Kurzgesagt – In a Nutshell
Sources – What doesn't kill you makes you weaker.
Thanks to our expert —
Prof. Dr. Thomas Brocker
Institute for Immunology, LMU München
Prof. Maristela Martins de Camargo
Institute of Biomedical Sciences, University of São Paulo
- The moment your cells notice that something is off, they release an onslaught of signal proteins called cytokines. They are like air raid sirens that activate all sorts of immune cells, that then themselves release many more cytokines, amplifying the alarm. Soon you are flooded with signals that trigger precautions and counter-measures. Mobilization is under way.
We made a whole video about the immune system and the daily, epic defense battle in your body.
#Kurzgesagt (2021): How The Immune System ACTUALLY Works – IMMUNE
https://www.youtube.com/watch?v=lXfEK8G8CUI&t=499s
- Your brain activates sickness behavior and reorganizes your body's priorities to defense. The first thing you notice is that your energy level drops and you get sleepy. You feel apathetic, often anxious or down and you lose your appetite. Your sensitivity to pain is heightened and you seek out rest. All of this serves to save your energy and reroute it into your immune response.
The numerous effects such as fatigue, loss of appetite, social withdrawal can be called "sickness behaviors". We can’t go into every detail here and the benefit of some symptoms is debatable, but basically many symptoms serve to fight the disease on different levels and the following sources provide an overview. For example, there are various theories as to why people are not hungry when they have an infection.
#Schrock, J. M. et al. (2020): Lassitude: The emotion of being sick. Evolution and Human Behavior, Vol. 41 (1)
https://www.sciencedirect.com/science/article/abs/pii/S1090513819302429?via%3Dihub
Quote: “1. Increasing food intake requires paying the costs (physical, social, ecological, or economic) of obtaining more food.
2. In many environments, increasing one's own food intake may reduce the food available to family members, thereby incurring inclusive fitness costs.
3. Greater food consumption increases the rate of pathogen intake, which further increases the immune system's workload. In some cases, food consumption may also provide energy and nutrients that fuel the reproduction of pathogenic agents.
4. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are molecules produced as a byproduct of cellular metabolism. At low/moderate levels, ROS and RNS have beneficial effects, including anti-pathogen properties (Valko et al., 2007).
(...)
5. Increasing food intake increases the amount of energy spent on diet induced thermogenesis (DIT), which reflects the increase in metabolic rate caused by food consumption. Consuming food may actually decrease the proportion of the energy budget that is immediately available for immune function. While consuming more food increases energy availability in the long term, digesting and metabolizing food imposes a short-term energetic cost (5–15% of nonfasting TEE, or even more when consuming high-protein diets) (Westerterp, 2004). The energy cost of human DIT following a meal temporarily elevates metabolic rate by about 20–30%, returning to near pre-meal levels approximately 4–6 h later (Secor, 2009). Thus, there is a period of a few hours post-ingestion when a substantial proportion of metabolic resources are invested on DIT. During active infection, investment in DIT at the cost of immune function may provide a critical window of opportunity for rapidly replicating pathogens to reach a lethal population size.”
#Wrotek, S. et al. (2020): Let fever do its job - The meaning of fever in the pandemic era. Evolution, medicine, and public health, Vol. 9 (1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/
Quote: “In addition to the local inflammatory response to infection, the systemic defensive responses to infection are known as the acute phase response [13, 89]. Besides fever, other components include mobilization of leukocytes; production of a variety of protective proteins (acute phase proteins); reduced blood levels of iron, zinc, and manganese; reduced erythrocyte production (beyond simple iron deficiency); reduced appetite (anorexia); breakdown of muscle protein and fat (cachexia or hypercatabolism); and the uncomfortable, motivation-sapping sickness symptoms and behaviors we associate with infection, including lethargy, depression and aches. The acute phase response is induced and regulated by the infected individual’s own pro-inflammatory cytokines and other mediators acting on specific cell receptors. Because these responses are initiated by the host, not by the pathogen, and because they are evolutionarily conserved—appearing in all vertebrates and many invertebrates [32, 33]—the acute phase response is considered an adaptive non-specific response to infection.
While some components of the acute phase response are generally accepted to be beneficial, other acute phase responses—lassitude, anorexia and cachexia—can seem more harmful than beneficial and their function has been debated [16, 18, 90–92]. Each of the components of the acute phase response involves either self-harm or the expenditure of limited resources. This includes manufacturing acute phase proteins and supporting an increased metabolic rate. Indeed, in humans, a 2°C higher febrile temperature uses about 20% more energy than that used at normal temperature [17, 93].
The most widely-cited explanation for these elements of the acute phase response was proposed by Hart [16] and extended by Straub et al. [92]. This hypothesis centers around the need to conserve resources and to reallocate energy resources towards supporting an effective immune defense. Resources are conserved by restricting less essential activities and not foraging for food. Another hypothesis is that replicating pathogens can be especially vulnerable to many of the harmful components of the acute phase response, so that the harm involved is directed more to pathogens than to the host [18, 49]. In this view, reduced appetite is a nutritional strategy that disproportionately starves pathogens of energy and micronutrients. A recently proposed additional hypothesis views sickness behavior as an evolved defense that primarily benefits close relatives. In this view, termed the ‘inclusive behavioral immune system’, social withdrawal and self-isolation prevent infection from spreading to relatives who share genes with an infected individual [91, 94].”
- Take fever: it speeds up your metabolism and makes your cells work harder and faster, while creating heat that is pretty stressful for many invaders – but it uses up a lot of calories to maintain.
During fever, the “thermostat” in the hypothalamus (a control center in the brain) is dialed up. This happens through so-called pyrogens, which certain immune cells produce in their defense to fight against pathogens. The brain now sets a new, higher body temperature. The body then generates new heat (e.g. by shivering) and conducts heat from the surface to the center of the body (which can be felt as you feeling cold).
