This answer briefly covers
- Mechanisms that maintain core body temperature.
- Mechanisms that raise core body temperature during fever.
- Benefits to raised core body temperature: Typically Immune Function Enhancement & Harm to Pathogens.
Mechanisms that maintain core body temperature
For many years a single thermoregulatory center was supposed to regulate human body temperature. Now, evidence () suggests there are several somewhat independent loops, part of a thermoregulatory circuit, that regulate core body temperature.
Located in various parts of the body such as the hypothalamus, spinal cord, skin, and abdominal organs such as the urinary bladder,monitor the body for temperature changes. These thermoreceptors work through negative feedback loops to autonomously conserve or lose body heat, the former via shivering and vasoconstriction, the latter via sweating and vasodilation. However, one site, the preoptic region of the anterior hypothalamus is still considered the major CNS thermoregulatory center that receives and integrates temperature signals from various parts of the body.
Thermoregulatory neurons present in the median preoptic nucleus of the hypothalamus are either warm or cold sensitive (2). These neurons reduce and increase their firing, respectively, in cold environments. This leads to activation of mechanisms to conserve heat, skin vasoconstriction, piloerection, reduced sweating, increased muscle contraction, non-shivering thermogenesis, and warmth seeking. Reverse occurs in hot environments leading to activation of mechanisms to dissipate heat such as vasodilation, sweating and cold seeking.
For example, the anterior hypothalamus detects the core body temperature rise during exercise () through the temperature of the blood passing through it and when the temperature rises past an internal set point, it triggers vasodilation of peripheral blood capillaries and sweat, both of which promote heat loss.
Thus, current thinking holds that the hypothalamus controls core body temperature the way a thermostat regulates room temperature in a house (), responding by conserving or dissipating heat depending on external conditions (see below from ).
Mechanisms that raise core body temperature during fever
Fever arose millions of years back in evolution (see below from 6,), giving rise to the notion that it is an ancient defense strategy deployed by most animals.
Fever can be both behavioral as well as physiological. Andepends on the environmental temperature to maintain its thermoregulation. Its moving to a warmer place in response to an infection is an example of behavioral fever ( , , ). However, a human who chooses to swaddle in warm clothes in response to sudden drop in environmental temperature is also an example of behavioral fever.
OTOH, in human physiologic fever, the internal set point of the hypothalamic thermoregulatory center shifts upwards, apparently in response to increased local levels of(PGE2), a prominent endogenous pyrogen (11, , , see below from ). Such changes in turn activate neurons in the vasomotor center that start the process of vasoconstriction.
Benefits to raised core body temperature: Typically Immune Function Enhancement & Harm to Pathogens
Adaptive benefits of fever remain disputed simply because experimental studies and indeed clinical experience of fever in conjunction with serious debilities such as sepsis clearly demonstrate circumstances where outcome of fever (and associated physiological changes) can be unambiguously harmful (15, 16).
Clearly there are costs to fevers (), costs such as anemia due to iron sequestering, anorexia due to fever-driven loss of appetite and attendant malnutrition as well as higher calorie expenditure necessary to maintain higher body temperature ( ). Clearly, fever must have mitigating benefits to make it such a widespread feature across animals. Broadly speaking, two main benefits postulated for fever are
- Immune function enhancement.
- Harm to pathogens.
Multiple studies have demonstrated fever enhances immune function (see summations below from 15, 16).
Damage to pathogens is another obvious benefit (15, 19,).
Substantial scientific and clinical evidence suggests fever improves survival and reduces the duration of infections (, , ).
Fever can be Harmful to Pathogens: In Vitro Studies
From malaria parasites to Salmonella to viruses, sustained high temperature hinders their growth (, 23).
- Malaria parasites are found not to survive 16 hours at 41oC, with majority already dead at 8 hours ( , ). This is why malaria parasite lab culture is typically 37oC, same as human body temperature.
- Iron is critical for normal cellular function, especially for eukaryotic cells. Sequestering it is obviously a cost whose benefit is revealed by examining its effect on pathogens. For example, Salmonella typhimurium is unable to synthesize iron transport compounds it needs at temperatures >40oC and thus stops proliferating at such temperatures. Though poultry are often i carriers, birds are by and large less susceptible to salmonellosis, with their higher body temperature suspected to play a role in such resistance ( , 27, ).
- can be and often is a serious respiratory pathogen in humans. While it replicates easily at 37oC, at 41oC, it cannot and dies ( ).
Important to note here that tests of pathogen heat sensitivity in culture are inherently limited in scope and in fact, effect of core body temperature rise on pathogens may be even more profound for the following reasons,
- Local heat experienced by pathogens at an infected site is largely a black box.
- Heat exposure in culture is a blunt contrivance that cannot and indeed does not recapitulate the many other ‘inflammatory stressors’ ( ) a pathogen would experience during an infection, stressors that are typically set in motion simultaneously with core body temperature rise in response to an infection and that tend to work synergistically. Consider the observation that neither heat nor iron restriction was found effective in vitro to kill Pasteurella multocida, a pathogenic bacterium, while together they could do so (30).
Fever can be Harmful to Pathogens: In Vivo Veritas
- A mouse model study (see below left from ) housed them at ambient temperatures ranging from 23 to 35.5oC. Mice were then intraperitoneally injected with Klebsiella pneumoniae. Though the bacteria were growing at identical rates in culture at 37oC and 39.5oC, in vivo, only the febrile temperature yielded better bacterial clearance and survival rate.
- A seminal 1975 study (see below right from 32) established just how critical behavioral fever could be in ensuring an ectotherm’s survival from an infection. In this study the lizard Dipsosaurus dorsalis was observed to develop a fever of ~2oC when injected with the bacterium Aeromonas hydrophila. Since this bacterial infection is usually lethal, the study explored whether this body temperature increase was related to infection resistance by placing lizards infected with live bacteria either at neutral (38oC), low (34 or 36oC) or high (40 or 42oC) ambient temperature. Elevated body temperature clearly influenced survival from infection. Infected lizards placed at 42oC had maximal survival of ~80% after 7 days of infection while all of those placed at 34oC died within 4 days of infection.
- There is even a Nobel Prize-winning experiment associated with demonstrating the benefits of fever. , the first of only two psychiatrists to have won the Nobel Prize for Medicine or Physiology, induced fever in neurosyphilis patients, ( , ), by infecting them with malaria using the least aggressive malaria parasite, , and then treated them later with quinidine. At that time, 1917, neurosyphilis was a terminal diagnosis but this form of pyrotherapy succeeded in curing patients, albeit with a malaria fatality rate of 15% (16, 34, ).
deserve the final word or more accurately, questions. What is the effect of fever on an individual’s microbiota? Do some stay while others go? Could stable residence during and after physiological fever be an indicator of stable association? Could such stable residence be used to differentiate true symbionts or mutualists from pretenders (Janus-faced pathobionts)? Fever as purifying forest fire in other words. Or do fevers determine otherwise, embolden the more combative or even the downright nasty? Intriguing as-yet unanswered questions.
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