1. Infectious Diseases: Past, Present and Future Impacts on Human History George Risi, MD, Msc Infectious Disease Specialists, PC 614 West Spruce St Missoula, MT 59802 www.infectionspecialists.org grisi@saintpatrick.org

2. Aims of This Series To acquaint the student with the fundamental aspects of the immune system that are important in order to understand infectious diseases To discuss the major infectious diseases that have impacted the course of history To discuss the current and future infections that are currently impacting mankind To discuss the two edged sword of antibiotics and introduce the concept of the microbiome To discuss the history of vaccines, their successes, failures, misconceptions and prospects for future uses To discuss the prospects for global elimination of disease

3. Topics for Discussion Immunology and how the body contends with organisms in the environment The impact of Infectious diseases on human history – Smallpox – Plague Persistent or new scourges – Malaria – Tuberculosis – HIV – Influenza Recurrent scourges: measles, polio, whooping cough Antibiotics, antibiotic resistance and the effects of antibiotic use on the global microbiome Vaccines and other control measures; Whether it is feasible to attempt global eradication of infectious diseases, and what the world might look like with Infectious Diseases eliminated

4. Lecture I The broad range and diverse number of potential pathogens that are encountered by the human immune system Innate immunity Adaptive immunity – Humoral immunity – Cell mediated immunity The major histocompatibility complex Overview of how successful pathogens evade the immune system Societal and host factors that contribute to disease prevalence and transmission

5. What Our Immune System Deals With

6. Infectious Diseases and the Immune System It has been estimated that there are between 10 7 and 10 9 different species of bacteria in the world * There are at least as many viruses in the world ** The total number of species of viruses and bacteria that have been described as able to cause disease in humans is 1,415 The majority of these are “opportunistic” and only can cause disease in immune compromised individuals How does the immune system work so well against >99.9% of all viruses and bacteria? *Schloss, Microbiology and Molecular Biology Reviews 2004;68:686 ** Breitbart, Trends in Microbiology 2005;13:278

7. Mechanisms of Defense The innate immune system The adaptive immune system

8. The Innate Immune System Evolutionarily much older Little changed compared to annelids (earthworms) and arthropods Much of what is known about innate immunity has been learned by studying the fruit fly, Drosophila melanogaster Drosophila melanogaster

9. The Innate Immune System Includes physical barriers such as skin The first line of defense against pathogens Represents the immediate response of the body upon encountering a substance that is recognized as “non-self” Circulating proteins – Complement – C-reactive protein – Others Three main cell types – Polymorphonuclear leukocytes (PMN’s or poly’s) – Macrophages – Dendritic cells

10. Pathogen Associated Molecular Patterns (PAMPs) Pathogens express certain components known as pathogen associated molecular patterns. These are essential for the survival of the pathogen. All pathogens express one or more PAMPs PAMPs

11. Pattern Recognition Receptors (PRRs) Located on the surface of cells, within cells and soluble within the circulation are pattern recognition receptors which bind the PAMPs and initiate various defense processes.

13. Tubingen, Germany, 1984 The embryologist, Christine Nusslein-Volhard was studying embryogenesis by analyzing mutations in fruit flies Saw a weird looking fly larva in which the ventral portion of the body was underdeveloped Her spontaneous comment was “Das war ja toll!” (that is so amazing.) The gene responsible for this became known as the “toll” gene Nature 1984;311(5983):223

14. Lemaitre B, Cell 1996;86:973 What Happens if You Delete the Toll Gene?

15. Mammalian Toll-like receptors

16. TLR’s Not The Only PRR’s Cell associated – Toll-like receptors – C-type lectins – Scavenger receptors – N-formyl met-leu-phe receptors – NOD like receptors – CARD containing proteins Circulating – Complement – Mannose binding lectin – C-reactive protein

17. Molecules not found in Annelid or higher cells

18. Engagement of PRRs Triggers a Series of Events Generation of pro- inflammatory cytokines, “messenger molecules” for the immune system – Fever – Proliferation of WBC’s – Migration of WBC’s to the site of infection – Increase efficiency of killing Synthesis of interferon which stimulates > 200 proteins to be synthesized, resulting in the “antiviral state”

19. Innate Immunity Provides the immediate response to a pathogen, buys time for the adaptive immune system to generate a more specific immune response

20. Cooper, Cell 2006;124:815 “Each metazoans lineage that We recognize today, including The vertebrate lineage to which We belong, appeared more than 500 million years ago.”

21. Adaptive Immunity First appeared in jawed vertebrates (sharks, skates, rays) and became increasingly sophisticated with further evolution Major advantages of adaptive immunity – Specificity – Diversity. Able to respond to a much larger variety of antigens – Memory. More rapid response when exposed to the same antigen – Clonal expansion. Increase numbers to keep pace with the microbe’s growth – Specialization. Just the right kind of response for a specific pathogen – Contraction after the danger has passed

22. Mechanisms of Defense Innate immune systemAdaptive immune system Humoral immunity (Antibodies) Cell mediated immunity Cytotoxic (CD8 + ) T cells Helper (CD4 + ) T cells Th1 Th2TregTh17 others Cell surface associated Intracellular Soluble in circulation

23. Mechanisms of Defense Innate immune systemAdaptive immune system Humoral immunity (Antibodies) Cell mediated immunity Cytotoxic (CD8 + ) T cells Helper (CD4 + ) T cells Th1 Th2 TregTh17 others Cell surface associated Intracellular Soluble in circulation

24. Lymphocytes: Cells of the Adaptive Immune System Thymus derived (“T”) lymphocytes – Helper (CD4+). Several subsets – Cytotoxic (CD8+) – Regulatory – Natural Killer (NK) cells Bone marrow derived (“B”) lymphocytes. Responsible for making antibodies (Immunoglobulins) – Immunoglobulin (Ig) A – IgG – IgM – IgE – IgD