#McCance, K. L. et al. (2013): Pathophysiology: The Biologic Basis for Disease in Adults and Children. Elsevier Health Sciences
https://books.google.it/books?id=l9XsAwAAQBAJ&pg=PA498&redir_esc=y#v=onepage&q&f=false
The source already mentioned above, has a nice summary of the benefits of fever:
#Wrotek, S. et al. (2020): Let fever do its job - The meaning of fever in the pandemic era. Evolution, medicine, and public health, Vol. 9 (1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/
Quote: “Fever’s ability to protect against infection has been well established through numerous in vitro and in vivo experiments and has been extensively reviewed [13, 14, 16, 17, 23]. A variety of infection-fighting mechanisms have been proposed for fever, though the relative importance of each mechanism remains to be established. Febrile temperatures enhance a variety of immune cells functions, reviewed in [13] and [14]. These include motility, phagocytosis and reactive oxygen species production by neutrophils and monocytes, as well as enhanced function of natural killer cells, dendritic cells, T-helper cells and antibody-producing cells. Febrile temperatures increase type I interferon responses [35], notable here because interferons have antiviral activities, and reduced type I interferon activity is associated with severe COVID-19 disease [36]. In addition, fever can induce heat shock proteins in both pathogens and host cells, resulting in downstream induction of adaptive and innate components of the host immune response [17, 37]. Fever also increases the vulnerability of rapidly dividing pathogens to destruction, acting in concert with other stresses such as iron deprivation [38] and the effects of antibiotics [39].”
One study looked at patients who suffered from overheating (hyperthermia) for a variety of reasons. Usually, you cool down these people. The study examined how various values in the metabolism changed as a result. The body temperature was lowered by an average of more than 2°C and it was found that the daily energy expenditure in kcal per day decreased from an average of 2,481 to 1,990 (V02 = oxygen consumption, CO2 production).
#Manthous, C. A. et al. (1995): Effect of Cooling on Oxygen Consumption in Febrile
Critically III Patients. American Journal of Respiratory and Critical Care Medicine, Vol. 151
https://pubmed.ncbi.nlm.nih.gov/7812538/
Quote: “As temperature was reduced from 39.4 ± 0.8 to 37.0 ± 0.50 °C, VO2 decreased from 359.0 ± 65.0 to 295.1 ± 57.3 ml/min (p < 0.01) and VCO2 decreased from 303.6 ± 43.6 to 243.5 ± 37.3 ml/min (p < 0.01). The respiratory quotient (RQ) did not change significantly, and calculated energy expenditure decreased from 2,481 ± 426 to 1,990 ± 33 kcal/day (p < 0.01).”
- B Cells produce millions of antibodies every second, each requiring hundreds of amino acids to construct. Billions or even trillions of proteins need to be made to refresh the complement system, a minefield inside your blood. Cytokines, the mobilisation and information signals, also need constant refreshing.
#Alberts, B. et al. (2002): The Shape and Structure of Proteins. Chapter 24 - The Adaptive Immune System - B Cells and Antibodies. Molecular Biology of the Cell, 4th edition
https://www.ncbi.nlm.nih.gov/books/NBK26884/
Quote: “Effector B cells can begin secreting antibody while they are still small lymphocytes, but the end stage of their maturation pathway is a large plasma cell (see Figure 24-7B), which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second.”
A healthy adult has about 5.3 micro molar of C3 in their blood. For this calculation, we'll round it to 5. One micro molar equals 6.022 x 1017 molecules in a liter. An average adult contains roughly 5 liters of blood. So 6 x 1017 x 5 x 5 = 1.5x 1019, or 15 quintillion.
#Rodriguez, E. et al. (2015): A Revised Mechanism for the Activation of Complement C3 to C3b - A molecular explanation of a disease-associated polymorphism. Immunology, Vol. 290 (4)
https://www.jbc.org/article/S0021-9258(20)57771-5/fulltext
Quote: “The complement system comprises over 30 proteins arranged in a cascade as part of the innate immune response and is important for clearing immune complexes and cellular debris and for the elimination of pathogens (1, 2). C3 (complement component 3) is the most abundant complement protein, occurring at about 1.0 mg/ml (5.3 μm) in plasma and at higher levels during inflammation.”
- So it reaches for the easiest source of amino acids and starts breaking down your muscles. All that muscle that you worked so hard for is sacrificed to keep you alive.
The phase in which you feel really sick, i.e. you have no appetite, have a fever and you're sleepy, is called the "acute phase response". It is used to gather all possible resources for the defense fight, i.e. resources for the actual immune defense, for energy and for repairing damage. It can take weeks to recover from this fight.
#Friman, G. & Ilbäck, N.-G. (1998): Acute Infection: Metabolic Responses,
Effects on Performance, Interaction with Exercise, and Myocarditis. International Journal of Sports Medicine, Vol. 3
https://pubmed.ncbi.nlm.nih.gov/9722283/
Quote: “Acute infections are associated with multiple host responses that are triggered by cytokines and correlated to fever, malaise and anorexia. The purpose of this systemic acute phase host reaction ("the acute phase response") is to mobilize nutrients for the increased needs of the activated immune system. as well as for energy production and tissue repair. Important effects include wasting of striated muscle. degradation of performance-related metabolic enzymes and, concomitantly, deteriorated central circulatory function. These effects result in decreased muscle and aerobic performance, the full recovery of which may require several weeks to months following weeklong febrile infections.”
The body takes amino acids mainly from skeletal muscles and converts them to proteins or energy in the liver. However, it is also important to note that the heart (which is also a muscle) is also affected and can be weakened.
