Ch.17 - Infectious Diseases and Vaccines

global facts about infectious disease burden

Approximately 25% of deaths worldwide are associated with communicable diseases

Kill an estimated 11-12 million people annually

Sepsis kills another 11 million people per year

Top 10 causes of death in the year 2000

Lower respiratory infections

Diarrheal diseases

Tuberculosis

HIV/AIDS

Types of microbes/microorganisms

1) Commensals

2) Primary Pathogens

3) Opportunistic pathogens (pathobionts)

1) Commensals

Microbiome, virome, fungome

2) Primary Pathogens

Can cause disease in most healthy people

3) Opportunistic pathogens (pathobionts)

**Usually cause disease only if the immune system is weakened or if the microbe gains access to a part of the body where it is normally not found

Pathogens can cause ________ & __________ problems

They can be _________, ______________, or ________________

they contribute to . . .

acute & chronic problems

can be viruses, bacteria or eukaryotes

Contribute to cancer, cardiovascular disease and other chronic illnesses

Physical + chemical barriers must be ___________________ to cause infection

Physical (Epithelial linings of the skin & gut are important barriers)

+

chemical barriers (Innate mechanisms recruit & initiate adaptive response)

must be BREACHED!!! to cause infection

Pathogens are either ___________ or _____ ____ ________

cleared or kill the host

*Often, survive long enough to spread from one host to another before being cleared*

Viruses are ________________________

What material are they made of?

Outer surface may be ________________ or __________________________

Intracellular obligate pathogens

-- RNA or DNA genetic material

-- Outer surface may be enveloped or non-enveloped

Basic Biology of Viral infections

Typically, viruses enter host cells through a cell-surface receptor

Genome replication is often error-prone, leading to ________________

**Viruses are more likely to thrive if they _________ _______ ____ _______

mutations

DON'T kill the host 🠊A greater chance for replication and spread!

I. Viral Infections types? (3)

1) Innate Immune Receptors (PRRs)

2) Cell-Mediated Immune Response

3) Humoral Immune Response - Antibody Dependent Enhancement

1) Innate Immune Receptors (PRRs)

Antibodies - inhibit many viruses

>> Viruses must be outside a host cell for Abs to function

2) Cell-Mediated Immune Response:

CD8+ CTLs & NK Cells -- kill virally infected host cells (MHC Class I Defects)

CD4+ T Cell purpose in cell-mediated response?

IFN-gamma and IL-2 production that promote anti-viral activity

3) Humoral Immune Response - _______________ ____________________ __________________

Observed in which viruses?

Antibody Dependent Enhancement

Observed in:

-- Dengue virus (Philippines, Dengvaxia)

-- Respiratory syncytial virus (RSV)

-- HIV - Human Immunodeficiency virus

-- Feline infectious peritonitis virus

-- Coronaviruses

Viral Ag expressed on MHC class I or II; how are CD8+ and CD4+ involved?

CD8+ CTLs actively find and destroy virally infected host cells (MHC class I)

CD4+ helper T cells secrete cytokines that promote antiviral activity (MHC II)

What two cytokines are involved with CD4+?

>> IFN-γ directly induces an antiviral state in adjacent cells

>> IL-2 promotes CTL proliferation & differentiation of T and NK cells

4 Examples of Viral Evasion of Host Defenses (detailed)

1. Blocking cytokine signaling (e.g. PKR blocking by Hepatitis C, preventing IFN signaling effects)

2. Blocking MHC Class I presentation to CD8+ CTLs

3. Inhibiting MHC Class II expression & presentation to CD4+ T Cells

4. Coding for anti-complement proteins

**Anti-Viral Responses** (4):

1) FUNCTIONAL BLOCKING: Ab binds to virus preventing it from binding to target cell receptor → virus CANNOT enter host cell

2) Activate COMPLEMENT (enveloped viruses) = lysis

3) Facilitate phagocytosis (opsonization) from ab binding

4) Neutralizing immunity are preexisting Abs that bind and inhibit virus as it enters the body

Hepatitis C virus overcomes _____________ ____________ ___________ by . . .

interferon antiviral effects by [blocking/inhibiting a critical signaling protein called PKR]

Herpes viruses shut down _______ _________ __

MHC class I presentation to CD8+ T cells at various steps

**>> Multiple viruses inhibit MHC class II expression & presentation to T cells

Some microbes code for anti-complement proteins (________) ___________________

e.g......

