IMM250F 2020 Lecture 2
Innate Immunity: First Line of Defense L. 1: Requirements for infectious disease
Segment 2: New challenges of infectious disease
Segment 3: Physical and chemical barriers to infection
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Segment 1. Requirements for infectious disease
What is a pathogen?
• A true pathogen possesses the inherent ability to cross anatomical barriers and breach innate host defenses that normally limit commensal microbes.
• capable of causing disease in healthy persons with normal immune defenses
• It’s in their genes – pathogens possess genes (pathogenicity islands) encoding “virulence factors” that facilitate host penetration and invasion and allow them to cause disease.
• These genes are mobile, can transfer pathogenicity from a virulent strain into a non-virulent one
What are virulence factors?
Flagella – allows bacteria to move independently Adhesins – allow bacteria to stick to cells
What are virulence factors?
Type 3 secretion system
Effector proteins
Exotoxin receptor
Cytoskeleton Signal transduction
Effector proteins – proteins from the bacteria that hijack host cell proteins to allow bacterial entry and survival inside the cell
Toxins – direct damage to the host tissue
Koch’s Postulates: determining causation
How do we know that a particular pathogen causes a particular disease?
Disease association does not necessarily mean causation
(e.g. Hemophylus influenzae does not cause flu!)
20th century re-visitation of Koch’s postulates
• infects himself to prove Koch’s postulates for Helicobacter pylori
• Gastritis and ulcers at the time were thought to be caused by excessive acid production in turn caused by too much stress!
Marshall’s self-experimentation was immortalized by the comic Ulcer Tales which was distributed to many US physicians
Chronology of Helicobacter pylori research
• 1979 – 1984. Dr. , an Australian pathologist, discovers spiral- shaped bacteria in stomach biopsies of patients with severe gastritis – a heretical observation since at the time the stomach was thought to be sterile. Dr. collaborates with Dr. Warren on a project aimed at isolating Warren’s spiral shaped bacteria from 100 patients undergoing routine endoscopy: 26 out of 30 patients with ulcers had the spiral bacteria (the remaining 4 had other explanations for their ulcers).
• Warren and Marshall needed more evidence, so Marshall decides to resort to a self-experiment
Chronology of Helicobacter pylori research
1984. Their results were published in The Lancet in 1984 but it took ten more years before their results were accepted by the medical community.
It is well accepted now that H. pylori infection is the cause of gastric ulcers and is also associated with an increased risk of gastric carcinoma and gastric lymphoma.
2005. Warren and Marshall won the in Medicine for their discovery of H. pylori as the cause of most peptic ulcers.
Retrospective studies have shown that H. pylori was part of the normal microbiota of the majority of individuals since ancient times. In the late 90s antibiotics have been heavily used to eradicate H. pylori infection in Western countries bringing the incidence in children from 50% to 5%.
Epidemiologic studies, showing a concomitant association with increased asthma rates and obesity seem to indicate that destroying H. pylori might not have been a good idea after all! (More on this in our last lecture).
Factors promoting infectious diseases 1. Immunocompromised host
Most times our innate mechanisms of defense are sufficient to avoid the establishment of infection
When the immune system is defective, same microbes that are normally controlled, cause “opportunistic” infections
2. Factors promoting infectious diseases Going to the hospital puts you at risk…. Nosocomial infections
• Also called healthcare- associated infections
• Factors that contribute to nosocomial infections:
• Microorganisms in the hospital, introduced into the body through such medical procedures as surgery and catheterization
• Immuno-compromised host
• The chain of transmission (direct contact, contaminated surfaces)
(No need to memorize this table)
Many are antibiotic resistant
Different types of pathogens cause very different types of diseases
Microbes and humans
• Some bacteria are entirely adapted to the pathogenic way of life in humans. They are never part of the normal microbiota but may cause subclinical infection, e.g. M . tuberculosis
• Some bacteria that were part of the normal flora acquire virulence factors making them pathogenic, e.g. E. coli (0157:H7) that causes “hamburger disease”
• Some bacteria from the normal microbiota can cause disease if they gain access to deep tissues by trauma, surgery, e.g. Group A Streptococcus can cause (flesh- eating disease also called necrotizing fasciitis)
• In immunocompromised patients, many free-living bacteria and components of the normal flora can cause disease, e.g. Pseudomonas aeruginosa in cystic fibrosis patients, all sorts of infectious diseases in AIDS patients.
