Why do you feel sore all over when you have a fever? It's actually a sign that your protection is about to be upgraded

Produced by: Science Popularization China

Author: Hu Zhiguo (PhD in Biochemistry and Molecular Biology, Chinese Academy of Sciences)

Producer: China Science Expo

Editor's note: In order to decode the latest mysteries of life science, the China Science Popularization Frontier Science Project has launched a series of articles called "New Knowledge of Life" to interpret life phenomena and reveal biological mysteries from a unique perspective. Let us delve into the world of life and explore infinite possibilities.

Friends who have experienced COVID-19 infection or severe colds all have the impression that fever and body aches go hand in hand like twin sisters. Little do they know that such pain is actually intentional by nature, and is the external manifestation of the immune system's desperate fight for survival.

Fever - powerful enemy invades the border, wartime mobilization

Our immune system is the body's defense system, and the outermost layer of the skin and mucous membranes are the body's "Great Wall of Defense", blocking most of the invading viruses and bacteria through physical barriers. Just like the Great Wall is guarded and patrolled, there are many patrolmen under our skin and mucous membranes - macrophages.

Macrophages are the body's cleaners . During their normal operations, they engulf the debris and garbage produced by cells. When they detect foreign invasion, macrophages will transform into "hexagonal warriors". Not only will their phagocytic function of pathogens be greatly enhanced, but they will also secrete cytokines to "shake people" and recruit other immune cells to fight and pass on the collected enemy information to them (called antigen presentation function in immunology).

Macrophages engulf bacteria

(Image source: Medical Quick View - Everyone Learns Immunology)

Macrophages and immune cells involved in the battle transmit information by secreting cytokines, among which a class of cytokines called endogenous pyrogens (interleukins, tumor necrosis factors, interferons, etc.) can reach the hypothalamus.

The hypothalamus is the logistics headquarters . It controls the body temperature like an air-conditioning control system. It usually sets the temperature to around 37 degrees Celsius (the body temperature set point). When the hypothalamus receives information from endogenous pyrogens, it will raise the body temperature set point. At this time, the body needs to increase heat production to reach the new body temperature set point. This is a fever (commonly known as "fever" in immunology).

Fever is an important part of wartime mobilization and logistics support.

Why do you say that?

On the one hand, the increase in body temperature will expand blood vessels, which is equivalent to widening the road, which is conducive to the rapid arrival of the immune army on the battlefield. On the other hand, the increase in body temperature can inhibit the reproduction of pathogens and increase the activity of immune cells. Studies have shown that the increase in body temperature can induce the expression of heat shock protein 90 (Hsp90) in immune cells. This protein can enhance the adhesion and migration ability of immune cells and improve their efficiency in fighting pathogens.

Cytokines for immune cell communication

(Image source: Medical Quick View - Everyone Learns Immunology)

In addition, the increase in body temperature increases the body's metabolic rate, which helps the body eliminate viruses and toxins as quickly as possible.

Therefore, a proper fever is more conducive to good health (drinking more hot water when you are sick is indeed effective), but if the temperature is higher than 38.5 degrees Celsius, the function of normal cells in the body will be significantly affected, and various cooling measures must be taken at this time. (How to deal with a fever must be followed by the doctor! !)

My whole body aches - a million bucks for armor, thousands of bucks a day

When fighting against pathogen invasion, the body mainly relies on skeletal muscle tremors to produce heat, which is one of the reasons why we shiver and feel body aches when we are sick. Muscles throughout the body are called upon to provide energy for the body, and muscle glycogen and glucose are the military rations.

Aerobic and anaerobic respiration

(Image source: High school biology compulsory textbook)

Under normal circumstances, the energy supply of glucose oxidation decomposition needs to go through three stages in sequence: glycolysis, tricarboxylic acid cycle and electron transport chain. The third stage produces the most energy. However, this stage not only requires the participation of oxygen, but also requires the change of reaction site, and has many steps and takes a long time.

