Module 5: The Pathology Of Infectious Disease And Population Health Flashcards
Four Classes of Microbes
Bacteria
- Microscopic unicellular prokaryotes
- Contain circular double-stranded DNA
- Most have cell walls distinct from eukaryotic cells
Examples:
Mycobacterium tuberculosis (tuberculosis)
Salmonella species (food poisoning)
Viruses
- Obligate microbes requiring host cells for replication
- Have DNA- or RNA-based genomes within a protein coat
- Infect specific host cells, including bacteria, plants, and animals
Examples:
Influenza (flu)
Rhinovirus (common cold)
Measles morbillivirus (measles)
Fungi
- Unicellular or multicellular eukaryotes with thick cell walls
- Cause superficial infections or invade deeper tissues
Examples:
Dermatophyte fungi (athlete’s foot, jock itch, ringworm)
Aspergillus (respiratory tract infections)
-Candida species (thrush)
Parasites
- Eukaryotic organisms that cause disease in a host
- Include protozoa, parasitic worms (helminths), and ectoparasites
- Some ectoparasites act as disease vectors
Examples:
Plasmodium parasites (malaria)
Sarcoptes scabiei (scabies)
The Microbiome: Normal Flora
- The microbiome is the collection of microbes (bacteria, viruses, fungi, and parasites) that live symbiotically in and on the human body.
- Found mainly on the skin and mucous membranes.
Functions of the microbiome:
Aids in digestion
Prevents inflammation
Protects against infections
Produces essential vitamins
- Mucous membranes: Membranes lining body cavities and internal organ surfaces.
Microbes as Pathogens
Opportunistic Microbes (Potential Pathogens):
- Normally part of the body’s normal flora but can cause disease if an imbalance occurs.
- Example: Staphylococcus aureus – a skin bacterium that can cause infections if it enters deeper tissues.
Always Pathogenic Microbes (Pathogens):
- Not part of the normal flora and always cause disease.
- Example: Rhinovirus – causes the common cold and spreads through airborne droplets or direct contact.
Immunity and Response
Innate Immune System (Immediate, Non-Specific Response)
- First line of defense, prevents pathogen spread.
Components:
- Physical barriers: Skin, mucous membranes.
- Chemical barriers: Enzymes in saliva and tears.
- Immune cells: Cause inflammation or engulf pathogens.
Adaptive Immune System (Delayed, Specific Response)
- Takes days to activate but targets specific pathogens.
- Recognizes antigens (foreign molecules) and triggers a strong response (pus, swelling, redness, pain).
- Forms immune memory to quickly fight future infections from the same microbe.
How Pathogens Cause Infection
- Entry: Pathogen enters the body (e.g., SARS-CoV-2 enters through the oral/nasal passages into the lungs).
- Invasion & Colonization: Pathogen attaches to human cells (SARS-CoV-2 uses spike proteins to bind to ACE2 receptors in the lungs).
- Evasion of Immune Response: Pathogens use different tactics to avoid detection (SARS-CoV-2 delays the adaptive immune response).
- Infection: Pathogen replicates and spreads (SARS-CoV-2 hijacks cell machinery to reproduce and infect more cells)
Conditions for Infectious Disease
Reservoir:
- Locations where pathogens persist long-term.
- Examples: Biological (humans, bats, chickens) or environmental (soil, lakes, swamps).
Mode of Transmission:
- Pathogens spread through various means:
Direct contact: With infected organisms or surfaces.
Droplets: From sneezing or coughing.
Airborne: Spores in the air.
Vectors: Carriers like mosquitoes or fleas.
Vehicles: Contaminated water or food.
Opportunistic Conditions:
- Factors that promote infection or weaken immune defenses.
- Examples: Stress, surgery, aging.
Infectious Disease Prevention
Eliminating Reservoirs:
- Removing sources of pathogens prevents disease spread (e.g., eliminating malaria-carrying mosquitoes).
Enhancing Barriers:
- Physical measures like face masks, hand washing, and social distancing reduce transmission.
Distributing Vaccines:
- Vaccines help the immune system recognize and fight infections before exposure.
