activation [view large image]

    It is not known why the 2nd shot is so effective. Probably, it triggers the release of a lot more IL-2 chemical messagers by more helper T cells to proliferate and activate the killer T cells (see Figure 16e,b and update).

    
    

    B cell immunity is the preferred way to combat the COVID-19 virus as it stops the infection into the cell by tagging antibody onto the virus killing it; while T cell immunity eliminates the cell already been infected. However, killer T cell seems to recognize more variety of viral segments, such feat is more suitable to deal with the variants (see "Killer T Cells Could Boost COVID Immunity Amid New Variants"). B cell immunity involves more steps as shown in Figure 16f. It runs as a humoral immunity component of the adaptive immune system by secreting antibodies which mark the pathogen for

    Figure 16f B Cell Activation

    destruction (e.g., by phagocyte, and see Figure 13a,left). It also serves as professional APC, secretes cytokines to activate the memory B cell and regulate the various components of the immune systrem (as shown in the update below, the process takes time to work).

  
  

  As the B cell immunity is humoral, vaccination is most effective by injection into the body fluid. However such shot is very painful, that's why everyone receives the dose via the muscle in upper arm (aka intramuscular (IM) injection). Here's a video to show a certain COVID-19 expert in Hong Kong doing humoral injection by himself. It shows that he knows better (click Figure 16f2 to see the video).

  Figure 16f2 Humoral Vaccination [image, video]

  • Many restrictions such as the minimum age of 16, dosage, injection preparation, ... are imposed by the setup of the clinical trials or packaging. Pfizer vaccine efficacy is 52% after first dose and 95% after second dose. It means that among 100 cases of infection, there is 52% and 95% respectively in the placebo group (or 48% and 5% in the vaccinated group) during the clinical trials.
  According to "Scientists are divided over dosing strategies" published by Nature, 14 January 2021:
  
  ...
  
  Many vaccines consist of multiple jabs — the first to trigger an initial immune response to certain proteins produced by a virus or bacterium, and later booster shots calling the immune system’s memory cells into action. It usually takes weeks for these memory cells to be generated. Over time, the immune system also broadens its response, developing memory cells capable of responding not only to specific proteins, but also to some variants of them. This means that a later booster shot is sometimes more effective, says immunologist Akiko Iwasaki at Yale University in New Haven, Connecticut: “Immunologically speaking, it may even help to delay a little.”
  
  This might be especially true for vaccines that use harmless viruses to shuttle the genetic code for coronavirus proteins into cells (e.g., mRNA), says Hildegund Ertl, an immunologist at the Wistar institute in Philadelphia, Pennsylvania. Cells read the code and make the coronavirus protein, triggering immune responses against it. But the immune system might also generate antibodies against the harmless vector virus. If the booster is administered while levels of those antibodies remain high, the vector could be neutralized before it has a chance to deliver its cargo.
  
  This kind of vaccine can also cause cells to express the coronavirus protein for weeks after vaccination. A booster given too soon could arrive while the immune system’s initial response is still raging and memory cells are not yet established. “Until you have memory, your booster immunization is not doing you any good,” says Ertl.
  
  ...
  
  

  Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or SARS2) is the virus that causes coronavirus disease COVID-19 and now the Variants :

  
  
  • All viruses evolve and mutate over time, the SARS-CoV-2 (SARS2) viruse is no exception, acquiring 1-2 new mutations every

    month. A mutation is an alteration in the sequence of nucleic acid in DNA or RNA caused by insertions, deletions, substitutions or rearrangements of bases. While most mutations are harmless (actually deleterious to the virus itself), a few can result in new proteins or altered cellular processing that turns it into more vicious variant. Naturally all organisms mutate in nature, the smaller genomic size makes the mutation in virus more noticeable (Figure 16g). Mutation is one of the elements in "Darwinian Evolution".

    Figure 16g Size of Organisms [view large image]

    Figure 16k shows the genome of SARS2, and will be examined in details later, while Figure 16i illustrates some mutations in the spike protein.