In developed countries, infectious diseases have regressed
Infectious diseases remain a dominant cause of death
Prompt for Quercus Graded Discussion
You’ve just been hired by the World Health Organization, where your job is to develop a list of diseases that might realistically be targeted for global eradication. You are also asked to develop a list of diseases for which eradication is most unlikely. Describe the characteristics of disease and infectious agents on your two lists (e.g. presence of a reservoir, etc.)
Lecture 2 Segment 2.
of Infectious Diseases
Emerging and re-emerging infections
Drug-resistant microbes
Growing recognition of a link between microbes
Infectious Diseases Caused 26% of Global Deaths in 2002
and chronic diseases
1. Emerging infections and zoonosis
(for your reference)
Zika Virus
• Zika virus is primarily transmitted by the bite of an infected mosquito from
the Aedes genus, mainly Aedes aegypti, in tropical and subtropical regions. This is the same mosquito that transmits dengue, and yellow fever.
• Zika virus is also transmitted from mother to fetus during pregnancy, and can cause birth defects, including microcephaly.
2013-2016 Ebola outbreak in West Africa
The new england journal of medicine
Pre-Outbreak
Post-Outbreak Outbreak end
Capacity building
n Vaccination
Human-to-human
transmission E
Vaccination
Convalescent
Zoonotic transmission
Intermediate or
Index case
Safe burial
amplifying hosts
(end hosts)
Chimpanzee
Counseling
Treatment (persistence)
Figure 2. Outbreak Phases.
Shown are the key elements of the three phases of an Ebola virus outbreak, including control measures.
N Engl J Med 2020; 382:1832-1842
positive-sense RNA transcripts are translated by host ribosomes, leading to intracellular assem- bly of the nucleocapsid and budding from the
foster therapeutic development. Future efforts should focus on studying differences between these viruses and the more recently discovered
/AP/Press Association Images
plasma membrane.2,16-18 filoviruses with unknown pathogenic potential.
Scientific American 323, 1, 32-37 (July 2020)
Photo courtesy of @CityofToronto on Twitter
2. Drug-resistant microbes
Bacteria’s strategies to fight back against antibiotics
http://www.cdc.gov/drugresistance/threat-report-2013/
3. The link between infectious and chronic disease
• Hodgkin lymphoma and Burkitt’s lymphoma: can be caused by Epstein-Barr virus ⇢ transformation of host cell
• Stomach ulcers and cancer: 555,000 new cases per year due to Helicobacter pylori
• Cervical cancer: increased risk due to human papilloma virus
• Liver cancer: 8 in 10 cases due to Hepatitis B or C virus
• Atherosclerosis: Chlamydia pneumoniae may contribute to its progression
Sources: American Society for Microbiology. New and Reemerging Infectious Diseases: A Global Crisis and Immediate Threat to the Nation’s Health, The
Role of Research. Washington, D.C.: ASM, 1997. Cited in Emerging Crisis in Infectious Diseases.
Volume 70: Epstein-Barr virus and Kaposi’s sarcoma herpesvirus/human herpesvirus 8. IARC monographs on the Evaluation of Carcinogenic Risks to
Humans. 1997. Cited in Emerging Crisis in Infectious Diseases.
Bahrmand AR, Bahadori M, et al. Chlamydia pneumonia DNA is more frequent in advanced than in mild atherosclerosis lesions. Scand J Infect Dis. 2004;36:119-123. Cited in Emerging Crisis in Infectious Diseases.
Prompt for Quercus Graded Discussion
Why do you think it is that chronic infections are associated with cancer?
Lecture 2 Segment 3
• Physical and Chemical Barriers to Infection
• Innate recognition of pathogens
Prevention
Protection against pathogens relies on several levels of defense
Containment
Tailored response
First line defense strategies
Natural peptide antibiotics: Defensins
Charles , Jr. (1943-2003)
“In order to obtain readily detectable responses to (protein) antigens they must be incorporated into a remarkable mixture termed complete Freund’s adjuvant.” “The most likely possibility (to explain this) is that primitive effector cells bear receptors that allow recognition of certain pathogen-associated molecular patterns that are not found in the host. I term these receptors pattern recognition receptors.” “I propose that these pattern recognition systems activated effector functions of primitive immune systems before the development of rearranging gene families and continue to play a role in host defense today.”