#Friman, G. & Ilbäck, N.-G. (1998): Acute Infection: Metabolic Responses,
Effects on Performance, Interaction with Exercise, and Myocarditis. International Journal of Sports Medicine, Vol. 3
https://pubmed.ncbi.nlm.nih.gov/9722283/
Quote: “An important feature of the acute phase reaction is the induction of a generalized catabolism of muscle protein. In humans, muscle protein degradation and tissue wasting was originally shown in experimental nitrogen balance studies of viral (sand fly fever), bacterial (tularemia) and protozoan (malaria) infections (Fig. 2) (9). At the onset of fever, a negative nitrogen balance develops which persists throughout the active phase of the infection. In each of these infections, the accumulated nitrogen loss at the end of the acute disease is related to the height and duration of the fever. A large part of the amino acids that are released from the muscles, including the heart muscle, are taken up by the liver and are used for de novo synthesis of proteins, such as acute phase proteins participating in the combat of the infection, as well as for energy production through gluconeogenesis (Fig. 3). The skeletal muscles, making up approximately 45% of the body weight, constitute the major source of the amino acids (9) but the heart muscle also contributes (48).”
- One of your first responders are Neutrophils – imagine crazy aggressive chimps with machine guns. If a Neutrophil encounters enemies it showers them with chemicals that cut them open but can also damage civilian cells, especially if the patient is already compromised, for example by smoking.
Neutrophils can fight pathogens by ejecting some sort of net of their DNA combined with other substances (NETs: neutrophil extracellular traps). They die in the process and there are various studies on collateral damage, e.g. to the lungs (pneumocytes) or blood vessels (vascular endothelium).
#Iba, T. et al. (2014): Neutrophil extracellular traps, damage-associated molecular patterns, and cell death during sepsis. Acute medicine & surgery, Vol. 1(1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997206/#ams210-bib-0017
Quote: “In contrast to the well understood cell death types apoptosis and necrosis (oncosis), a unique type of cell death known as “NETosis”, which involves the release of neutrophil extracellular traps (NETs),9 has become well publicized. NETosis plays an important role in the removal of pathogens, but when cellular components that have antimicrobial effects, such as histones, myeloperoxidase, and elastase, are dumped into the circulation, they are also harmful to the host cells. (...)
Neutrophil extracellular traps, released by neutrophils, were first described by Brinkmann et al. in 2004.9 Neutrophils have an important role in the first line of defense against invading microorganisms. Phagocytosis is well known as the process by which neutrophils remove pathogens. Aside from this, a further mechanism named NETosis has become accepted. This is the process whereby NETs are expelled extracellularly and microorganisms are removed through contact with these NETs, which is a network of chromatins (DNA) attached to bactericidal nucleic proteins such as histones, myeloperoxidase, and elastase (Figs. 1, ,22).10 (...) The process of NETosis is a powerful means of disposing of pathogens; however, the damage to host cells is also significant, in particular on the vascular endothelium and on pneumocytes.17 Granular proteins such as myeloperoxidase and elastase, and nucleic substances such as histones and nucleosomes are thought to be some of the harmful factors in NETs.
There does not appear to be any organ specificity in the pathogenesis of NETs, but there have been many reports focusing on the lungs, where neutrophils are physiologically highly distributed. In an LPS-induced acute lung injury model, it was reported that the formation of NETs within the alveoli and bronchoalveolar lavage fluid correlates with the finding of acute lung injury.18 However, based on the total number of neutrophils, evidence suggests that NETosis occurs in only a low proportion of cells, estimated at 10–30%.19 ”
#Lodge, K. M. et al. (2020): The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host. International Journal of Molecular Sciences, Vol. 21 (4)
https://www.mdpi.com/1422-0067/21/4/1183
Quote: “In order to affect pathogen killing, these granules can fuse with the pathogen-containing phagosome, releasing their toxic contents into the vacuole to destroy the ingested micro-organisms. Neutrophil granules can also fuse with the plasma membrane, secreting their arsenal of proteins extracellularly (degranulation); this may be in response to pathogens that cannot be internalised, or due to an overwhelming extracellular inflammatory milieu [3,4]. In addition, granule proteins can be released extracellularly in association with neutrophil extracellular traps (NETs) [5]. Although the primary function of granule exocytosis is host defence, the release of cytotoxic granules into the extracellular environment also has the potential to cause damage to nearby host tissue.”
The damage that cigarette smoke causes is very complex and not fully understood. The following source can therefore only provide a small insight.
It shows that cigarette smoke can "reprogram" neutrophils. They switch from programmed cell death, apoptosis,(which causes no inflammation) to dying, necrosis, which causes inflammatory responses.
#Heijink, I. H. et al. (2014): Cigarette Smoke Induced DAMP Release from Necrotic Neutrophils Triggers Pro-inflammatory Mediator Release. American Journal of Respiratory Cell and Molecular Biology, Vol. 52 (5)
Quote: “The chronic and pathogenic inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) is predominantly characterized by neutrophilic infiltration, and neutrophil numbers show a positive correlation with disease progression (1). The major causative factor for the development and progression of COPD is chronic exposure to noxious gasses and particles (e.g., cigarette smoke [CS]) (2–4). However, the mechanism by which the inflammatory response to CS is maintained and perpetuated is not fully understood. Neutrophilic inflammation is a defense mechanism to remove pathogens and to initiate repair of injured tissue. However, when this host defense mechanism is exaggerated or inefficiently cleared, inflammation can become chronic, resulting in lung tissue damage and remodeling (5, 6). During physiological conditions, neutrophils undergo apoptosis shortly after their recruitment, leading to resolution of the inflammatory response (7) and preventing development of chronic inflammatory diseases (8, 9). Apoptosis, a regulated and caspase-dependent form of cell death, requires sufficient levels of cellular energy (ATP), which is produced by mitochondria. Previously, we showed that ATP levels decrease upon CS exposure of human airway epithelial cells (10), which is likely mediated by disruption of the mitochondrial respiratory chain. Under this condition, an apoptotic trigger induces a switch from apoptosis to necrosis (10).
(...)
