What does not kill you may weaken you in short term, but when the immune system response to the pathogens, it actively defends the host body, and created anti-bodies which prevent inflection of the disease, and facilitate higher tolerance, meaning this incident/ inflection will make you stronger in long term
– looking into sickness behaviour: immunity vs. immunopathology
– sickness behaviour is defined as infections in animals and humans lead to dramatic changes in behaviour, resulting in fatigue, anorexia, social withdrawal, fever and sleep alterations
– the host body tissues will be damaged, and have sickness behaviour (weaken in the process of fighting the pathogens/ viruses)
– Not clear whether and how it helps the infected host
o E.g. fatigue is thought to preserve energy so as to fight infection better, however fatigue is commonly accompanied by anorexia and therefore reduced energy consumption
o E.g. fever is thought to enhance immune function, but there is little evidence of the positive effect of increased temperature on immune defence; it also thought to make the host less suitable niche for the pathogens, yet different pathogens can have very different temperate preference, and as fever is induced whenever an infection results in systemic inflammation
– Sickness behaviour may yet have some undefined positive effects on the host resistance, largely with promoting host tolerance to infection
o E.g. fever may induce tissue protection inducing HSF-1 mediated cellular heat shock response; heat shock can render cells transiently resistant to TNF-mediated killing
o E.g. anorexia and fatigue may help preserve vital processes and promote stress tolerance in multiple tissues
– Therefore, the presence/ absence of protective effects of sickness behaviour and their mechanisms are pathogen specific
– Moving on to tolerance vs. defence
– Tolerance: host defence strategy- reduces the negative impact of an infection on host fitness without directly affecting the pathogen burden
o Different from immunological tolerance, which is defined as unresponsiveness to self-antigens
o In some contexts, however, the how terms can be used interchangeably because immunological tolerance is a special case of a multitude of mechanisms that protect the host from immune or pathogen inflicted damage
– Increased tolerance to tissue damage can be achieved, in general, through tissue protection and repair
– Tolerance capacity: one of the factors that define the tolerance level- different tissues have different repair capacity
o tissues with high turn-over rates, including most epithelia, and hematopoietic cell types, are repaired very efficiently, and therefore have higher intrinsic tolerance to damage compared to tissues with low or no renewal capacity, such as neurons and cardiomyocytes, where damage can be irreversible and often lethal
– Adaptive immunity: antigen-dependent and antigen-specific; has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen
– sickness behaviour eventually make one stronger because a pathogen can become less virulent in a given host because of an increase in host tolerance to damage that can be caused by the pathogen
– At the extreme, a pathogen may even become a part of a normal ‘commensal’ microbiota, and colonise the host constitutively without causing a disease
– Thus, host-microbial symbiosis could be due to increased host tolerance from experiencing other pathogens/ viruses
2. stress does not kill you, and it may potentially make you stronger
– cellular stress responses are inducible adaptations to adverse conditions
o stress response genes perform various emergency functions that help the affected cells survived the adverse condition
o e.g. oxidative stress leads to activation of transcription factor Nrf2, which in turn induces dozens of proteins that scavenge free radicals, eliminate damaged proteins, metabolize oxidized membrane lipids and repair damaged DNA
– in each case, a given stress stimulus activates dedicated sensors and transcriptions factors that induce the expression of genes required to tolerate the stressor
– each stress response pathway operates at the cost of normal cell and tissue function, which is why these genes cannot be constitutively turned on and have to be inducible only when needed (stress response only in ‘kill me’ situation)
– pre-conditioning
– the basis of it is the induction of protective mechanisms by a mild insult that in turn permits tolerance to a greater and potentially damaging insult
– when cellular stress response pathways are activated by a mild stressor, they become more tolerant to a more severe insult
3. in some cases, Nietzsche’s statement is not applicable:
3i. ‘what does not kill you weaken you’
3i.a. case study: Spanish flu 1918 pandemic
– age of exposure to the pandemic is critical in this case
– Age-specific morbidity: Obtained a high point at age 28 because they encountered an earlier pandemic before their immune system was fully developed
– Spanish flu has a W-shaped curve, the patterns are relatively similar for males and females
o ‘antigenic seniority’
– OAS (‘original antigenic sin’) by Thomas Francis et al.: a memory antibody response generated during the first infection that is faster and greater in magnitude than the de novo response, but not protective against the new strain
– OAS refers to the tendency of the immune systems to use immunological memory based on a previous infection when a subsequent, slightly different version of that virus is encountered
o These memory cells essentially out-compete the protective cells that would normally be newly generated against the subsequent exposures
o being ‘trapped’ by the first response the immune system is unable to build up more effective responses during subsequent exposures
3i. b. maternal health may deteriorate in reproduction as there are conflicts between foetus, paternal and maternal interest of pregnancies
– nutrition trade-off: interest of foetus and mother
– (example) women who has more children tend to have shorter life span
3i. c. what does not kill you will evoke hypersensitivity reactions of immune system that can cause undesirable impact on host’s body
– dysregulated tolerance can lead to pathology
o e.g. fibrosis that can result from excessive tissue repair
3ii. There is no strong correlation between ‘what does not kill you’ and a reduced risk of mortality/ greater fitness
3ii. A. The Predictive Adaptive Response (PAR) hypothesis were not applicable in humans (Ian, 2016)
o Meta-analysis of the fitness benefits of environmental matching across a range of animal and plant species concluded that evidence of it is weak, in other words, individuals experiencing poor early conditions were not better able to later cop with such environments in later life
The fact that a long time period in between development and adulthood increase the potential for the environment to change in the interim reduces the likelihood of beneficial matches occurring
Such evidence appears thus far absent for animals that are long-lived such as humans
3ii. b. concept of tolerance on specific case of ‘Typhoid Mary’
– healthy carrier that remain asymptomatic despite being infected (high level of tolerance to the pathogen with which they are infected)