    RNA virus replication typically has a high error rate that results in its existing as diverse populations of mutants. While low replicative fidelity allows the RNA viruses to adapt to different environments and selective pressures, it is also associated with an increased chance of catastrophic error leading to extinction. This suggests the need for a finely tuned balance between stability and diversity. The COVID-19 virus develops a RNA proofreading process in its nsp14 enzymes to maintain a relatively lower rate of mutation (comparing to other RNA viruses). Up until now, the virus has been circulating unhindered in a large host population with little immunity, and hence has encountered minimal resistance, or selection pressure as evolutionary biologists call it. The evolution that has occurred is therefore mostly just random genetic drift rather than being the virus adapting. The situation may change with the introduction of vaccines and the attempts to disrupt the viral genome including nsp14 (see "Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting"). Figure 16h shows the viral infections process in an updated version including the step with proofreading.

    Figure 16h Virus Infection with Proofreading [view large image]

    See the older version of Virus Infection in Figure 15.

    The big worry is the emergence of “escape mutations” that enable the virus to dodge the immune system or render vaccines or drugs useless. Such an escape becomes even more likely as we begin to exert selection pressure on the virus in the form of vaccines, natural immunity and drugs. Mutants that can evade these interventions could slip through the net and start circulating wildly, potentially pushing us back towards square one in our efforts to beat the pandemic. Mutation of the spike protein is particularly worrying as it directly involves entry of the virus into the host cell. If this part of the spike protein changes, neutralising antibodies may not bind as well. Initial studies of antibodies from those previously infected by the coronavirus or given the Pfizer and BioNTech vaccine show little or no drop in effectiveness against B.1.1.7, although they might be slightly less effective against two variants, one that emerged in South Africa and one from Brazil. See "Emerging SARS-CoV-2 Mutations and Variants".

    Figure 16i Mutations of Spike Protein

    Figure 16i shows the various kinds of spike protein variations in the B.1.1.7 (designated by some sort of convention, see "Lineage B.1.1.7") variant emerged at UK, and "Rare COVID reactions might hold key to variant-proof vaccines"; also a list of the amino acids.

    
    
  • It is difficult to predict whether SARS-CoV-2 will evolve to be more harmful; but bear in mind that "its aim is not to kill us or make us sick, it is successful when it can operate unnoticed and gets transmitted easily". We spend a lot of money and efforts to eliminate the variants that cause severe illness, while pay no attention to the harmless ones. According to this

    logic, the SARS2 will follow a similar evolutionary trajectory of the 4 endemic (localized disease) coronaviruses that cause the “common cold”. It is possible that the virus has to change a little just to maintain itself in children (they typically have less severe disease than adults), or it may evolve to escape immunity by being able to better replicate in the nose and so turn into an upper respiratory infection, which makes the patient uncomfortable but not fatal. It is possible that SARS-CoV-2 vaccines will need to be updated, possibly every year like the flu vaccines. But even then, immunity from either past vaccination or infection will probably blunt serious disease. In case the SARS-CoV-2 vaccines block infection and transmission for life, the virus might become something akin to measles - two doses and a person is protected for life.

    Figure 16j Endemic SARS2 [view large image]

    Figure 16j presents the result of a survey about the driving factor in endemic circulation. See original article : "The Coronavirus Will Become Endemic".

    
    
  • Here's the nitty-gritty of the SARS2 genome (see Figure 16k) :
    
    
    • Open Reading Frame (orf) is a continuous stretch of codons (1 condon = 3 nucleotide bases translating to 1 amino acid) that

      begins with a start codon (usually AUG or ATG) and ends at a stop codon (usually UAA, UAG or UGA). In eukaryotic genes with multiple exons, introns are removed and exons are then joined together after transcription (from DNA to RNA) to yield the final mRNA for protein translation. The orf1ab gene constitutes 2/3 of the SARS2 genome, encodes a total of 16 non-structural proteins (nsp's) within the pp1ab gene (pp = polyprotein) as shown in Figure 16k (yellow), and a table for nsp's.

      Figure 16k SARS2 Genome [view large image]

    • The other 1/3 of SARS2 genome includes 4 genes (in green) that encode four structural proteins (S, M, E, N), and six accessory genes (in blue) that encode six accessory proteins (orf3a, orf6, orf7a, orf7b, orf8, and orf10). See Figure 16k.
    