We hypothesize that CS exposure disturbs mitochondrial function of lung neutrophils, causing a switch from apoptotic to necrotic cell death with concomitant release of DAMPs. Repeated CS exposure will therefore promote the production of CXCL8 by innate immune cells, including epithelial cells, and perpetuate the inflammatory response to CS.
(...)
In conclusion, our study demonstrates that CS induces dysfunction of both intrinsic and extrinsic apoptotic programs in neutrophils, leading to a switch from apoptosis to necrosis, and the subsequent release of DAMPs. These molecules act as alarmins to activate proinflammatory responses of the airway epithelium and promote neutrophilic airway inflammation in a self-augmenting process. Our findings contribute to the understanding of chronic airway inflammation in COPD and may open new therapeutic strategies aimed at the inhibition of neutrophil necrosis and DAMP release.”
At the same time, however, the image of neutrophils in science has changed: Away from the immune cell armed to the teeth, which drags everything to ruin, to a player that has an important role in the resolution of inflammation and in tissue repair. This review provides an overview of this "new role".
#Peiseler, M. & Kubes, P. (2019): More friend than foe: the emerging role of neutrophils in tissue repair. Journal of Clinical Investigation, Vo. 129 (7)
https://www.jci.org/articles/view/124616
Quote: “However, until recently, the prevailing view of neutrophils was that of simple foot soldiers of the innate immune system: equipped with a lethal arsenal of proteases and oxidants, neutrophils rapidly invade sites of infection to eradicate pathogens and prevent their spread (8, 9). Upon completion of their tasks, neutrophils were thought to commit suicide on the battlefield. Overexuberant neutrophil recruitment was associated with collateral tissue damage, defective healing, and chronic inflammation (2). Adding to this was the discovery of NETosis (10), a novel killing mechanism by which neutrophils release neutrophil extracellular traps (NETs), nuclear DNA coated with histones, proteases, and granular and cytosolic proteins to entrap bacteria. While effective in capturing bacteria, NETs produced in infections and noninfectious perturbations have been postulated to cause bystander tissue damage (11). The prevailing and rather simplistic view of the neutrophil has undergone substantial revision in the past decade, and numerous novel paradigms have emerged (12).
(...)
It is now apparent that neutrophils have crucial homeostatic functions in various organ systems (14, 15): they interact with cells of the innate and adaptive immune system to direct immune responses (16), are implicated in chronic inflammatory diseases (17), experience shaping by the microbiome (18), and contribute to injury repair. Tumors may also hijack these properties to aid in growth and metastasis (19). Yet, despite encouraging advancements in many areas in recent years, some fundamentally unresolved questions remain (20). In this Review, we outline the neutrophil’s role in tissue injury and repair, focusing on its emerging role in resolving inflammation and participation in repair. Since the mechanisms by which neutrophils are integrated in resolution are likely context-dependent, we also highlight neutrophil contributions to repair in different organs.”
- On top of that the microorganisms that invade you often release chemicals and toxins that can cause significant damage and cell death.
One example is the type III secretion system (T3SS), which is responsible for the virulence of numerous diseases. This system transports proteins ("effectors") into the host cell and triggers various processes there that damage the organism.
For example, the YopP/J and YopM proteins of the plague pathogen Yersinia spp. (table 1) are responsible for initiating apoptosis, the programmed cell death (e.g., of immune cells such as macrophages).
#Dean, P. (2011): Functional domains and motifs of bacterial type III e¡ector proteins and their roles in infection. FEMS Microbiology Reviews, Vol. 35
https://pubmed.ncbi.nlm.nih.gov/21517912/
Quote: “Several of the world’s most important diseases are caused by bacterial pathogens that deliver effector proteins into eukaryotic host cells using a type three secretion system (T3SS) (Troisfontaines & Cornelis, 2005; Table 1). Bacteria that possess a T3SS cause a wide range of diseases in plants, animals and humans (Troisfontaines & Cornelis, 2005), while others have symbiotic relationships with plant or animal hosts (Preston, 2007; Table 1). The best-studied pathogens to date, which have provided the most knowledge about bacterial effectors, are species of Chlamdyia, Salmonella, Shigella, Yersinia, Pseudomonas, Xanthomonas, Ralstonia and pathogenic Escherichia coli. In all of these organisms, the T3SS is an essential virulence factor, highlighting the central importance of the effector proteins in disease (Coburn et al., 2007). Up to 100 different effector proteins may be delivered into individual host cells by a single bacterium (see Kenny & Valdivia, 2009; Table 1). Effectors are often multifunctional proteins with many overlapping properties and may also cooperate with each other to orchestrate specific responses in the host cell (see Galan, 2009; Fig. 1). In general, although not always, type three effectors display subtle functions inside host cells, often causing more restrained alterations in host cell physiology compared with the more overt effects of bacterial exotoxins. The effector protein family is evolutionarily diverse and exhibits a range of functions within host cells (Fig. 1), targeting most aspects of eukaryotic physiology (Fig. 1).”
#Pha, K. & Navarro, L. (2016): Yersinia type III effectors perturb host innate immune responses. World Journal of Biological Chemistry, Vol. 7 (1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768113/
Quote: “Similar to what was observed with extracellular Yersinia, translocation of YopJ by intracellular Yersinia induces apoptosis of macrophages[96]. Apoptosis is a process initiated by an extracellular “death” signal (extrinsic pathway) or an intracellular signal (intrinsic pathway) that converges on the mitochondria and the release of cytochrome C. The extrinsic and intrinsic pathway involve the activation of caspase-8 or caspase-9, respectively, and the subsequent processing of the effector caspases (e.g. caspase-3) to induce apoptosis[97]. YopP/J-mediated inhibition of the MAPK and NFκB signaling pathways, along with Toll-like receptor 4 signaling, induces apoptosis of macrophages and dendritic cells[98-102].
(...)
Moreover, YopM has also been shown to activate caspase-3 to presumably induce apoptosis of PMNs and/or macrophages in the liver of infected mice, and thus promote Yersinia virulence[137].”