Developing Targeted Medicines:
- Drugs can treat or prevent infections (e.g., ivermectin for parasitic worms)
Chickenpox Vaccination
- Cause: Chickenpox is a highly contagious viral disease.
- Symptoms: Blister-like rash (lasting ~1 week), fever, fatigue, headache.
- Vaccine Development:
Available in Canada since 1998.
Government-subsidized starting in 2004.
Now part of routine childhood immunizations. - Impact: Over 100-fold reduction in chickenpox prevalence in Canada
Herd Immunity
- Vaccines: Most effective and cost-efficient protection against infectious diseases.
- Vulnerable Groups: Some individuals cannot get vaccinated (e.g., infants, elderly, pregnant women, immunocompromised individuals).
- Herd Immunity: When a large portion of the population is vaccinated, it indirectly protects those who cannot be vaccinated by reducing disease spread.
Infection from Colonization
Disease Introduction: European settlers brought smallpox, tuberculosis, and measles, leading to devastating epidemics among Indigenous Peoples.
Consequences:
High mortality rates wiped out entire groups.
Survivors were often too weak to sustain themselves.
Loss of oral histories due to community collapse.
Unequal Public Health Response: Colonists used quarantine and vaccines but let diseases spread in Indigenous communities.
Biological Warfare: In 1763, Jeffrey Amherst used smallpox-contaminated blankets to weaken First Nations resistance—the first documented case of biological warfare.
Eradication of Smallpox: Due to global vaccination efforts, the World Health Organization declared smallpox eradicated in 1980—the first disease eliminated by public health measures
Infections In First Nations Communities
Strep Throat Case:
- 2014: Brody Meekis, a 5-year-old from Sandy Lake First Nation, died of strep throat due to inadequate healthcare services, such as poorly staffed clinics and unreliable medical transportation.
- This highlights failures in the Canadian healthcare system, particularly for Indigenous communities, where even treatable diseases can lead to death.
Tuberculosis (TB):
- TB was introduced to Canada by European settlers, and crowded reserves, residential schools, and Indian hospitals contributed to its rapid spread among Indigenous populations.
- Mortality rates for TB were historically highest among Indigenous peoples.
Current incidence rates of TB:
0.6 per 100,000 among non-Indigenous
23.8 per 100,000 among First Nations
170.1 per 100,000 among Inuit
2.1 per 100,000 among Métis
Bacteria
Bacterial Evolution:
- Bacteria were among Earth’s first lifeforms and evolved into multicellular eukaryotes over time, including humans.
- Most bacteria in the human body are crucial for health maintenance.
Gram Positive Bacteria:
- Thick peptidoglycan wall
- Stains purple with Gram stain due to the thick cell wall.
Gram Negative Bacteria:
- Thin peptidoglycan wall surrounded by an outer membrane.
- Stains pink with Gram stain due to the outer membrane.
Gram Staining:
- The Gram stain distinguishes bacteria based on their cell wall structure.
- This staining helps determine treatment options in healthcare.
- Peptidoglycan: A mesh of amino acids and proteins surrounding the bacterial plasma membrane.
Pathogenic Bacteria and Antibiotics
Bacterial Pathogenicity:
- Some bacteria are pathogenic and can cause diseases in humans.
- Antibiotics have revolutionized healthcare by helping to combat bacterial infections.
Bacterial Cell Envelope:
- Composed of the plasma membrane and the cell wall.
- The cell wall contains peptidoglycan, which differs between Gram positive and Gram negative bacteria.
- The primary role of the cell envelope is to contain internal pressure within the bacterial cell, preventing it from bursting.
Importance in Drug Design:
- Since cell walls (with peptidoglycan) are absent in eukaryotic cells, they become an ideal target for antibiotics.
- Antibiotics can be designed to target specific components of the bacterial envelope, without harming human cells.
Antibiotics and Antimicrobials
Antimicrobials:
- Broad term for agents, natural or synthetic, that stop the growth of or kill microorganisms.
- Includes substances like antibiotics, but also includes non-antibiotic agents such as bleach.
