MCB3020 - Infectious Disease - SP26

Immunity origins

extant immunity in vertebrates can be traced back 0.7-1 billion years to rudimentary systems in microbes

do all living things have some form of an immune system

yes

Immunity

1. acellular/humoral

2. cellular components in multicellular organisms

3. tissues

4. organ systems

differentiates self from non-self and destroys pathogens or harmful substances

MALT

Mucosal-associated lymphoid tissue; tissue in the mucous membranes that helps fight infection

anatomy of immunity: organs

bone marrow, thymus, and spleen

anatomy of immunity: tissues

lymphatics and blood

anatomy of immunity: proteins

antibodies, complement,etc. aka humoral

Innate immunity

first line of defense, constitutive

1. physical

2. chemical barriers

3. cellular

4. humoral defenses

constitutive

rapid and non-specific

Adaptive Immunity

inducible and pathogen-specific

1. cellular

2. humoral defenses

how are innate and adaptive systems connected?

antigen presentation by dendritic cells

Barriers

skin and mucosal surfaces

innate physiochemical barriers to pathogens

corneocytes

dead Keratinocytes on the surface that have hardened; impermeable

sebum

contains membrane damaging free fatty acids

SALT

includes immune cells and humoral defenses

functions to detect and destroy pathogens, to communicate with adaptive immunity

Where is the SALT

under the epidermis

What is part of the SALT of the dermis

Langerhans's cells, macrophages, antibodies, and AMPs

AMPs

antimicrobial peptides

produced by immune cells and tissues and target cell membranes of pathogens

How do AMPs work?

AMPs form pore structures in membranes, leads to barrier defects and cell death

AMPs examples

alpha-defensins

alpha-defensin example mechanism

Perforation of B. cereus cell membrane

Mucosa

Lines inner cavities of organs and systemic membranes

Mucosa location example

respiratory tract, genitourinary tract, gastrointestinal tract

Mucociliary clearance

Mucin and cilia in the respiratory tract trap and remove pathogen from sterile tissues

How does mucin work in mucociliary clearance?

Mucin in goblet cells trap pathogens attempting to access host tissues (AMP, no production)

How does cilia work in mucociliary clearance

Cilia moves toward URT to remove mucus-trapped pathogens

innate immune cells

macrophages, dendritic cells, mast cells, natural killer cells, granulocyte

innate immune cells mechanism

pathogens are destroyed by phagocytosis, AMP production, and antigen presentation

adaptive immune cells

B cells (makes antibodies), T cells, CD4 T cell, CD8 T cell

how do adaptive immune cells handle pathogens?

making toxins, antibodies, and complements

phagocytosis

macrophages engulfing pathogens in a vescicle

lysosomes

delivers antimicrobials (hydrolases, AMPs, and ROS) to phagosomes to destroy the engulfed pathogen

What is the first step in the process of phagocytosis?

Bacterium binds to phagocytic cell surface, with the possible assistance of antibodies or complements.

What happens after the bacterium binds to the phagocytic cell surface during phagocytosis?

Phagocyte pseudopods extend and engulf the cell.

What is formed when the phagocyte invaginates to trap the bacterium?

A phagosome.

What occurs when the lysosome fuses with the phagosome?

Enzymes are deposited into the phagosome to cleave macromolecules and generate reactive oxygen species to destroy the organism.

opsonins

chemicals that bind to pathogens and tag them so they are recognised more easily by phagocytes

ex. antibodies and complement

What makes antibodies

B cells

What makes complements

T-cells

opsonization

binding of opsonins to pathogens triggering phagocytosis

opsonophagocytosis

when a pathogen is recognized by an opsonin, causing an immune cells to absorb it

Neutrophils

aka PMNs

what other tissues can do a type of phagocytosis

neutrophils and some non-immune tissues

where else can complement proteins be created?

can be produced by other immune cells (ex. macorphage) and by non-immune tissues (ex. hepatocytes, astrocytes)

AMPs in bacteria

colicins, structurally different than vertebrate AMPs, discovered in 1920s

What is a micro biome?

A collection of microbes and their activities within a given environment - J. Whipps, 1998

Later definition of microbiome

The ecological community of commensal, symbiotic and pathogenic microbes that share body space - J. Lederberg, 2001

How did microbiome research change over time

Before 2000, there were 5 publications a year, by the mid-2000s there were over 6000

HMP

NIH Human microbiome project (2007-2016) >$250m dollars spent

what did the HMP map?

microbiota of the nose, mouth, skin, gut and urogential tract: bacteria, archaea, fungi, protists, and viruses

How much microbiota on the body within the 1st year of life?