- Your Neutrophils and Macrophages help by releasing chemicals that signal the body to start repairs, and most of the damage is quickly filled up with regrowing cells.
One of the weapons neutrophils use to fight pathogens (NETs, as seen above) can also serve as a control of inflammation by trapping messengers that promote inflammation (rightmost column). In addition, they can stop the inflammation signal chain by eliminating debris. They also release substances that can cause a resolution of the inflammation. For example, they release a protein (annexin A1 or AnxA1) that prevents further recruitment of neutrophils.
#Peiseler, M. & Kubes, P. (2019): More friend than foe: the emerging role of neutrophils in tissue repair. Journal of Clinical Investigation, Vo. 129 (7)
- But others are filled with collagen, a sort of fix-all organic cement that gives your gooey tissue structural integrity.
You have seen the result on your skin as scars. A scar is different from the original tissue. It has no functioning cells in it, it is like a sloppily applied cement patch. It can’t do what the original tissue was doing.
Wound healing is very complex. In the following, we can only give a rough overview of the main stages. However, the source below provides a comprehensive introduction to the topic. The process is illustrated using an example of an injury on the skin, but is basically similar everywhere in the body.
The first stage is to limit the direct damage: stop the blood flow, alert the immune system and clean up. The second phase builds new tissue and new vessels slowly and replaces the material in the first phase as the wound closes. In the third stage, the former wound adapts to the environment. An attempt is made, so to speak, to remodel the original tissue.
Gurtner, G. et al. (2008): Wound repair and regeneration. Nature, Vol. 453
https://www.nature.com/articles/nature07039
Quote: “In general, the wound repair process occurs in almost all tissues after exposure to almost any destructive stimulus. Thus, the sequence of events that follows a myocardial infarction (heart attack), for example, is remarkably similar to that following a spinal-cord injury, a burn or a gunshot wound, despite the different types of insult and the different organs affected. Likewise, scar formation that occurs during wound repair leads to similar tissue dysfunction wherever it takes place.”
(...)
“Figure 1 | Classic stages of wound repair. There are three classic stages of wound repair: inflammation (a), new tissue formation (b) and remodelling (c). a, Inflammation. This stage lasts until about 48 h after injury. Depicted is a skin wound at about 24–48 h after injury. The wound is characterized by a hypoxic (ischaemic) environment in which a fibrin clot has formed. Bacteria, neutrophils and platelets are abundant in the wound. Normal skin appendages (such as hair follicles and sweat duct glands) are still present in the skin outside the wound. b, New tissue formation. This stage occurs about 2–10 days after injury. Depicted is a skin wound at about 5–10 days after injury. An eschar (scab) has formed on the surface of the wound. Most cells from the previous stage of repair have migrated from the wound, and new blood vessels now populate the area. The migration of epithelial cells can be observed under the eschar. c, Remodelling. This stage lasts for a year or longer. Depicted is a skin wound about 1–12 months after repair. Disorganized collagen has been laid down by fibroblasts that have migrated into the wound. The wound has contracted near its surface, and the widest portion is now the deepest. The re-epithelialized wound is slightly higher than the surrounding surface, and the healed region does not contain normal skin appendages.”
After chronic or severe diseases, part of the normal wound healing can be pathological, which is called fibrosis.
#Henderson, N. C. et al. (2020): Fibrosis: from mechanisms to medicines. Nature, Vol. 587
https://www.nature.com/articles/s41586-020-2938-9
Quote: “Fibrosis is not a disease but rather an outcome of the tissue repair response that becomes dysregulated following many types of tissue injury, most notably during chronic inflammatory disorders. The formation of fibrotic tissue, which is defined by the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin, is in fact a normal and important phase of tissue repair in all organs. When tissues are injured, local tissue fibroblasts become activated and increase their contractility, secretion of inflammatory mediators, and synthesis of ECM components; together, these changes initiate the wound healing response. When damage is minor or non-repetitive, wound healing is efficient, resulting in only a transient increase in the deposition of ECM components and facilitating the restoration of functional tissue architecture.”
- A scar on your heart makes it beat a tiny bit weaker. A scar on the lungs no longer captures oxygen. A scar on your liver makes it a worse filter.
The following source provides an overview of possible organ damage. For example, there is evidence that a long-term consequence of COVID-19 disease may be weakening of the heart. The reasons for this are not yet entirely clear, but various processes are suspected, such as cell death of cardiac muscle cells (cardiomyocytes) as a direct result of viral invasion.
#Xie, Y. et al. (2022): Long-term cardiovascular outcomes of COVID-19. Nature Medicine 28
https://www.nature.com/articles/s41591-022-01689-3
Quote: “In this study involving 153,760 people with COVID-19, 5,637,647 contemporary controls and 5,859,411 historical controls—which, altogether, correspond to 12,095,836 person-years of follow-up—we provide evidence that, beyond the first 30 d of infection, people with COVID-19 exhibited increased risks and 12-month burdens of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease and other cardiac disorders. The risks were evident regardless of age, race, sex and other cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease and hyperlipidemia; they were also evident in people without any cardiovascular disease before exposure to COVID-19, providing evidence that these risks might manifest even in people at low risk of cardiovascular disease.
(...)