Antibiotics:
- Antibiotics are a type of antimicrobial specifically used as medications produced by microorganisms or synthetically, designed to stop the growth of or kill microorganisms.
- All antibiotics are antimicrobials, but not all antimicrobials are antibiotics
Antibiotic Classification
How They Target Bacteria:
-Bactericidal Antibiotics:
Kill bacteria directly, without needing the host’s immune system.
Effective in treating life-threatening infections.
Bacteriostatic Antibiotics:
Inhibit bacterial growth, relying on the host’s immune system to eliminate bacteria.
Not ideal for life-threatening infections.
What They Target:
Broad-Spectrum Antibiotics:
Target a wide range of bacteria, both Gram-positive and Gram-negative.
Narrow-Spectrum Antibiotics:
Target a small group of specific bacteria.
Cell Wall Synthesis Inhibitors
- The bacterial cell wall provides structural integrity and prevents osmotic rupture.
- These antibiotics block enzymes responsible for building the peptidoglycan layer.
- Example: Penicillin, a β-lactam antibiotic, binds permanently to the enzyme that crosslinks peptidoglycan, leading to weak cell walls and bacterial death.
- Some of these antibiotics are specific to Gram-positive or Gram-negative bacteria due to differences in cell wall composition.
Metabolic Pathway Disruptors
- These antibiotics target bacterial metabolic pathways that are absent or different in humans.
- A common target is folate synthesis, which bacteria need to produce DNA and proteins, whereas humans get folate from their diet.
- Example: Cotrimoxazole combines two antibiotics that each block a different enzyme in folate synthesis. Alone, they are bacteriostatic (stop growth), but together, they become bactericidal (kill bacteria).
Protein Synthesis Inhibitors
- These antibiotics block bacterial ribosomes, preventing translation of mRNA into proteins.
- Bacteria have prokaryotic ribosomes (70S), which differ structurally from human eukaryotic ribosomes (80S), allowing selective targeting.
- Example: Doxycycline binds to bacterial ribosomes, blocking protein synthesis and preventing bacterial growth.
- This class is useful for infections like Lyme disease, where a single dose of doxycycline can prevent illness after a tick bite.
Cell Membrane Disruptors
- These antibiotics disrupt the bacterial plasma membrane, causing leaks that interfere with essential cellular functions.
- Since bacterial and human membranes are similar, these drugs tend to have stronger side effects.
- Example: Daptomycin inserts into the bacterial membrane, creating leaks that lead to cell death by disrupting protein synthesis and other critical processes.
- Despite its side effects, daptomycin is increasingly used for multi-drug-resistant infections.
Nucleic Acid Synthesis Inhibitors
- Bacteria have circular DNA that must be supercoiled to fit inside the cell.
- During replication and transcription, an enzyme called gyrase temporarily relaxes this supercoiling.
- These antibiotics block DNA gyrase, preventing proper supercoiling and leading to DNA degradation and cell death.
- Example: Fluoroquinolones selectively target bacterial DNA gyrase, disrupting replication without harming human cells (which use different enzymes).
Antibiotic Resistance Pathways
Bacteria can develop antibiotic resistance through various mechanisms:
1. Alter Targets – Mutations change the drug’s target structure or replace its function, making the antibiotic ineffective.
2. Restrict Target Access – Bacteria block antibiotic entry or use efflux pumps to remove the drug.
3. Develop Drug-Specific Enzymes – Bacteria produce enzymes that break down or modify antibiotics, neutralizing them.
These adaptations allow bacteria to evade treatment, making infections harder to cure.
Development of Antibiotic Resistance
Antibiotic resistance develops through four key steps:
1. Infection – A host is infected with bacteria, including some that are drug-resistant.
2. Treatment – Antibiotics kill susceptible bacteria, but drug-resistant ones survive.
3. Proliferation – Resistant bacteria multiply, unaffected by the antibiotic.
4. Gene Transfer – Resistant bacteria can pass their resistance genes to other bacteria, spreading resistance.
This process allows antibiotic-resistant bacteria to thrive, making infections harder to treat.