In a "state of war", the body urgently needs a large amount of energy supply, resulting in insufficient oxygen supply. At this time, muscle cells start anaerobic respiration mode: after the glycolysis stage, the intermediate products produced are converted into lactic acid and accumulated in muscle cells. Although the production capacity is small, the supply is rapid. The accumulation of lactic acid will stimulate the chemical receptors in the muscles, which are transmitted to the brain through nerves to produce soreness . At the same time, lactic acid will cause the osmotic pressure of muscle tissue to increase , similar to a person who drinks a lot of water after eating salty food. The increase in the osmotic pressure of muscle cells will absorb water from the surrounding area, causing the muscle cells to swell, thereby producing a feeling of distension and pain .

In addition to the effect of lactic acid, when infected, the immune system will also release some inflammatory factors to fight pathogens . Inflammatory factors have multiple functions such as promoting vasodilation, enhancing immune function, and promoting wound healing. At the same time, they will increase the body's sensitivity to pain , so we will have headaches, back pain, and bone pain.

However, don't underestimate the pain, and don't just hate the pain.

Why do you say that?

Pain is an alarm for physical problems, and it alerts the brain to physical diseases and dangers . Without pain, the body cannot perceive external damage, which is extremely dangerous for life and health. However, some pain is really unbearable, so scientists invented painkillers based on the principle of pain generation. The commonly used ibuprofen relieves pain by inhibiting the production of prostaglandins (a type of inflammatory factor).

"Fever" plug-in: Version 2.0 of immune system upgrade

Fever and aches are not innate in all animals. It is the 2.0 version of the upgraded immune system, an immune system plug-in produced by long-term evolution of organisms.

Although the body temperature of poikilothermic animals changes with temperature, they do not have the function of mobilizing the whole body to produce heat in preparation for war, so there is no fever, let alone soreness caused by it. However, the effect of temperature on physical activity remains consistent in homeothermic and poikilothermic animals. Increased body temperature can improve immunity and athletic ability, while decreased body temperature leads to decreased immunity and athletic ability.

Because homeothermic animals have a temperature control system that can self-adjust their body temperature according to needs, they greatly improve their ability to adapt to different environments, which greatly increases their living space and survival rate.

However, the ability of warm-blooded animals to control body temperature varies at different ages. For example, the immune system of infants and young children is not fully developed, making them susceptible to infection by pathogens. Because their body temperature regulation center is immature, it is difficult for them to regulate their body temperature as effectively as adults when they have a fever, which makes it easier for children to have a high fever than adults. For adults, high fevers only occur when they have low immunity or encounter serious illnesses such as severe infections.

Please cherish your precious wealth, health

Fever and body aches are immune system plug-ins that have evolved over a long period of biological evolution to ensure that the body can respond to changes in the internal and external environment in a timely manner. The temperature regulation of the hypothalamus provides solid logistical support for the immune system to defeat the invading enemy, and some of the many immune cells involved in the battle will sacrifice themselves in the fight against the invasion of pathogens, and some will also end their lives after the war is over. This can not only prevent excessive immune responses from damaging normal tissues, but also save a lot of energy for the body in "peacetime".

Behind our health is the exquisite design of the human body system and the constant busyness and collaboration of cells! Let us cherish life and wish everyone a healthy body and a strong physique!

References:

[1].https://www.who.int/publications-detail/the-use-of-non-steroidal-anti-inflammatory-drugs-(nsaids)-in-patients-with-covid-19 (Accessed on April 21, 2020).

[2].https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19 (Accessed on March 19, 2020).

[3].National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://covid19treatmentguidelines.nih.gov/ (Accessed on August 08, 2022).

[4].National Institute for Health and Care Excellence. Fever in under 5s: Assessment and initial management (NG143). November 2019. www.nice.org.uk/guidance/ng143CG160 (Accessed on January 13, 2021).

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[7] Nakamura Y ,et al. Prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling. Sci Adv. 2022 Dec 23;8(51):eadd5463. doi: 10.1126/sciadv.add5463. Epub 2022 Dec 23. PMID: 36563142; PMCID: PMC9788766.

[8] ChangDong Lin, et al. Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins. Immunity. VOLUME 50, ISSUE 1, P137-151.E6, JANUARY 15, 2019.