    
    • The SARS2 don’t need the accessory proteins to replicate in a test tube, but they do need the molecules to counteract the host’s innate immune system. They are the least-well understood.
      See "What do we know about the novel coronavirus’s 29 proteins?".
    
    
    • Replication of the genomic RNA of SARS2 is mediated by 2 viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro) in nsp3 and nsp5 respectively. They are necessary to cleave the resulting pretein (after translation by the host ribosome) into functional segments. These segments are then re-assembled into a complex (through a mechanism of self assembly) for replication of the viral RNA (see steps 6, 7 and 8 in Figure 16h). These segments are nsp 7, 8, 10, 12 (RdRp for replication), 13 (Hel), 14 (Proofreading). See a summary of the nsp functions :

      

    • In a study of 3067 SARS-CoV-2 genomes from December 24, 2019 to March 25, 2020 with the Wuhan-Hu-1/2019 as

      reference, 38 recurrent non-synonymous mutations were identified. Among these mutations, 22 locate in the pp1ab nsp genes and 16 within the "more recent" additions of 4 structural genes. By taking into account the frequency of mutated alleles (= #-of- occurance/3067), the rate of mutation is > 0.28/month in the pp1ab and > 0.26/month in the structural genes for a total of > 0.54 mutations/month (see Figures 16l, and 16k, and compare to the 1 - 2 mutations/month quoted earlier). These numbers indicate that the mutations occur at random and the rate is much lower that the flu's 4 mutations/month (of genome size about 1/2 as much, see "Coronavirus seems to mutate much slower than seasonal flu").

      Figure 16l SARS2 Variation [view large image]

      And don't miss "Coevolution Scenario for the Virus and Cell".

  • DNA Vaccine :

    	On 20 August 2021, India’s drug regulator authorized the DNA vaccine for people aged 12 and older. The efficacy figure of 67% came from trials involving more than 28,000 participants, which saw 21 symptomatic cases of COVID-19 in the vaccinated group and 60 among people who received a placebo. The name of the product is ZyCoV-D (see Figure 16m). Here's a summary :
    Figure 16m ZyCoV-D [view large image]

    • As shown in the left-half of Figure 16n, the vaccine is created from the gene making the spike protein of the SARS2 virus. This segment is encoded into a plasmid with promoter sequence for turning the gene on.
    • This plasmid is incorporated into the genome of the cell in its nucleus. mRNA is produced from there, it exists the nucleus into the cytoplasm.
    • The rest of the action is exactly the same with mRNA as mentioned previously and shown on the right side of Figure 16n. The body’s immune system would mount a response against the artificial spike protein, and produces tailored immune cells that can clear future infections. Plasmids typically degrade within weeks to months, but the immunity remains. There is no need to worry about harboring SARS2 gene in our body.
    • The challenge for DNA vaccines is that they need to make it all the way to the cell nucleus, that's why it enters the market

      later than the other types and has only 67% efficacy (mainly against the Delta variant in the clinical trial). The problem is somehow solved by having the vaccine deposited under the skin. The area under the skin is rich in immune cells that gobble up foreign objects, such as vaccine particles, and process them. This helps the delivery far more efficiently than in the muscle. It is administered using a needle-free device pressed against the skin, which creates a fine, high-pressure stream of fluid that punctures the surface and is less painful than an injection. However, it requires a minimum of three doses to achieve its initial efficacy presenting certain logistical challenge, which may be neutralized by its more stable structure than mRNA vaccines.

      Figure 16n DNA Vaccine

      See original article : "India’s DNA COVID vaccine is a world first – more are coming".

  [Top]

  ---

  Immune System Disorders

  		Immune system disorders are the abnormally over-activity or low activity of the immune system. In case of over-activity, the defence attacks and damages its own tissues. It is also known as auto-immune diseases (see Figure 15 for some examples). The treatment generally focuses on reducing immune system activity. Immune deficiency diseases decreases the body's ability to protect itself. Primary immuno-deficiency is cause by inherited genetic mutations (see Figure 16a for an example of mutation in the T and B cells), while secondary immuno-deficiency is the result of pathogenic intrusion. Table 01 lists some specific examples of the various disorders.
  Figure 17 Auto-immune Diseases	Figure 18 Immunodeficiency, SCID [view large image]	The "~ genetic" in the table signifies possible genetic mutation causing the failure.