Transfer of Antibiotic Resistance
Bacteria can spread antibiotic resistance genes through both vertical (to offspring) and horizontal gene transfer (to other bacteria), resulting in faster and more widespread accumulation of resistance.
Horizontal transfer occurs in three ways:
Transformation – Bacteria absorb free DNA from their environment and integrate it into their genome.
Conjugation – Direct cell-to-cell transfer of resistance genes via plasmids.
Transduction – Bacteriophages (viruses) transfer resistance genes between bacteria.
Maintenance of Resistance
Antibiotic resistance has a metabolic cost for bacteria, as producing resistance proteins and enzymes requires extra energy.
From an evolutionary perspective, resistant bacteria lose their advantage when antibiotics are absent. Non-resistant strains, which use fewer resources, can outcompete them and grow faster.
Selective pressure ensures that resistance is maintained only if antibiotics remain in the environment. Without the drug, resistant bacteria may die off over time.
Screening for Antibiotic Resistance Bacteria
Antibiotic-resistant bacteria pose a serious challenge in hospitals, where patients with weakened immune systems are at higher risk of infection. Two key resistant strains screened upon admission are:
1. MRSA (Methicillin-Resistant Staphylococcus aureus) – A strain of S. aureus that causes skin and soft tissue infections but is difficult to treat due to methicillin resistance.
2. CPO (Carbapenem-Resistant Organisms) – Rare but highly resistant bacteria, often resistant to multiple or even all antibiotic classes, making treatment extremely difficult.
Infected or colonized patients require strict contact precautions:
- isolation
- protective gear for healthcare workers
- frequent handwashing
- enhanced room cleaning to prevent hospital-wide spread.
Evolution of MRSA
- Penicillin introduced in the 1950s, but S. aureus developed resistance through beta-lactamase (enzyme that destroys penicillin).
- Methicillin (1959) was introduced as it was resistant to beta-lactamase.
- Some S. aureus strains developed methicillin resistance by altering penicillin-binding protein (PBP), preventing methicillin from inhibiting cell wall synthesis.
- By the mid-1980s, MRSA became widespread, especially in hospitals, making infections difficult to treat.
Vancomycin Treatment with MRSA
- Vancomycin became the default treatment for MRSA after methicillin resistance.
- Widespread use of vancomycin led to:
Vancomycin-resistant Enterococci (VRE): Extremely common.
Vancomycin-resistant S. aureus (VRSA): Very rare, but still a concern. - Vancomycin resistance limits available treatment options for infections.
Multidrug Resistance
- Multidrug resistance occurs when bacteria acquire resistance to multiple antibiotic classes.
Common multidrug-resistant bacteria:
MRSA: 30-40% of S. aureus infections in Canadian hospitals are caused by MRSA.
ESBLs (Extended-Spectrum Beta-Lactamase Producing Organisms): Includes E. coli and Klebsiella. These bacteria resist beta-lactam antibiotics, causing infections like UTIs and bloodstream infections.
CPOs (Carbapenemase Producing Organisms): Gram-negative bacteria resistant to multiple antibiotics, making infections extremely difficult to treat. - Impact: Increasing resistance limits treatment options, especially for ESBLs and CPOs, which are harder to treat with existing antibiotics.
Overuse of Antibiotics
Hospitals:
- Non-prescription antibiotic use is common, especially in low and middle-income countries.
- In China, hospitals depend on pharmaceutical sales for revenue, including antibiotics.
- Widespread illegal sales of antibiotics without prescriptions in Chinese pharmacies.
- In India, doctors often receive compensation from pharmaceutical sellers.
Agriculture and Aquaculture:
- Antibiotics are used to maintain growth and prevent disease in animals, especially in dense living conditions.
- Disease prevention in agriculture and aquaculture contributes to antibiotic overuse.
- In Canada, agriculture accounts for 82% of antibiotic use.
- A significant portion of antibiotics manufactured each year is used in agriculture, aquaculture, and veterinary settings.
Preventing Antibiotic Resistance
Surveillance:
Continuous monitoring of antibiotic use and resistance patterns.
Stewardship:
Appropriate and careful use of antibiotics across all industries and sectors.