(vRCAs - regulators of complement activation)

--Bordetella pertussis (whooping cough)

-- Yersinia pseudotuberculosis (foodborne illness, swollen glands, fever)

-- Treponema denticola (periodontitis)

-- Staphylococcus aureus (staph infection, MRSA)

-- Neisseria meningitides (meningitis and sepsis)

-- Pseudomonas (lots of infections)

-- Herpes viruses

T cells - important for _________ ____________ & ________________

viral control & clearance when the virus is inside a host cell

Influenza has been responsible for some of the worst pandemics in history

3 basic types? what other properties?

⭐⭐⭐ A (common for pandemics), B, C

2 key viral glycoproteins on virus surface

what are the two key viral glycoproteins?

Hemagglutinin (HA) ― allows attachment of virus to cells

Neuraminidase (NA) ― helps new virus escape from host cells

Genome has eight segments of ___________

ssRNA - 10 proteins

Influenza facts? Each strain defined by what?

IStrains tracked yearly by the CDC and WHO

Each strain defined by its host of origin, geographical origin, strain number, year of isolation, and HA/NA type

Influenza A is recognized by

innate immune receptors that result in IFN and TH1 response

1. Antigenic Drift occurs due to

mutation potential of a RNA genome.

==>> RNA polymerase make errors during replication

Reason for changing flu vaccine formulation every year?

Viral RNA polymerase lacks proofreading capability (errors during replication)

Humoral Feedback Inhibition

Once we have an effective response, we won't initiate a new one UNTIL the old one is no longer effective at all

2. Antigenic shift occurs when . . .

DIFFERENT strains of a virus infect a single cell

-->> RNA genome segments can be swapped to make virus progeny that have newly recombined RNA segments or a hybrid virus

Antigenic shift could generate . . .

how does this relate to pandemics?

new viral attachment proteins

-->> A population may have little to no resistance against a new combination 😨

!! *Responsible for pandemics* !!

II. Bacterial infections (2)

1. Extracellular bacteria

2. Intracellular bacteria

1. Extracellular bacteria

-- What cells are involved? What processes do they entail?

Innate Immune Cells (e.g. Macrophages, Neutrophils, Mast Cells) & Lymphocytes

⬇️

Ab, complement lysis, phagocytosis, and degranulation are major mechanisms of elimination

NK cells, CTLs, and macrophages for clearance

NK cells are also critical to clear virally infected cells

Bacteria evade host DEFENSE MECHANISMS at several different stages ⬇️

*Yersinia* intoxicates macrophages (hollow needle injected into cytoplasm) with Yop proteins

What do Yop proteins do?

block cytokines/cytoskeletal components, prevent phagocytosis and activate apoptosis

III. Parasitic infections

Malaria (#1 cause of parasite-induced death) ➡️ poor immunity in children

Genus Plasmodium species carried by female Anopheles mosquitoes

Evasion of the immune system:

Life cycle moves through the liver & RBCs

Short blood circulation time of free parasite stage

Intracellular phases resist Ab-based responses

Maturational changes allow Ag shifting

Ab responses avoided by outer coat shedding

African sleeping sickness: Caused by trypanosome species; transmitted by tsetse fly bites 🠚🠚 Protozoan differentiates and divides every six hours in blood

Moves from blood to central nervous system

Expresses 1 VSG gene at a time (makes hard for ab to target pathogen)

Prevents effective immunity

Leishmaniasis: Transmitted by sandflies; Produces one of two syndromes

Localized cutaneous often self-resolving skin lesion

Systemic visceral leishmaniasis 🠊 Nearly always fatal without treatment

Replicates in MACROPHAGES!!

Resistance is mediated by an effective TH1 response and IFN-γ secretion.

Individuals skewed to TH2 response are less likely to resolve leishmaniasis

Worms (helminths): Mainly reside in GI; exclusively EXTRAcellular

Most don't replicate in hosts, limiting immune engagement

Some wrap themselves in host proteins to further limit immunity

Immunity dependent on:

IgE production

Eosinophilia

ADCC

Concept of Premunition - The state of balance between a host in an infectious agent

IV. Fungal infections; Classification of mycoses based on (3):

1) Site of infection. 2) Route of acquisition, 3) Virulence

Commensal microorganisms also help "_________ ______" . . .

"crowd out" pathogenic fungi

antibacterial medications may result in what?

oral thrush or vulvovaginal candidiasis (yeast infections)!!!