25. The Dendritic Cell is the Bridge Between Innate and Adaptive Immunity Journal of Virology 2006;80:10

26. Receptors on Lymphocytes Receptors on the surface of lymphocytes are different for every individual One individual has approximately 1 X 10 8 separate T cell types, each with its own unique receptor Lymphocytes can only see proteins that are presented to them by an antigen presenting cell

29. The Major Histocompatibility Complex The genetic locus whose products are responsible for binding to and presenting proteins to lymphocytes In humans it is known as the Human Leukocyte Antigen (HLA) system There are a limited number of HLA molecules – Every person is not able to bind every protein HLA molecules are inherited HLA in Humans

31. What Does it Take to be a Successful Pathogen? Viruses – Inhibit antigen digestion and processing (Herpes simplex, cytomegalovirus) – Block interferon production or blunt its effects (Ebola, West Nile virus) – Synthesize molecules that mimic immune suppressing cytokines (Epstein-Barr virus) – Synthesize decoy receptors that soak up host cell cytokines (smallpox) – Infect and kill the cells that are responsible for generating immunity (HIV) – Alter their protein coat to evade antibodies (influenza, rhinovirus, HIV) Disable or bypass host defenses

32. What Does it Take to be a Successful Pathogen? Bacteria – Altered PAMPs to avoid PRR’s ( Helicobacter pylori, Burkholderia pseudomallei, Coxiella burnetti, Yersinia pestis ) – Prevent the activation of complement, a crucial innate immune mechanism (multiple species) – Elaborate a capsule rendering them resistant to ingestion ( Streptococcus pneumoniae ) – Detoxify molecules (reactive oxygen etc.) that normally would kill them ( Staphylococcus aureus ) – Grow inside immune cells and suppress multiple pathways ( Mycobacterium tuberculosis, Salmonella typhimurium, Legionella pneumophila ) – Alter their outer membrane to avoid antibodies ( Neisseria gonorrhoeae, Salmonella typhimurium, Borrelia recurrentis )

33. What Does it Take to be a Successful Pathogen? Parasites – Reside inside cells that are hidden from the immune system (Plasmodium species) – Coat themselves with human proteins and hide from the immune system (Schistosoma species) – Stimulate the proliferation of immune suppressing cells (Leishmania species) – Vary their outer protein coats (Trypanosoma rhodesiense, agent of sleeping sickness)

34. Sickness and Sedentism The human immune system evolved primarily while we were hunter gatherers – Small, isolated bands – Seldom remain in one place for long – Minimal fouling of water supplies – Minimal accumulation of garbage, rotting carcasses, human waste to attract vermin Infectious Diseases of hunter gatherers? – Infection of injuries by resident skin flora ( Staphylococcus aureus, others) – Intestinal worms – Diseases transmitted by lice, flies, mosquitoes

35. Transition to Farming and Livestock Domestication Increased birth rate, population increases Exposure to animals and their diseases – 75-80% of all human diseases originated in animals Drinking water polluted with human waste Garbage attracts rats, flies, other pests Flooding of lowlands for crops creates ideal haven for snails that carry Schistosomiasis Many of the diseases we deal with today are the result of the transition away from nomadic way of life

36. The Great Plagues of Antiquity The Pharaoh's plague (~1900 BCE). Snail fever (Schistosomiasis) from flooding of the Nile The plague of Athens (430 BCE). Typhus (Rickettsia typhi) from body louse most likely The Roman fever. Malaria (high density of human carriers) The plague of Antonius (164-180 CE). Smallpox The Cyprian plague (250 CE). Measles The plague of Justinian (541 CE). Bubonic plague (Yersinia pestis) Sherman, The Power of Plagues, ASM Press

37. Other Major Agents Viruses – Influenza – Yellow fever – Human immunodeficiency virus Bacteria – Mycobacterium tuberculosis (Tuberculosis) – Vibrio cholerae (Cholera) Parasites – Guinea worm (Dracunculus medinensis) – Hookworm (Necatur americanus and Ancylostoma duodenale) – River blindness (Onchocerca volvulus)

38. Morens et. al., Nature 2004;430:242

39. Factors Contributing to Disease Emergence and Spread

40. Physical Environmental Factors Genetic and Biological Factors Microbe Ecological Factors Social, Political and Economic Factors Human The Convergence Model Institute of Medicine: Microbial Threats to Human Health, 2003

41. Societal, Political, Economic Transition from nomadic hunter-gatherer lifestyle to sedentary agrarian – Schistosomiasis Increasing population density – Smallpox requires population of 1-200,000 to be maintained – Tuberculosis as a consequence of the Industrial Revolution Crowding together of people and their unwanted guests – Plague War, famine, malnutrition – Typhus – Diarrhea- all types

42. Commerce and Travel West Nile virus imported into US HIV imported from Africa Plague imported from China Yellow fever imported from Africa Measles, smallpox imported to New World from the Old World SARS carried around the globe from China

43. Climate or Environmental Changes Dam building – Schistosomiasis – Rift Valley fever Global warming – Dengue – Malaria Reforestation – Lyme disease

44. Interspecies Transfer Due to Behavioral Changes Simian AIDS to humans through bush meat SARS from crowding different species together in wet markets Nipah, Hendra from bats leaving their usual habitats

45. Changes in Hygiene Cholera, typhoid fever from water contaminated by human waste Polio epidemic due to exposure occurring later in life (Loss of protective maternal antibodies)

46. Subsequent Lectures Smallpox- past, present, future? Plague HIV and Malaria Tuberculosis Antibiotics, antibiotic resistance, and the effect of antibiotics on the global microbiome Vaccines. Myths, realities and the prospects for elimination of infectious diseases