Research and Innovation:
Ongoing research and development in antibiotic discovery and alternatives.
Infection Prevention and
Control:
Strict adherence to best practices in hygiene, sanitation, and infection control to prevent infections and their spread.
Regulation of Antibiotic in High Income Countries
- Banned the use of antibiotics in food production in 2006.
- Medical schools and associations have established clear guidelines for prescribing antibiotics and educating physicians on appropriate use.
- Guidelines prohibit physicians from accepting gifts from pharmaceutical companies and limit drug advertisements to patients.
- Statistics are maintained on the number of antibiotic prescriptions made for different classes.
- Hospitals and long-term care settings screen for antibiotic-resistant organisms and isolate those that test positive to prevent the spread.
Difficulties in Antibiotic Development
Drug Discovery Process for New Antibiotics:
- Identify a target (enzyme or receptor unique to bacteria).
- Develop an assay to test drug interactions.
- Conduct high-throughput screening of thousands to millions of compounds.
- Perform structure-activity relationship (SAR) testing to optimize drug effectiveness.
- Identify lead candidates with strong activity and specificity.
- Conduct pre-clinical testing in human cell lines and animal models.
- Proceed to clinical trials, a process that can take years and may still fail.
Challenges in Developing New Antibiotics:
- High cost & low financial incentive:
- Penicillin and existing antibiotics are cheap and widely available.
- New antibiotics would be reserved as a last resort, limiting sales.
Lengthy development process:
- Can take over a decade to bring a new antibiotic to market.
- Reliance on biotech startups:
- Small companies conduct early-stage research.
- Government grants often fund initial screening.
- Large pharmaceutical companies typically invest only after pre-clinical trials.
Example: Dr. Pruss’s Work at EpigenX (Santa Barbara, CA):
- Studied bacterial DNA methyltransferase inhibitors as a potential antibiotic target.
- Focused on EcoDam in E. coli, which methylates DNA for self-recognition.
- Developed an assay to detect methylation inhibition.
- Screened 50,000 compounds, identifying promising lead candidates.
- Project halted due to biotech industry downturn and lack of funding.
Future of Antibiotic Discovery:
- Biotechnology startups play a key role in innovation.
- Need new funding models and incentives to encourage antibiotic development.
- Government and industry partnerships may help bring new antibiotics to market.
Introduction to Viruses
- Viruses replicate only inside living cells and lack cells, growth, and energy production.
- Each virion has an envelope (protection) and genome (genetic material).
- Cause varied illnesses, from mild (common cold) to severe infections.
- Mutate rapidly, sometimes jumping from animals (birds, pigs, bats) to humans (e.g., Influenza A).
Structured of a Viral Particle
- Viruses vary in shape and size and have DNA or RNA genomes (single or double-stranded).
- Surrounded by a capsid (protein coat); some have an envelope from the host cell membrane.
- Outer layer (capsid or envelope) contains viral proteins that bind to host cell receptors for entry.
Viral Infection and Disease
- Viruses must replicate inside host cells to cause infection.
- The viral life cycle begins with attachment to specific host receptor proteins, enabling entry.
- Once inside, viruses uncoat, replicate their genome, translate viral proteins, and assemble new virions using host cellular machinery.
- Virions are released through processes like lysis or budding, allowing further infection.
- Antiviral therapies (e.g., COVID-19 treatments) target these replication steps to limit viral spread.
- Virus names differ from diseases (e.g., SARS-CoV causes SARS, while SARS-CoV-2 causes COVID-19).
The 1918 Influenza Pandemic
- Bacteria and viruses can both cause infectious diseases, potentially leading to epidemics and pandemics if uncontrolled.
- The 1918 influenza pandemic was the last major global pandemic, caused by an influenza virus.
- Similar to COVID-19, the 1918 flu had several waves of infections, with the second wave being especially lethal.
- Over two and a half years, the virus spread in three waves, eventually evolving into the annual influenza seasons we experience today.
Introduction to COVID 19 and SARS COV 2
- Both the 1918 influenza and COVID-19 pandemics were caused by novel viruses that humans had not encountered before, resulting in no pre-existing immunity.