  
  

  Disease	Symptoms	Affected Body Parts	Failing Immune Components	Cure
  Allergy	Runny nose, itchy eyes, and sneezing	Nose, lungs, eyes, and skin	Excessive activation of the mast cells and basophils by antibody (~ genetic)	Avoid the environmental or dietary allergens, take steroids to reduce immunity
  Asthma	Wheezing, coughing, chest tightness, shortness of breath	Airways	Increase in eosinophils, macrophages, neutrophils, or T cells (~ genetic)	Avoid smoke, dust, fumes, take corticosteroids
  Rheumatoid Arthritis	Inflammation, swelling and pain at the joints	Joints	Antibodies attach to the joints (~ genetic)	Antirheumatic drugs, exercise, surgery
  Multiple Sclerosis (MS)	Pain, blindness, weakness, poor coordination, muscle spasms	Insulating covers of nerve cells in the brain and spinal cord	Destruction by the immune system (~ genetic)	No known cure
  Type 1 Diabetes	Frequent urination, increased thirst, increased hunger, and weight loss	Pancreas	Antibodies attack and destroy insulin producing cells (genetic)	Immunosuppressive drugs, injections of insulin, pancreas transplantation
  Inflammatory Bowel Disease (IBD)	Diarrhea, rectal bleeding, urgent bowel movements, abdominal pain, fever	Lining of the colon and small intestine	Immune system attacks elements of the digestive system (genetic)	Anti-inflammatory steroids, surgery
  Severe Combined Immunodeficiency (SCID)	Vulnerable to infectious diseases	Defect in one of at least 9 possible genes	Absence of functional T cells leading to improper B cells activation (genetic)	Bone marrow transplantation.
  Acquired Immune Deficiency Syndrome (AIDS)	Opportunistic infections and tumors	The whole body	Human immunodeficiency viruses (HIV) destroy T-helper (CD4) cells	No cure or vaccine, avoid unprotected sex and contaminated blood transfusions

  Table 01 Some Immune Disorder Diseases

  Immune disorders are not the only diseases suffered by humans. There is a list of "medical conditions" to cover all kinds of illness by courtesy of Wikipedia.
  
  [2024 Update]
  
  As inflammation becomes the scourges of modern world causing a lot of problems even its response to a disease has long gone. Here's a conversation on this subject (and more) with ChatGPT (in Italic text) :
  
  Inflammation is a crucial part of our response to injury (by lifeless objects) and disease (by bacteria and viruses). why does it persist to attack the body's own cells when the threats have gone?
  
  ChatGPT said:
  
  Inflammation is a tightly regulated biological response, but when this regulation fails, it can persist unnecessarily and begin attacking the body's own cells, leading to chronic inflammation or autoimmune diseases. This persistence often results from a complex interplay of factors:
  
  1. Dysregulated Immune Response
  " Failure to shut down the response: Normally, inflammation resolves after the threat is eliminated, aided by signals that suppress immune activity. If these resolution signals (e.g., specialized pro-resolving mediators) are deficient, inflammation can persist.
  " Immune memory errors: The immune system may mistakenly "remember" normal tissues as threats due to prior molecular mimicry (where a pathogen closely resembles body tissue) or genetic predispositions.
  2. Molecular Mimicry
  " Certain infections (e.g., streptococcal infections in rheumatic fever) can trigger the immune system to attack body tissues because some bacterial proteins closely resemble human proteins. This can perpetuate inflammation long after the infection is gone.
  3. Chronic Presence of Damage
  " Unresolved damage: If the original injury or infection caused long-term tissue damage, ongoing repair processes can maintain inflammation.
  " Persistent irritants: Some materials, like silica or asbestos, or undigested foreign bodies, can continuously trigger the immune system.
  4. Autoimmune Diseases
  " Autoimmune diseases like rheumatoid arthritis or lupus occur when the immune system misidentifies the body's own cells as harmful. Genetic predispositions, infections, or environmental factors can contribute to this misidentification.
  5. Failure to Clear Dead Cells or Debris
  " Dead cells and tissue debris need to be efficiently cleared to resolve inflammation. If these are not removed (due to defects in phagocytosis or signaling), they can act as a continuous source of inflammatory stimuli.
  6. Chronic Stress and Environmental Factors
  " Lifestyle factors such as poor diet, chronic stress, and pollution can cause low-grade, persistent inflammation by continuously activating immune cells.
  7. Senescent Cells
  " As we age, some cells enter a state called senescence, where they no longer divide but release pro-inflammatory signals (senescence-associated secretory phenotype, or SASP). This can lead to chronic inflammation.
  8. Gut Microbiome Dysbiosis
  " The gut microbiome plays a key role in immune regulation. Disruption of the microbiome can cause systemic inflammation by allowing harmful bacteria or their byproducts to cross into the bloodstream.
  9. Genetic and Epigenetic Factors
  " Variants in genes related to immune regulation (e.g., cytokines, HLA genes) can predispose individuals to excessive or persistent inflammatory responses.
  
