How do we compete with pathogens?  Bacteria and viruses reproduce much more rapidly  Bacteria and viruses are very numerous  Bacteria and viruses tolerate vast fluctuations in population size  Recover so quickly  1% of bacterial population is insignificant but 1% of human population is a major proportion  Enormous genetic diversity with rapid evolution  Summary: Pathogens have large populations that undergo rapid fluctuation, evolving at a much higher rate than their hosts.

Pathogens have a shared interest in our survival; with few exceptions, a dead host inhibits the spread of the pathogen.

Evolutionary mechanisms include intraclonal (within the cell) and interclonal (between different cells) processes.

Intraclonal Processes  DNA Replication: microbes are constantly exposed to chemical and physical mutagens, resulting in high variation of genomes  RNA Replication: no repair mechanisms means a mutation rate so high that for many RNA viruses virtually every particle is genetically different  Haploid Organisms: single copy genomes means no delay in expressing new genetic factors  Phase Variation: many pathogens seem to have an archive of genetic material that may be silent under normal conditions but can become expressed and give the appearance of an adaptive change

Interclonal Processes  Genetic Exchange: conjugation, transduction, and transformation increase the genetic, and often the phenotypic, diversity  Host-Parasite Coevolution: hosts and parasites coadapt with parasites generally prolonging their survival by overcoming host defenses and mitigating their virulence  Symptoms: symptoms may be a host defense or a virulence mechanism

The Germ Theory of Disease (Revisited)

Foundations of Microbiology  Antoni van Leeuwenhoek first observed microorganisms  Louis Pasteur laid the foundation for modern microbiology  Robert Koch developed methods and concepts

Koch’s Postulates  The disease-causing organism must be present in all diseased hosts and absent in healthy hosts.  The disease-causing organism must be isolated and grown in pure culture.  Inoculation of a healthy host with the disease-causing organism must result in the original disease.  The disease-causing organism must be re-isolated and shown to be the same as was inoculated.

Ignaz Semmelweis  Observed that mortality rate of new mothers was higher with physicians than with midwives  Suggested better hygiene to reduce mortality  Friend died of puerperal sepsis contracted during autopsy  Hypothesized “invisible agents” responsible for the spread of disease

The Germ Theory of Disease: Microbes are responsible for the spread of disease.

Leading Causes of Death in the U.S.

Darwinian Medicine: The influence of evolution on disease.  How does a disease affect reproductive fitness?  An inherited disease with a severe fitness cost will be selected against. “When diseases have been present in human populations for many generations and still have a substantial negative impact on people’s fitness they are likely to have an infectious cause.” ---- Paul Ewald

Darwinian Medicine and Microbiology  Evolutionary change occurs very rapidly in the microbial world  Evolutionary drive is to reproduce  Do reproductive and transmission strategies influence disease symptoms?  Are disease symptoms caused by the pathogen or the host?

Evolution of Infectious Disease  Too many copies of an infectious agent can kill or immobilize a host before it can spread  Pathogens transferred by a vector tend to be more virulent

Chronic Diseases Diseases that could not fulfill Koch’s Postulates were attributed to heredity, environmental, or “multifactorial” causes

Darwinian Medicine and Microbiology II Some of the diseases attributed to genetic or environmental factors, including some forms of heart disease, cancer, and mental illness, are in many cases actually due to microbial infections.

Heart Disease  Clogged coronary arteries have been found full of Chlamydia pneumoniae  Some estimates that 80% of coronary heart disease is caused by C. pneumoniae  C. pneumoniae also found in autopsied brains of Alzheimer’s patients (not in controls)

HIV  High mutation rate  Preventative measures curb the spread of infection  Would transmission-prevention programs be more effective than the search for a vaccine?

Cancer  HTLV-1, a retrovirus endemic in parts of Asia, Africa, and the Caribbean, has been linked to some leukemias and lymphomas  Epstein-Barr Virus, the cause of mononucleosis, has been linked to some lymphomas and nasopharyngeal cancers  HPV has been shown to cause cervical cancer  Hepatitis B and C have been linked to liver cancer

Ulcers  Barry Marshall demonstrated that up to 75% of ulcers may be due to Helicobacter pylori  Over 90% of cases are cured with antibiotics  Infection by H. pylori causes a 6-fold greater risk of stomach cancer

Prediction from Ewald: Throughout history most people have died of infectious disease, and most people continue to die of infectious disease.