Innate immunity & PRRs control _______ ___________ _________________

What type of T cell and what other receptor is involved?

most fungal infections

(T cells e.g. Th1= PRRs (TLRs)) involved also)

Fungi have evolved evasion mechanisms (2):

1) Capsules that prevent PRR binding

2) Fungi-induced expulsion from macrophages

Vaccine strategies with unique advantages and challenges (3):

-- Safety

-- Effectiveness (efficacy)

-- Delivery strategy should be achievable in the desired population

Vaccines: Passive immunization is the delivery of ___________________ ___________________ to treat (3):

preformed antibodies to treat:

a) Immune deficiency

b) Toxin or venom exposure

c) Exposure to pathogens that can cause death faster than an adaptive immune response can develop (Rabies)

IVIG treatment for ___________________ inflammatory diseases

What can this treatment lead to?

**This treatment can lead to Type I (if made in a different species) or Type III hypersensitivities

Active immunization

to induce immunity and memory

Are fungal infections easy for the immune system to fight off?

usually quickly resolved by the host unless the host is immunocompromised

Types of vaccines? 6

(1) Live, Attenuated Vaccines

(2) Inactivated Vaccines

(3) Subunit Vaccines

(4) Toxoid Vaccines

(5) Recombinant

(6) mRNA

Live, attenuated vaccines:

Pros/cons?

Weakened pathogens

Pros: Retain their ability to replicate, promote humoral & T-cell responses

-->> Spread immunity to someone else; often do NOT need boosters

Cons: Not for immunodeficient; may have more side-effect complications

==>> May also require a "cold chain" for stability during transport

-- May mutate back (revert) to pathogenic form (very unlikely)

Live, attenuated vaccine examples?

Examples: MMR, Yellow fever, chickenpox, BCG (Tb)

Inactivated or "killed" vaccines:

Examples?

Heated or chemically treated to inactivate

Examples: Rabies, Hepatitis A, most Influenza vaccines

Pros/cons of "killed" vaccines?

Pros: No reversion to pathogenic form

-- Often more stable/easy to store and transport

Cons: --> Often require booster shots

**Don't replicate in host, so often don't induce strong cell-mediated immunity (humoral only)

== Possible chemical exposures/adjuvants often required

Subunit vaccines:

Use purified macromolecules derived from pathogen

Inactivated exotoxins/toxoids

Vaccinate with bacterial toxins that have been inactivated (called toxoids).

--> Antibodies will recognize and neutralize the toxin.

pros/cons of inactivated exotoxins? examples?

Pros: Very effective

Cons: Booster required

Examples: Tetanus, diphtheria

second example of subunit vaccine?

Inactivated capsular polysaccharides or surface glycoproteins

Subunit vaccine pros/cons?

Examples?

Pros: Never will spread, noninfectious

Cons: Similar to those of inactivated/killed vaccines

Examples: Hib (Haemophilus influenzae type b) disease, Hepatitis B, HPV (Human papillomavirus)

Recombinant vector vaccines:

Use an attenuated virus; genetically engineer it to carry another pathogen's genes and express them

recombinant vector vaccines pros/cons?

Pros: All the benefits of attenuated vaccines

==> Fewer risks―not using the actual

pathogen, but something else entirely!

Cons: Stability issues

-- Safety for the immunocompromised

5) mRNA vaccines

A specific gene for a pathogen is injected into muscle tissue

Host cells take up RNA and express the protein internally

mRNA vaccines provide Ag presentation via . . .

MHC I, stimulating CTL (CD8+) production

Cell surface expression can

Enhancing Immune Response to Vaccines:

Promoting inflammation can recruit more immune cells to the area, enhancing effectiveness

pros/cons of mRNA vaccines?

Pros: Induces humoral and cell-mediated immunity

-- Prolongs expression, enhancing memory

>> VERY stable and customizable

Cons: new

Example: Moderna and Pfizer Covid vaccine

Slowing down Ag release can ____________

...

promote longer interactions, enhancing the effectiveness

Adjuvants:

chemicals that help enhance the immune response to vaccines

adjuvant examples? 4

***1. Alum―good at stimulating T cell response

2. MF59―oil in water emulsion, slows Ag delivery

3. AS04―alum plus a TLR4 agonist

--> Encourages TH1 responses

4. Thimerosal - approved as a preservative and used as an adjuvant. Contained mercury. Removed in US in 1999.

Conjugate, adjuvant, or multivalent vaccines:

can improve immunogenicity & outcome

Consider immune target - Inducing CTL response:

deliver Ag into cells for presentation in MHC class I molecules

Creation of lipid carriers known as . . .

⭐immunostimulating complexes (ISCOMs) for delivery