  Conclusion Persistent inflammation is often the result of a failure in the resolution phase of the immune response. It is a hallmark of many chronic diseases (e.g., cardiovascular disease, diabetes, arthritis). Understanding the mechanisms behind this persistence is crucial for developing therapies that can modulate or resolve inflammation without suppressing the immune system entirely.
  
  Are there any cures to avoid such over-response?
  
  ChatGPT said:
  
  Preventing or mitigating an overactive immune response that leads to chronic inflammation or autoimmune disorders involves addressing the underlying triggers and restoring balance to the immune system. While "cures" depend on the specific condition and its cause, there are several approaches to manage and potentially prevent such over-responses:
  ________________________________________
  1. Anti-Inflammatory Medications
  " Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Commonly used for short-term relief of inflammation and pain.
  " Corticosteroids: Powerful suppressors of inflammation, though they come with side effects if used long-term.
  " Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Specifically for autoimmune diseases like rheumatoid arthritis to slow disease progression (e.g., methotrexate).
  " Biologics and Targeted Therapies:
  o Monoclonal antibodies (e.g., adalimumab, infliximab) targeting specific inflammatory molecules like TNF-alpha or interleukins.
  o JAK inhibitors (e.g., tofacitinib) that block signaling pathways involved in inflammation.
  ________________________________________
  2. Lifestyle Modifications
  " Dietary Changes:
  o Anti-inflammatory diet: Rich in fruits, vegetables, whole grains, healthy fats (e.g., omega-3 fatty acids), and low in processed foods and sugar.
  o Probiotics and prebiotics: Promote gut health, which plays a critical role in regulating the immune response.
  o Avoid triggers: Identifying and eliminating food intolerances or allergens that may provoke inflammation.
  " Exercise: Regular physical activity reduces systemic inflammation and helps maintain a healthy immune system.
  " Stress Management: Chronic stress can exacerbate inflammation. Practices like meditation, yoga, and deep breathing help regulate immune responses.
  ________________________________________
  3. Addressing Root Causes
  " Infections:
  o Treating bacterial, viral, or fungal infections that might have triggered the immune overactivity.
  " Environmental Exposures:
  o Limiting exposure to irritants like pollutants, smoking, or industrial chemicals that may trigger chronic inflammation.
  ________________________________________
  4. Gut Microbiome Restoration
  " Dysbiosis (imbalance of gut bacteria) can lead to chronic inflammation. Strategies include:
  o Probiotics: Supplementing beneficial bacteria.
  o Prebiotics: Providing food for healthy gut microbes (e.g., fiber-rich foods).
  o Fecal microbiota transplantation (in experimental stages for some conditions).
  ________________________________________
  5. Immunotherapy
  " Tolerance Induction: Strategies aimed at "retraining" the immune system to tolerate self-tissues. For example, therapies exposing the immune system to small amounts of autoantigens to reduce autoimmunity are being studied.
  " Stem Cell Therapy: Experimental treatments to reset the immune system, particularly for severe autoimmune diseases.
  ________________________________________
  6. Novel Therapies and Research
  " Targeting Resolution Pathways:
  o Research into promoting the body's natural inflammation-resolving processes (e.g., specialized pro-resolving mediators like lipoxins and resolvins derived from omega-3 fatty acids).
  " Gene Therapy:
  o Editing genes associated with immune dysfunction to correct the overactive response.
  ________________________________________
  7. Monitoring and Early Intervention
  " Regular Checkups: Monitoring for early signs of inflammation through blood markers like C-reactive protein (CRP) or interleukin-6.
  " Personalized Medicine: Using genetic, microbiome, and other individual-specific data to tailor interventions.
  ________________________________________
  8. Emerging Treatments
  " Nanomedicine: Using nanoparticles to deliver anti-inflammatory drugs precisely to the affected tissues.
  " Autoimmune Vaccines: Vaccines designed to modulate the immune system's response to specific self-antigens without broad suppression.
  