Approaching the Asymptote? Evolution and Revolution in Immunology. Cold Spring Quant Biol. 1989. 54: 1–13
What starts an immune response?
: “The Immunologist’s Dirty Little Secret”
To get adaptive immune responses (e.g. in vaccination) there needs to be innate immune recognition of molecular patterns
Danger-associated molecules (DAMPs) also exist!
Sensing Pathogens: the types of receptors used in innate responses differ from those used in adaptive responses
Created with BioRender.com
Innate immune cells recognize conserved features of infectious agents called PAMPs (Pathogen- Associated Molecular Patterns) or MAMPs (Microbial associate molecular patterns) using PRR (Pattern Recognition Receptors) . PRRs are germline receptors (genes do not rearrange)
B and T lymphocytes express specialized receptors called B Cell Receptor (BCR) and T Cell Receptor (TCR) that recognize pathogen- specific molecular structures generically called antigens. BCR and TCR genes undergo rearrangement during development
Components of the bacterial cell wall represent a source of PAMPs
Gram positive cell wall
Gram negative cell wall
Bacteria can be differentiated into 2 groups based on the
“Gram-stain” of cell wall
Gram-positive stain purple with crystal violet. Examples of Gram-positive bacteria are Streptococcus and Staphylococcus
Gram-negative do not retain crystal violet and are counterstained red. Examples of Gram- negative bacteria are E. coli, Salmonella
Gram Staining procedure
• Peptidoglycan
• Lipoteichoic acid
• Flagellin
• G sequences
• Modified cytosolic and endosomal ssRNA
• dsRNA (not found in host cells)
• G sequences
• Several glycans (e.g. zymosan)
• G sequences
• GPI anchors
• G sequences
PAMPs are conserved molecular structures present on microbes
Toll-like Receptors (TLRs) were the first PPR discovered, named after the Toll molecule in the fruit fly Drosophila
• Drosophila Toll had been cloned in 1985 by – Volhard. “Toll” means “weird” in German
• Helps the Drosophila embryo to differentiate its top from its
Toll Mutant
• (She won the Nobel prize for Medicine for her work on Drosophila development in 1995)
Cell, Vol. 42, 791-798, October 1985,
10 years after its discovery Toll is shown to regulate the antifungal response in Drosophila
• Infected Toll-deficient adult flies with Aspergillus fumigatus
• All flies died after 2-3 days
• Flies use Toll to defend from fungi
• Thus, in Drosophila, Toll is involved in embryonic development and adult immunity
was awarded a half share of the 2011 in Medicine for his work on Toll
Cell, Vol. 86, 973–983, 1996
B. Lemaitre et al ( lab)
& : discovery of human Toll
• Argued that an ancient immune defence system based on the Toll signalling might exist in humans
• Searched for human proteins that resemble Drosophila Toll
• (also reported similarity to plant proteins)
Several TLRs were discovered within a couple of years and human Toll was renamed TLR4. identified TLR4 as the receptor for LPS. He shared for this discovery the 2011 in Medicine with J. Hoffmann
NATURE | VOL 388 | 24 JULY 1997
Human TLRs: cellular location and ligands
Leucine-rich Repeat
General scheme of cell signaling
Transcription factors
Recognition of LPS and signaling through TLR-4
NFkB in action
Unstimulated cells PAMP-stimulated cells
NFkB in cytoplasm NFkB in nucleus
List of pattern recognition receptors and their cellular location
We only study TLRs (this lecture) and NOD1/2 (future lecture) in this course
What we learned in this lecture
o What is a pathogen. What is the difference between true pathogens and opportunistic pathogens.
o We went through the criteria that determine disease causation (Koch’s postulates and the story).
o We discussed why, even with improved hygiene, antibiotics and vaccination, infectious disease is still a critical problem
o How infectious agents are recognized by innate receptors (PRRs/PAMPs).
o What are the consequences of PRR activation? Next week we will look at the soluble and
cellular mediators of innate immunity that become mobilized following PRR engagement.
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