Lecture 4 - Febrile system

Question 1

Co-Evolutionary Armsrace

Answer 1

• Red Queen hypothesis
• Pathogens evolve more complex way of exploiting our resources, and we evolve to defend against it

Question 2

Medical Perspective on Fever

Answer 2

• In medicine it is saw as pathological or nuisance (according to one of the “bibles” of medicine). As opposed to an adaptive reaction of the body
• “No evidence that fever facilitiates recovery from infection” - Harrison’s Principles of Internal Medicine
  • One of the most respected books in medicine
  • Statement is a lie.

Question 3

4 Components of the Febrile System

Answer 3

1. Preoptic anterior hypothalamus
   
   1. Homeostatic control, sensor/regulator of temperature
2. Cytokines (immune chemical messengers)
   
   1. Tigger fever and are regulated by it
3. Innate immune system
4. Adapative immune system
   
   1. Anitbodies

Question 4

Types of Immune cells

Answer 4

• Many kinds
• Neutrophils, Monocytes, Lymphocytes, Eosinphils

Question 5

Evidence for Fever as an Adaptation

Answer 5

1. Fever is energetically expensive
   
   1. Human Basal(36-37.8)/Febrile Temperature (37.9-41)
   2. 10% increase in metabolism per degree
2. Febrile temperatures enchance immune response
   
   1. Ellingson & Clark, 1942
3. Hypothermia reduces phagocytic activity of macrophages, cytokines and other immune response cells
4. Temporal staggering of cytokines
5. Lymphocyte trafficking specific to tissues where pathogens go
6. Above all inconsistent with a byproduct hypothesis
7. Effect of antipyretics on pathogen load

Question 6

(Ellingson & Clark, 1942)

Answer 6

• Looked at people’s temperature when they injested a certain amount of an infectious bacteria (staph)
• Temperature is highest in the optimal range before you cook your brain
• Enhancement of pagocytosis is specific to febrile range
• Suggests that by-product of heat and chemical flow in the body is the use of fever because there is an optimal range to kill infection within this range

Question 7

Cytokines

(2 kinds, and evidence)

Answer 7

• TNF-a: triggers migration of neutrophils
• IL-B: Activation of lymphocytes
• Co-expression can lead to organ failure/death
• Fever staggers cytokine expression
  
  • Peak of 1L-B is supressed and delayed at febrile temperatures
  • Provides additional evidence against a by-product hypothesis
• Febrile temperatures promote migration of lymphocytes
  
  • Pathogens are taken to lymph nodes
  • L-Selectin receptor cause lymphocytes to slowdown and attach to the lymph nodes (does not occur in other vascular tissues)
    
    • SPECIFICITY and non-random
  • Zebrafish experiment - Boltana et al. (2013)

Question 8

Zebrafish Experiment

(Behavioural Fever)

Answer 8

• “Behavioural fever” – organisms seek heat during fever to aid in raising core temp.
  
  • Origin of fever response is a behavioural one rather than a physiological one
• Attached a dna strand to zebrafish to activiate immune response
  
  • Infected fish seeked warmer environments

Experiment

• 10 fish per condition. Controls (no injection, no heat), Shams (injected with saline), Injected with dsRNA but no heat gradient, Injected and heat gradient.
  
  • Chamber 5 had a large group with the shams avoided them as well.
• Nearly all genes whose expression was uniquely upregulated by behavioural fever involved in immune response to viruses

Question 9

Effect of antipyretics on pathogen load

(IFNa)

Answer 9

• Increase pathogen load and prolong the infection
• Increased risk of death
• IFNa has antivral properties by reducing viral shedding
  
  • Antipyretics suppress IFNa
  • Increased viral shedding in ferrets by 78%.

Question 10

David Earn Paper

(proved and limitations)

Answer 10

AntiCalculated how many people taking antipyretics kills with influenza

• Needed to know shedding low and how far influence can infect a person based on this load
  
  • Also proportion of people suspetible
  • r0 has different levels based on the type of flu
• Used secondary attack rate (transmission) measured with a LMM
• Measured probability of treatment (90% of parents, 70% of nurses treat thier children/patients
• Prove: Antipyretic use kills 6k people at a seasonal flu level every year
• Limitations: based on 1 study of ferrets, but mortality measure is conservative and ignored increased contact due to pyretic use.