  ________________________________________
  Key Takeaway
  While no universal "cure" exists, combining lifestyle changes, early interventions, and targeted therapies offers promising ways to avoid or manage over-responses of the immune system. Ongoing research into inflammation resolution and immune tolerance mechanisms holds potential for more definitive treatments in the future.
  
  Is that an over-sight in the evolution of life?
  
  ChatGPT said:
  
  The tendency of the immune system to sometimes over-respond or attack the body's own tissues is not so much an "oversight" in evolution as it is a trade-off between protection and precision. Evolutionary processes prioritize traits that enhance survival and reproduction, even if those traits come with some risks or imperfections. Here are key reasons why such responses might arise:
  
  ________________________________________
  1. Evolutionary Trade-Offs
  The immune system evolved to prioritize survival against infections, which were historically the most significant threat to life. A hyper-vigilant immune system may occasionally overreact or target the body's own cells, but this is often a better trade-off than having an immune system that fails to respond effectively to pathogens.
  " Better safe than sorry: A strong, fast immune response could prevent deadly infections, even if it occasionally causes collateral damage.
  " Autoimmune risk as a side effect: The same immune mechanisms that allow for rapid and adaptable responses (e.g., through antibodies and T-cells) can also misfire and attack healthy tissue.
  ________________________________________
  2. Modern Context
  Our immune system evolved in an environment full of infections and physical challenges, which shaped its sensitivity and behavior. However, modern lifestyles have changed the context dramatically:
  " Reduced infections: In the absence of frequent infections, the immune system may turn its attention to less harmful stimuli (e.g., allergens or self-tissues).
  " Chronic exposure to triggers: Environmental changes, pollution, processed diets, and stress contribute to chronic low-grade inflammation.
  " Longer lifespan: Autoimmune diseases and chronic inflammation often develop later in life, beyond the age at which natural selection historically had a strong influence.
  ________________________________________
  3. Red Queen Hypothesis
  The immune system operates in a constant evolutionary "arms race" with pathogens. As pathogens evolve mechanisms to evade immune detection, the immune system evolves greater sensitivity. This heightened sensitivity increases the risk of mistakes, such as autoimmunity, but ensures survival in a world of ever-changing microbial threats.
  ________________________________________
  4. Genetic and Environmental Complexity
  " Genetic diversity: Some immune traits that predispose people to autoimmunity (e.g., certain HLA genes) also enhance resistance to specific infections. For example, the same genetic variants that make someone prone to inflammatory diseases might have helped ancestors survive epidemics.
  " Environmental triggers: Evolution could not account for artificial chemicals, sedentary lifestyles, and other modern stressors that amplify immune dysfunction today.
  ________________________________________
  5. Imperfections in Evolution
  " Evolution doesn't aim for perfection: Evolution works through random mutations and natural selection, leading to systems that are "good enough" for survival rather than flawless. The immune system, like all biological systems, is a product of compromises.
  " Path dependence: Once certain mechanisms evolved, they set constraints on how the immune system could further develop. For instance, self-reactive immune cells are eliminated during development, but the process is imperfect.
  ________________________________________
  6. Potential Adaptive Benefits
  Some degree of immune system "overreaction" might even have evolutionary advantages:
  " Wound healing: Inflammation helps with tissue repair and may promote faster recovery, even if it risks scarring or chronic inflammation.
  " Cancer prevention: A hyper-vigilant immune system may better detect and destroy early cancer cells.
  ________________________________________
  
  Conclusion Rather than an oversight, the immune system's imperfections reflect the inherent trade-offs of evolution. Its capacity to over-respond or misfire is a byproduct of its incredible complexity and adaptability. Evolution favors solutions that are beneficial in most circumstances, even if they come with occasional costs. However, modern lifestyles and environments exacerbate these costs, making what was once an advantageous system more prone to dysfunction.
  