The mechanism or mechanisms that underlie the association between COVID-19 and development of cardiovascular diseases in the post-acute phase of the disease are not entirely clear11,12. Putative mechanisms include lingering damage from direct viral invasion of cardiomyocytes and subsequent cell death, endothelial cell infection and endotheliitis, transcriptional alteration of multiple cell types in heart tissue, complement activation and complement-mediated coagulopathy and microangiopathy, downregulation of ACE2 and dysregulation of the renin–angiotensin–aldosterone system, autonomic dysfunction, elevated levels of pro-inflammatory cytokines and activation of TGF-β signaling through the Smad pathway to induce subsequent fibrosis and scarring of cardiac tissue11,13,14,15,16,17. An aberrant persistent hyperactivated immune response, autoimmunity or persistence of the virus in immune-privileged sites has also been cited as putative explanations of extrapulmonary (including cardiovascular) post-acute sequelae of COVID-19 (refs. 11,13,14,18). Integration of the SARS-CoV-2 genome into DNA of infected human cells, which might then be expressed as chimeric transcripts fusing viral with cellular sequences, has also been hypothesized as a putative mechanism for continued activation of the immune-inflammatory-procoagulant cascade19,20. These mechanistic pathways might explain the range of post-acute COVID-19 cardiovascular sequelae investigated in this report. A deeper understanding of the biologic mechanisms will be needed to inform development of prevention and treatment strategies of the cardiovascular manifestations among people with COVID-19.”
- Which makes evolutionary sense, as this protects our species from being wiped out by a single infection.
#Liston, A. et al. (2021): Human immune diversity: from evolution to modernity. Nature Immunology, Vol. 22
https://www.nature.com/articles/s41590-021-01058-1
Quote: “The immune system is possibly unique in the advantages that variation can confer. The Red Queen hypothesis, an evolutionary arms race between competing species (Fig. 1a), runs into a generational time asymmetry when considering the evolution of pathogens and hosts (Fig. 1b). Rather than unsustainable convergence toward a homogenous state of infection–resistance, evolution has selected for maintenance of immune diversity as a protective mechanism (Fig. 1c). When potential pathogens can rapidly specialize to take advantage of a fixed niche, an evolutionary advantage can be gained from possessing an immune system wired into a functional configuration that is different from that of the prior host (Fig. 1c,d).”
- Some people survived the black death, are more resistant to HIV or Corona virus or even resistant against Ebola. Others are killed easily by the flu or highly vulnerable to certain bacterial infections. Where you are on this spectrum is impossible to predict. And you also respond differently to every possible infection.
A very recent study discovered a gene variation in the DNA of 206 people who died before, during (or with) and after the Black Death. This variation has an impact on the length or effectiveness of a protein (ERAP2) that certain immune cells use to fight the plague pathogen.
#nature.com (2022): Bubonic plague left lingering scars on the human genome
https://www.nature.com/articles/d41586-022-03298-z
Quote: “One variant affected the expression of a gene called ERAP2. People with the variant produce a full-length version of an RNA molecule that encodes the ERAP2 protein; those who lack it make a shorter version of the RNA.
The ERAP2 protein is made by specialized immune cells called macrophages that engulf and digest bacteria. It is involved in cutting bacterial proteins into pieces, some of which are then displayed on the surface of the macrophage as a signal to other immune cells. “It’s a kind of alert system that there’s an infection going and they need to attack,” says Barreiro.
Barreiro and his collaborators speculated that having a full-length, fully functional ERAP2 protein might have improved immune protection during the Black Death. Laboratory studies backed up this idea: macrophages expressing the longer version of ERAP2 were able to keep Yersinia pestis from replicating more effectively than were macrophages expressing the truncated version.”
#Klunk, J. et al. (2022): Evolution of immune genes is associated with the Black Death. Nature; Vol. 611
https://www.nature.com/articles/s41586-022-05349-x
Quote: “We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages.
(...)
ERAP2 showed the most compelling evidence for selection, both from a genetic and functional perspective, with an estimated selection coefficient of 0.4 (95% confidence interval 0.19,0.62, Extended Data Figs. 2 and 10). This estimate suggests that individuals homozygous for the protective allele were about 40% more likely to survive the Black Death than those homozygous for the deleterious variant. This allele is associated with both increased expression of ERAP2 and production of the canonical full-length ERAP2 protein21,22. We suggest that this protein increases the presentation of Yersinia-derived antigens to CD8+ T cells, stimulating a protective immune response against Y. pestis38,39. Furthermore, we show that macrophages from individuals possessing the selected ERAP2 allele engage in a unique cytokine response to Y. pestis infection and are better able to limit Y. pestis replication in vitro.”
HIV or AIDS is an epidemic. Nearly 40 million people are currently living with HIV and 650,000 people died from HIV-related illnesses in 2021.
#WHO (2022): HIV
However, there are (very few people) who have gene mutations or defects that show very strong resistance to HIV-1 (one of two known types of HIV).
For example, a mutation called “CCR5-Δ32” encodes receptors (“C-C chemokine receptor type 5” or “CCR5”) that most HIV strands need to enter the cell, to simply not work.
#Marmor, M. et al (2006): Resistance to HIV Infection. Journal of urban health: bulletin of the New York Academy of Medicine, Vol. 83 (1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1539443/
Quote: “HIV-1 needs two receptors to gain entry into human cells: the CD4 receptor found on some cells of the immune system and the chemokine binding co-receptor. The chemokine co-receptor used by most circulating strains of HIV-1 is named CCR5. HIV strains that use this co-receptor are known as macrophage tropic (M-tropic) or R5 subtypes and account for more than 95% of incident HIV-1 infections.14,15
(...)
Variations in the genes encoding chemokines and chemokine receptors have been found to be important for both susceptibility to HIV infection and the rate of disease progression following HIV infection. To date, there are three well-studied variants of chemokine-related genes: CCR5-Δ32, CCR2-64I, and SDF1-3′A.
CCR5-Δ32 is a polymorphism in the gene encoding the CCR5 chemokine receptor in which a 32-base pair region has been deleted.
(...)
Individuals who have two copies of this mutation (i.e., CCR5-Δ32 homozygous or CCR5-Δ32/Δ32) have non-functional CCR5 receptors. This non-functionality renders CCR5-Δ32/Δ32 individuals immune to R5 strains of HIV.”
Although it takes little away from the dangerousness of the Ebola virus disease (EVD) and the topic is much debated, there is evidence that some people are asymptomatic or subclinical to an ebola infection. These people then show either no symptoms or very few symptoms.