- COVID-19, caused by the SARS-CoV-2 virus, is a respiratory disease with symptoms such as fever, cough, and fatigue, among others.
- SARS-CoV-2 is a coronavirus, which is spherical, enveloped, and contains a single-stranded RNA genome.
- The envelope of SARS-CoV-2 has spike proteins which play a significant role in the virus’s ability to infect host cells.
SARS-COV-2 Mechanism of Infection
- Entry: SARS-CoV-2 virions enter the body through the oral or nasal passages, traveling to the lungs.
- Attachment: The virus attaches to ACE2 receptors on lung cells using the spike protein. This binding acts like a lock and key, allowing the virus to enter the cell.
- Replication: Once inside the host cell, SARS-CoV-2 hijacks the cell’s machinery to replicate itself.
- Release: New virions bud out of the host cell, ready to infect more cells.
- Infection: These newly formed virions can infect other tissues in the body and be expelled from the host (e.g., through coughing or sneezing), potentially infecting other individuals.
SARS-COV-2 Tissue Targets
Tissue Targets: SARS-CoV-2 can infect a variety of human tissues, including those in the lung, respiratory tract, nasal passages, heart, eye, liver, bladder, kidney, pancreas, brain, prostate, testis, and placenta. The virus’s ability to target so many tissues contributes to the broad range of symptoms seen in COVID-19.
Symptoms: Typical COVID-19 symptoms include dry cough, tiredness, and fever. In mild cases, individuals may experience a loss of smell and taste. Some patients report brain fog, which can persist for months after the infection is cleared.
Covid-19 Infection Control
- Virus transmission: SARS-CoV-2 spreads via droplets and aerosols, requiring a host for replication, and does not survive long on surfaces.
- Social controls: Rapid implementation of social measures helped prevent transmission and overwhelmed healthcare systems.
Measures taken to stop the spread:
Distancing: Maintain at least 2 meters (6 feet) between individuals.
Closures: Close areas and activities involving large gatherings and close contact.
Masking: Wear face masks and shields to reduce person-to-person transmission.
Washing: Frequent handwashing, sanitizing, and cleaning commonly touched surfaces.
Staying: Stay-at-home orders to limit community spread.
Quarantining: Quarantine travelers and individuals with symptoms or close contact with infected persons.
Tracing: Track infected individuals and their contacts to control further spread.
Covid 19 Vaccines
Viral Vector Vaccines:
- Use a harmless virus (adenovirus) to deliver the gene sequence for the SARS-CoV-2 spike protein.
Examples: AstraZeneca (Vaxzevria), Janssen (Johnson & Johnson, Ad26.COV2.S)
mRNA Vaccines:
- Contain synthetic mRNA that codes for a piece of the spike protein of SARS-CoV-2.
Examples: Pfizer-BioNTech (Comirnaty), Moderna (Spikevax)
Whole Virus Vaccines:
- Contain either a live attenuated (weakened) or inactivated (killed) version of the virus.
Examples: Sinovac (CoronaVac), Bharat Biotech (Covaxin)
Protein Subunit Vaccines:
- Contain harmless pieces of the virus (such as modified spike protein) to trigger immunity.
Examples: Novavax (Nuvaxovid), Anhui Zhifei Longcam (Zifivax)
Virus-like Particles:
- Use plants, bacteria, or other biotechnologies to grow virus-like particles with viral surface antigens but no genetic material.
Example: Medicago (Covifenz)
New Screening Tools for Disease
Early Detection: A key strategy in controlling diseases by identifying them at an early stage for more effective treatment.
Cancer Screening Evolution: As understanding of biomarkers improves, screening programs will evolve to monitor cancer progression and intervene at the right time.
Next Generation Sequencing: Helps identify new biomarkers, enabling oncologists to intervene only when cancer reaches a treatable phase, avoiding over- or under-treatment.
New Diagnostic Tools: Emerging diseases, including antibiotic-resistant organisms and viruses, will require the development of new tools.
Example: The rapid development of SARS-CoV-2 PCR testing showcases how quickly new clinical tests can be deployed in response to new threats.