  All animals and even plants would have some immune system to ward off the bacterial invasion?
  
  ChatGPT said:
  
  Yes, all living organisms, including animals and plants, have evolved immune systems to protect themselves against bacterial invasion and other pathogenic threats. While the mechanisms vary widely between groups of organisms, they all share the goal of identifying and neutralizing harmful invaders while maintaining the health of their own tissues.
  ________________________________________
  1. Immune Systems in Animals
  A. Vertebrates
  Vertebrates (e.g., mammals, birds, fish) have highly developed immune systems with two main components:
  " Innate immunity:
  o First line of defense, present from birth.
  o Includes physical barriers (skin, mucous membranes), chemical barriers (stomach acid, antimicrobial peptides), and cellular responses (phagocytic cells like macrophages and neutrophils).
  " Adaptive immunity:
  o Unique to vertebrates, involving specialized cells (T-cells and B-cells) and antibodies.
  o Memory cells enable long-term protection against previously encountered pathogens.
  B. Invertebrates
  Invertebrates (e.g., insects, mollusks, crustaceans) lack adaptive immunity but possess robust innate immune systems:
  " Physical barriers: Exoskeletons or protective shells.
  " Cellular immunity: Hemocytes (immune cells) that engulf and destroy pathogens.
  " Chemical defenses: Antimicrobial peptides (AMPs) produced by cells to kill bacteria.
  " Example: The Toll pathway in fruit flies regulates the production of AMPs and is analogous to some innate immune pathways in vertebrates.
  ________________________________________
  2. Immune Responses in Plants
  Plants lack mobile immune cells but have sophisticated innate immune systems to detect and respond to pathogens.
  A. Structural Defenses
  " Cell walls: Provide a physical barrier against pathogens.
  " Cuticle: A waxy layer on leaves and stems that prevents microbial entry.
  " Trichomes: Hair-like structures that can trap or deter invaders.
  B. Molecular Defenses
  " Pattern Recognition Receptors (PRRs): Detect microbe-associated molecular patterns (MAMPs) like bacterial flagellin or fungal chitin.
  " Effector-Triggered Immunity (ETI): Recognizes specific pathogen effectors and mounts a localized defense response, often leading to hypersensitive response (localized cell death to contain the pathogen).
  C. Chemical Warfare
  " Phytoalexins: Antimicrobial compounds synthesized in response to infection.
  " Reactive oxygen species (ROS): Toxic to pathogens and can strengthen cell walls.
  D. Systemic Resistance
  " Plants communicate infection signals across tissues to prepare distant cells for potential attack, a process called Systemic Acquired Resistance (SAR).
  ________________________________________
  3. Microbial Symbiosis
  Many organisms, including both animals and plants, utilize beneficial microbes to support their immune defenses:
  " Gut microbiota in animals: Helps digest food, outcompete harmful microbes, and regulate immune responses.
  " Rhizosphere microbiota in plants: Beneficial soil microbes can protect roots by outcompeting pathogens or inducing plant immune responses.
  ________________________________________
  4. Evolutionary Conservation
  Certain immune strategies are highly conserved across life forms:
  " Antimicrobial peptides (AMPs): Found in animals, plants, and even some fungi.
  " Pattern recognition systems: Detecting conserved features of pathogens is a shared strategy in animals (e.g., Toll-like receptors) and plants (e.g., PRRs).
  " Programmed cell death: Used by plants (hypersensitive response) and animals (apoptosis) to limit pathogen spread.
  
  ________________________________________
  Conclusion
  
  While the specific mechanisms differ, the presence of immune systems in all animals and plants underscores their importance in the ongoing evolutionary battle between hosts and pathogens. These systems have evolved diverse and sophisticated strategies to ensure survival in a world teeming with microbial life.
  