As an example, below you will find a study that examined the households of people who had contracted Ebola.
It shows that 2.6% of the people who had contacts with people with Ebola in their household tested positive but showed no symptoms.
Kuhn, J. H. & Bavari, S. (2017): Asymptomatic Ebola virus infections—myth or reality? The Lancet Infectious Diseases, Vol. 17 (6)
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30110-X/fulltext
Quote: “In The Lancet Infectious Diseases, Judith Glynn and colleagues13 present a carefully conducted, well-controlled serosurvey to take a fresh look at the possibility of subclinical EVD exposure and infection. During the recent large EVD outbreak (over 28000 cases) in western Africa, Sierra Leonean household contacts of people with proven EVD were screened for IgG anti-Ebola virus antibodies using a newly developed, non-invasive oral fluid capture assay with high specificity and sensitivity. Seroprevalence among household contacts who did not experience clinical signs indicative of EVD was only 2,6%.”
Original paper:
#Glynn, J. R. et al. (2017): Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus. The Lancet Infectious Diseases,
Vol. 17 (6)
https://www.sciencedirect.com/science/article/pii/S1473309917301111
Quote: “Among the survivors from other treatment centres (for whom we did not have documented evidence of positive Ebola virus PCRs) 31 (86,1%) of 36 samples were positive for Ebola IgG. 40 (8,3%) of 481 samples from household contacts without diagnosed EVD were reactive on the first test. After subsequent tests, 21 were considered positive, 18 negative, and one indeterminate (table 1, appendix p 5). Among 389 asymptomatic contacts, ten (2,6%) of 388 were seropositive, compared with 11 (12,0%) of 92 symptomatic contacts (p=0,004).”
There are signs that T cells (immune cells of the adaptive immune system) stimulated by other coronaviruses (endemic human coronaviruses - huCoVs) may be associated with producing protection against SARS-CoV-2. Of course, this research is still very new and much is still uncertain, but the source below provides a first start.
#Kundu, R. et al. (2022): Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts. Nature Communications, Vol. 13 (80)
https://www.nature.com/articles/s41467-021-27674-x#Abs1
Quote: “Despite mass deployment of effective vaccines against SARS-CoV-2, correlates of protection against infection remain unknown. Exposure to SARS-CoV-2 does not universally result in infection and pre-existing T cells, primed by endemic human coronaviruses (huCoVs), might mediate protection in SARS-CoV-2-naive persons. Studies to date have described the prevalence of SARS-CoV-2 cross-reactive T cells in naive healthy controls1–4 and in hospitalised COVID-19 patients5,6. However, no study yet describes an association of cross-reactive T cells with outcome after SARS-CoV-2 exposure. Here we assess contacts of newly diagnosed COVID-19 cases to capture the earliest time-points after SARS-CoV-2 exposure. We quantify T cells specific for in silico-predicted and biologically confirmed pools of cross-reactive epitopes from 5 SARS-CoV-2 proteins, alongside protein-spanning peptide pools, using a highly sensitive dual cytokine fluorescence-linked immunospot (FLISpot) assay to detect both IFN-γ and interleukin-2 (IL-2). The frequency of baseline cross-reactive T cells is correlated with the infection outcome following SARS-CoV-2 exposure, and we observe significantly higher frequencies of cross-reactive memory T cell responses in PCR-negative contacts. The association of circulating SARS-CoV-2-specific T cells at exposure with lack of infection is the first evidence of a protective role for cross-reactive T cells in COVID-19, and establish the potential for secondgeneration T cell-inducing SARS-CoV-2 vaccines that could circumvent spike-antibody immune escape variants.”
- Vaccines basically pretend to be a disease and train your defenses to be ready if it ever shows up for real. The goal is to create the same memory cells that you would get after surviving an infection.
We simplified a lot here. For a more detailed look at how the immune system works, check out one of our recent videos and its source list.
#Kurzgesagt (2021): How The Immune System ACTUALLY Works – IMMUNE
https://www.youtube.com/watch?v=lXfEK8G8CUI&t=499s
Vaccination trains the immune system by simulating a natural infection and stores information about the corresponding pathogen in specific immune cells, which together can be seen as the memory of the immune system (B-lymphocytes and T-lymphocytes). In the case of a real infection, the immune response can then be faster or reduce the severity.
#CDC Center for Disease Control and Prevention (2022): Understanding How Vaccines Work
https://www.cdc.gov/vaccines/hcp/conversations/understanding-vacc-work.html
Quote: “To understand how vaccines work, it helps to first look at how the body fights illness. When germs, such as bacteria or viruses, invade the body, they attack and multiply. This invasion, called an infection, is what causes disease. The immune system uses your white blood cells to fight infection. These white blood cells consist primarily of macrophages, B-lymphocytes and T-lymphocytes:
Macrophages are white blood cells that swallow up and digest germs, plus dead or dying cells. The macrophages leave behind parts of the invading germs called antigens. The body identifies antigens as dangerous and stimulates antibodies to attack them.
B-lymphocytes are defensive white blood cells; they can produce antibodies to fight off infection.
T-lymphocytes are another type of defensive white blood cell, that recognizes a familiar germ, if the body is exposed again to the same disease
The first time the body is infected with a certain germ, it can take several days for the immune system to make and use all the tools needed to fight the infection. After the infection, the immune system remembers what it learned about how to protect the body against that disease. If your body encounters the same germ again, the T-lymphocytes recognize the familiar germ and the B-lymphocytes can produce antibodies to fight off infection.
How Vaccines Work
Vaccines can help protect against certain diseases by imitating an infection. This type of imitation infection, helps teach the immune system how to fight off a future infection. Sometimes, after getting a vaccine, the imitation infection can cause minor symptoms, such as fever. Such minor symptoms are normal and should be expected as the body builds immunity.
