Why is fever beneficial

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Find an Expert. National Institute of Allergy and Infectious Diseases. Patient Handouts. 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. The most widely-cited explanation for these elements of the acute phase response was proposed by Hart [ 16 ] and extended by Straub et al. 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. Many potential pathogens can survive and function over a wide range of temperatures cooler than their optimum. Temperatures that are slightly higher than the optimum can damage proteins including enzyme function , membrane lipids, and RNA and disrupt DNA synthesis in the cells of both hosts and pathogens [ 20 , 95 , 96 ]. However, one of the concerns about the efficacy of fever in harming pathogens is that febrile temperature i.

So how can the heat of fever be expected to harm or even kill most host-adapted pathogens [ 95 ]? And furthermore, why should we expect that the heat will harm the pathogens including virally infected cells more than the host [ 18 ]?

The temperature to which pathogens at the infected site are actually exposed is currently unknown [ 18 , 98 ]. However, it is almost certainly higher than that of the blood entering the infected site since heat is generated at inflammatory foci. It has been proposed that one source of this heat is from the macrophages in these inflamed plaques that have upregulated levels of mitochondrial uncoupling protein 2, which generates heat rather than ATP [ ].

Neutrophils activated to undergo the respiratory burst as with phagocytosis generate substantial heat [ — ], as expected from the oxidative reactions that produce reactive oxygen species. LeGrand and Day [ 18 ] proposed that since growth and replication are universally sensitive to disruption by stressors of any kind, replicating pathogens and infected cells generating pathogens localized at the infected site would tend to be more vulnerable to heat stress than non-replicating host cells stromal cells or infiltrating effector immune cells.

Immune cells recruited to the site of infection e. Therefore, it is not surprising that the optimal functional temperature of activated leukocytes is higher than normal core body temperature.

In this view, fever provides a crucial temperature boost to locally warmed tissues at infected sites, elevating the temperature to the level that damages pathogens. Additionally, the systemic febrile temperature may impair replication of pathogens that have spread. This is analogous to iron deprivation as a host defense during infection: systemically iron is mildly restricted, but locally at the infected site it is much more restricted, and limited even further within phagolysosomes [ 18 ].

All immune defenses involve important costs and benefits. The benefits of the acute phase response typically outweigh its costs, because fever and other nonspecific stressors exploit the vulnerabilities of rapidly dividing pathogens [ 49 ]. As a result, costs are preferentially imposed on pathogens instead of healthy host cells. Some pathogens have counteradaptations that protect against acute phase response stresses, but these impose trade-offs themselves for pathogens.

Microbe-derived heat shock proteins, for instance, impair pathogen replication and trigger additional immune responses from the host [ 37 ]. LeGrand and Alcock [ 49 ] identified a number of conditions where immune brinksmanship may be a losing strategy for an infected host. One example is having insufficient metabolic, nutritional or physiologic reserves needed to survive the stress. Having comorbidities, such as heart failure or impaired lung function, also reduce the potential payoff.

Other threats to the host, such as having co-infection with another pathogen or a recent previous infection, also decrease the odds of success. Other costs specific to fever include harming tissues with rapid growth, such as during spermatogenesis in the testes [ ] and embryonic and fetal development [ ]. Additionally, some specialized pathogens may be relatively resistant to stresses imposed by the host. Old age is a risk factor for respiratory failure and death in COVID, and in some of these cases, the costs of the immune response may exceed its benefits [ ].

Proximate explanations include attenuated immune responses in the aged immunosenescence [ ] or excessive innate immune activation inflammaging [ ]. We note that impaired infection control may impose additional immune costs, taking the patient to the brink with potentially lethal self-harm. Also, because SARS-CoV-2 is a novel virus, some lethal cases may occur because humans have had insufficient time to evolve optimal immune responses to it.

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