  So the entire biosphere is just the coexistence between bacteria and more complex multicellular life forms. It will cease to exist once the Sun evolves to the supergiant phase.
  
  ChatGPT said:
  
  Yes, in many ways, the biosphere can be seen as a delicate interplay between bacteria (and other microorganisms) and more complex multicellular life. Bacteria are foundational to life on Earth, influencing everything from nutrient cycles to the evolution of multicellular organisms. The eventual end of the biosphere, tied to the Sun's life cycle, reminds us of the impermanence of all ecosystems, no matter how robust.
  ________________________________________
  1. The Coexistence of Life and Bacteria
  " Bacteria as Life's Foundation:
  o They were among the first life forms on Earth, shaping the planet's environment through processes like photosynthesis (e.g., cyanobacteria) and nitrogen fixation.
  o Bacteria are critical for nutrient cycling (e.g., decomposition, carbon and nitrogen cycles) that sustain ecosystems.
  o Multicellular life evolved in close interaction with bacteria, including symbiotic relationships (e.g., mitochondria and chloroplasts, which originated as bacteria).
  " Interdependence:
  o Complex life depends on bacteria for essential processes (e.g., digestion in animals, nitrogen fixation for plants).
  o Conversely, bacteria benefit from multicellular hosts as habitats and sources of nutrients.
  ________________________________________
  2. The Sun's Evolution and the End of the Biosphere
  The ultimate fate of Earth's biosphere is tied to the Sun's lifecycle. Here's how it unfolds:
  A. The Sun's Current Stage (Main Sequence)
  " The Sun is currently about halfway through its 10-billion-year main sequence phase, where it steadily burns hydrogen into helium.
  " This phase is hospitable for life, as it provides stable energy.
  B. Transition to a Red Giant (5 Billion Years from Now)
  " The Sun will exhaust its hydrogen fuel, causing its core to contract and its outer layers to expand, turning it into a red giant.
  " Effects on Earth:
  o The Sun's luminosity will increase, causing Earth's surface to become too hot to sustain liquid water, ending most forms of life.
  o The oceans will evaporate, and the atmosphere will be stripped away.
  o Complex life will perish; only extremophilic microbes might persist in subterranean or otherwise shielded environments for a while.
  C. White Dwarf Phase
  " After shedding its outer layers (forming a planetary nebula), the Sun will collapse into a white dwarf.
  " Earth's surface will cool to an icy, inhospitable state, marking the end of any remaining life.
  ________________________________________
  3. The Fragile Yet Resilient Biosphere
  The history of life on Earth shows remarkable resilience-life has survived mass extinctions, asteroid impacts, and global climate shifts. However:
  " Microbial Life's Endurance: Bacteria and extremophiles are the most likely to persist until Earth's environment becomes completely uninhabitable.
  " Limits of Adaptation: Even these hardy organisms will eventually succumb as conditions exceed the threshold for biological activity.
  ________________________________________
  4. Beyond the Sun: Continuation of Life Elsewhere?
  While the Sun's death will end the Earth's biosphere, life could continue in other parts of the universe:
  " Exoplanets: Around stable stars with habitable zones.
  " Artificial Habitats: If humans or other advanced civilizations create sustainable environments beyond Earth.
  " Panspermia: The possibility that life's building blocks could be transferred to other planetary systems through meteoroids or comets.
  ________________________________________
  
  Conclusion
  
  The coexistence of bacteria and multicellular life defines the Earth's biosphere, but it is ultimately finite, limited by the Sun's evolution. The inevitability of the Sun's transformation into a red giant underscores the temporary nature of all planetary ecosystems. However, the persistence of life across vast timescales offers hope that its legacy might continue elsewhere in the cosmos (in a futile attempt).
  
  See "The End".
  
  
  
  There is no need to lament the end of "life". Every process has a beginning and end; even the universe would end in "heat death" as the dark energy progresses into the far future (In a heat death scenario, the universe will reach a state of maximum entropy, where all matter dissipates into entropy. This means that the universe will no longer be able to sustain processes that increase entropy, like life).
  
  [End of 2024 Update]