Once the vaccinated body is left with a supply of T-lymphocytes and B-lymphocytes that will remember how to fight that disease. However, it typically takes a few weeks for the body to produce T-lymphocytes and B-lymphocytes after vaccination. Therefore, it is possible that a person infected with a disease just before or just after vaccination could develop symptoms and get that disease, because the vaccine has not had enough time to provide protection. While vaccines are the safest way to protect a person from a disease, no vaccine is perfect. It is possible to get a disease even when vaccinated, but the person is less likely to become seriously ill.”
- Sometimes after a vaccine, you get sick for a few days, but that’s generally it. No scars, no permanent damage. We discussed vaccine side effects in detail in another video if you want to learn more.
Kurzgesagt (2019): The Side Effects of Vaccines - How High is the Risk?
https://www.youtube.com/watch?v=zBkVCpbNnkU&t=1s
- On top of that, the immunity you get from a vaccine is often better than the natural resistance, because they are engineered to engage your immune system in a more productive way.
Vaccines are a complex topic, so we had to simplify a bit here. What we mean with more productive is “tailored to try to get the best result.” This can entail a couple things: for example, immunity from vaccines can be more specific, because it targets only parts of pathogens and not the entire pathogen. Some vaccines also have adjuvants, substances that are designed to create a stronger immune response. This can be useful for example when it comes to flu shots, where older people sometimes show a weaker response. There are big differences between vaccines however and there are a lot of factors to be taken into account.
The following source provides an up-to-date overview of adjuvants.
Basically, these are "boosters" of a vaccine. There are numerous types and they can work in different ways. For example, they can reduce the number of vaccinations needed or provide for the half-time of the vaccinated antigens.
#Facciolà, A. et al. (2022): An Overview of Vaccine Adjuvants: Current Evidence and Future Perspectives. Vaccines, Vol. 10 (5)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147349/
Quote: “The efficacy of a vaccine depends not only on the antigen components, but also on adjuvants that are often used in order to stimulate the immune system in a more effective way. Adjuvants are defined as constituents added to vaccines in order to improve immune responses towards an antigen. In addition, adjuvants have several benefits, such as the reduction in the antigen amount per vaccine dose and the number of vaccination sessions, and in certain cases, they increase the stability of the antigen component, extending its half-life and indirectly improving its immunogenic power [5]. Many different types of adjuvants are now available to use in vaccine manufacturing (Table 1).
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Adjuvants can be grouped according to different criteria, such as their physicochemical properties, origins, and mechanisms of action [6]. One of the most followed classification systems is the one based on their mechanisms of action, dividing them into two main categories: delivery systems (particulate) and immune potentiators [7]. A further class of adjuvants is mucosal adjuvants, a group of compounds that shares some features with the previous ones. In delivery system adjuvants, antigens are associated with an adjuvant that works especially as an antigen carrier. In addition, they are able to induce a local proinflammatory response by activating the innate immune system, leading to the recruitment of immune cells to the site of injection [8]. Specifically, the antigen-adjuvant complex activates pattern-recognition receptor (PRR) pathways by acting as pathogen-associated molecular patterns (PAMPs). This causes the activation of innate immune cells with the production of cytokines and chemokines. The same pathway is directly activated by immune potentiators [9] (Figure 1).
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The addition of adjuvants is particularly useful for vaccines used in the elderly due to the physiological phenomenon of immunosenescence occurring in this category of subjects, which is responsible for the reduction of immune responses after natural infections or artificial stimuli (vaccinations) [10]. In this case, the presence of adjuvants can represent a valid tool to overcome this limit in the use of vaccines.”
Another example are "subunit vaccines" which are safer because they do not use the whole pathogen but only the parts that are important for the immune system.
#Bill, R. M. (2015): Recombinant protein subunit vaccine synthesis in microbes: a role for yeast? Journal of Pharmacy and Pharmacology, Vol. 67 (3)
https://academic.oup.com/jpp/article/67/3/319/6128040
Quote: “In the last 30 years, there has been a trend towards developing subunit vaccine formulations that contain defined antigenic components together with a potent adjuvant.[2] The antigen may be a polysaccharide, a nucleic acid or a protein. In the latter case, which is the focus of this article, the protein itself may be (1) a purified protein from the disease-causing pathogen, (2) a synthetic peptide or (3) a recombinant protein that has been synthesized in one of many possible heterologous host cells ranging from Escherichia coli to mammalian cells.[4] This ensures that the antigen has a well-defined composition, that there is effectively no risk of pathogenicity in its use and that antigen synthesis and purification can be scaled up in a cost-effective manner.[5]”
- In the end, if we look at the stunning progress humanity has made in the last century, eventually we may overcome disease for good.
As an example, we have shown measles. The graph, based on WHO, UNICEF and UN data, shows how as the level of immunization increases, reported cases decrease sharply.
#OWID (retrieved 2023): Measles vaccine coverage worldwide vs. measles cases worldwide
https://ourworldindata.org/grapher/measles-vaccine-coverage-worldwide-vs-measles-cases-worldwide
Based on the following sources:
#WHO/UNICEF (retrieved 2023): Immunization data
https://immunizationdata.who.int/listing.html?topic=coverage&location=
#WHO (2022): Global Health Observatory data repository. Measles
Reported cases by country
https://apps.who.int/gho/data/node.main.WHS3_62?lang=en
#UN (2022): World Population Prospects 2022
Another example is Smallpox. A very serious disease that, incidentally, led to the development of vaccines and, after hundreds of millions of victims, was eradicated by extensive vaccination programs in the 1980s.
#WHO (2019): WHO commemorates the 40th anniversary of smallpox eradication.
Quote: “Until it was wiped out, smallpox had plagued humanity for at least 3000 years, killing 300 million people in the 20th century alone. The last known endemic case of smallpox was reported and the outbreak promptly contained in Somalia in 1977.”
#WHO (1980): The global eradication of smallpox : final report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979