10^13 to 10^14 CFU/cm^3 and 500-1000 species in the GIT

How is the microbiome relevant to humans?

it affects human physiology, overall health and diseases (infectious and non-infectious)

Holobionts

assembly of microbiota living on skin and mucosal surfaces of human body.

C acnes

comeodones, bacteria contributing to inflammation

E faecalis

colonizes intestinal brush border

How does the microbiome train the immune system?

Conditioning, competition, and metabolism

Immune conditioning

probiotics combat intestinal putrefaction by immune stimulation

Ex. of immune conditioning

mucin and AMP (RegIII and alpha defensin) are stimulated by microbiota in the URT

How do microbiota interact with mucin?

they reside in the porous outer mucin layer and metabolize glycoprotein conjugates with mucinase

AMP shields

microbiota stimulate humoral defenses like AMPs to destroy pathogens

How do microbiota resist AMPs?

changing the charge chemistry of envelope LPS

Antigen sampling and presentation

microbiota antigens are presented to regulatory T cells (Tregs) that suppress immunity

Phagocytic APCs

precess microbes to present Antigens to T cells, with microbiota pathogens going to T-regs and non-self antigens going to Th cells

extended self concept

The microbiota having their antigens being recognized by regulatory t cells that suppress immunity, meaning they are seen as an extension of the self

Non-self

Antigens from pathogens

how do non-self antigens trigger the immune systems

They are non-self, so they stimulate T helper (Th) cell proliferation

M cells

microfold cells that transport microbes to APCs (ex. dendritic cells, DC) in MALT

competition

pathogens and microbiota having to fight for limited amounts of attachment sites (colonization resistance) and resources (nutrients like big 6 and metals)

How does competition stop pathogens

pathogens compete with microbiota for resources, like att, acting as a growth constraint

Competition example

C. diff can grow much more and survive more if there is no other microbes to compete with it.

symbiosis

>1 organism benefits from a relationship

antibiosis

>1 organism is harmed

Mutualism

example of symbiosis

human and microbe benefits

Commensalism

example of symbiosis

human is unaffected while the microbe benefits

Parasitism

antibiosis

humans are harmed, microbe benefits

Neutralism

neither human or microbe benefits or harms the other

Amensalism

antibiosis

human is harmed, microbe is unaffected

competition in antibiosis

human and microbe both harm each other

Opportunistic pathogens

pathogens that become a source of infection when immunity is compromised

How can immunity be compromised?

immune suppression, pre-existing infection, malnutrition, damage or injury, narcotics, alcohol, chemotherapy, heritable traits, pregnancy

most sources of infection

Most infections in a person's lifetime are opportunistic and endogenously acquired

Plague of athens

430 BC

infecto nosema (putrefaction sickness)

inflamed eyes, blindness, hemorrhage, necrosis

infecto

commonly used during the black death (mid 14th century)

Miasma theory

Hippocrates/Galen

infection comes from poisonous vapors of putrefying matter

theory prevailed to early 1900s

malaria in the Civil War

said to consist of small organisms,

a mysterious poison in the atmosphere

Pasteur

1860s experiments on putrefaction

Robert Koch

1870s experiments on the transmission of anthrax

Koch experiment

anthrax is caused by the Prescence and actions of bacteria (B. anthracis) in sheep and mice

cultured sample from diseased rat was grown in blood culture

Germ theory

diseases are caused by microbes

Koch Postulates/germ theory of disease causation

1. pathogen is present in all diseases cases, not in healthy people

2. pathogen is isolated from the host and grown in pure culture

3. when it is introduced to a health person, the same disease happens again

4. Same strain is obtained from the new host, and it shows the same characteristics as before.

ID

field of infectious disease, study of disease causation and intervention

Pathogens

1,400 named species, responsible for approx. 16m deaths a year

pathogenic potential

the ability of a microbe to be pathogenic, affected by host immunity

opportunists

require compromised immunity to cause infection, acquired endogenously

obligate pathogen

do not require compromised immunity to be effective, exogenously acquired

Opportunistic pathogen example

secondary opportunistic infection of S. pyogenes causes erysipelas due to skin barrier defects

Obligate pathogen example

B. anthracis escar forms cutaneous anthrax

Virulence

Measure of infection severity

measured by mortality (case fatality rate, CFR)

how is virulence factors influenced?

influenced by pathogen virulence factors and host factors

Virulence and pathogenic potential correlation

they are not directly correlated