BMS106 Pathobiology - Humphreys Flashcards
What percentage of all human deaths are caused by pathogens?
25%
What is a pathogen?
An organism that causes disease
May be infectious virus, bacteria, protozoa, fungi, some may include worms and prions
The average human contains 10^13 human cells and 10^14 bacterial cells
Hey that’s pretty rad! And the microbes are often beneficial to health!
What are the 3 categories of pathogen?
Obligate pathogens - can only survive in host, usually very specific to host species
Facultative pathogens - present in the environment (reservoir) waiting for host
Opportunistic pathogens - normally benign but cause disease in compromised host
Why do pathogens make us sick?
The symptoms of the disease usually help the pathogen to spread
The pathogen kills cells I order to replicate
In some cases the symptoms appears to have no advantage or are part of the host’s response
Two closely related species can be pathogenic and harmless, often differing by only a few genes called…
Virulence genes
Virulence genes are clustered on…
Pathogenicity islands
What types of viruses can carry virulence genes and incorporate them into bacterial DNA?
Bacteriophages
There are actually hundreds of strains of Vibrio cholerae, but only strains infected with a certain bacteriophage are virulent and cause cholera. What does the bacteriophage do?
Transfers the genes that encode cholera toxin to the bacteria
How does the cholera toxin cause diarrhoea?
By dehydrating the cells of the intestine. The infected bacteria can be spread to new hosts
Many pathogens have complex life cycles. For example Fungal pathogens often show dimorphism, growing as mold at low temps in soil and switching to yeast when…
Inhaled into the warm lungs. It is then engulfed by macrophages in the yeast form
How can protozoa pathogen life cycles e complex?
They often have more than one host, for example Plasmodium falciparum which causes malaria
What is an insect that transmits a disease known as?
a vector
In order to be successful pathogens must invade our protective barriers. How is flora used as a barrier to infection?
Much of our epithelia are densely populated by bacterial and fungal flora which serve as a barrier to infection
How is mucous (e.g. in lower lung, small intestine and bladder) a barrier to infection?
It is continuously swept away or flushed and is sticky to trap stuff
How do epithelia help prevent infection?
Fit together very tightly and are held together by tight junctions which act like a gasket to make sure that pathogens can’t squeeze between cells
How do pathogens that haven’t developed a special way to enter through epithelia enter the body?
Through epithelial wounds, but breaks in epithelia are quickly recognised by white blood cells.
What are the proteins that some bacteria use to anchor themselves to epithelia called?
Adhesins
They target receptors on the host cell that normally serve other functions
What kind of secretion systems are used to inject virulence effector proteins into host cells?
Type III secretion systems
How can extracellular pathogens modify host behaviour?
Using a type III secretion system.
E.g. E. coli can make the host cell create an actin pedestal to secure them by secreting Tir
How can pathogens evade the immune system?
By hiding in a phagocytic cell
E.g. Legionnaire’s disease is caused by a bacterium that normally infects amoebae, but replicates inside macrophages that have phagocytosed it if inhaled
What are the 2 mechanisms for bacterial invasion of non-phagocytic cells and give examples of bacteria which use each mechanism?
Zipper mechanism (e.g. Listeria) Trigger mechanism (e.g. Salmonella) Both mechanisms cause actin-polymerisation, the active rearrangement of the cell
What does Listeria use the protein Listeriolysin O for?
To break down the membrane of the phagosome
What do bacterial pathogens assemble in order to push themselves into neighbouring cells?
Actin tails
What does the bacterial protein ActA do?
Initiates actin polymerisation at the tail end of Listeria
How does the bacterium Yersina pestis modify the behaviour of its flea host to suit its needs?
Blocks the flea’s digestive tract causing it to starve and bite more
Antibiotics stop bacterial growth by disrupting…
Cell processes
What are the majority of antibiotics based on?
Natural products produced by fungi or bacteria, e.g. penicillin produced by the penicillium fungus
What does MDR stand for?
Multidrug-resistant (pathogens)
What are viruses?
Fragments of nucleic acid (DNA or RNA), which encode a small number of proteins, encased in a coat protein called a capsid
What is a virus’ protein coat called?
A capsid
What is a single virus particle called?
A virion
What are the proteins encoded by viral genomes for?
Replicating the genome, packaging the genome, transporting it to host cells and modifying host cells to enhance the replication of the virus
What are the 6 main stages of the DNA virus life cycle (lytic cycle)?
Entry, uncoating, transcription & translation, genome replication, assembly of progeny, exit
What does the lysogenic cycle involve?
Viruses integrate as DNA into the host genome for a period of quiescence or latency
How many classes of viruses are there. What are they classed in terms of?
6
Their genome type and how their mRNA (+ strand) is made
Like bacteria, what do viruses rely on the presence of in order to gain entry into the host cell?
Receptors present on the surface of the host cell
What are the 4 main virus entry strategies?
Fusion with the plasma membrane
Fusion with the membrane after endocytosis
Pore formation
Endosomal membrane disruption (DNA viruses insert DNA into nucleus directly)
DNA viruses can cause cancer. What percentage of all human cancer is caused by HPV?
6%
How can viruses lead to cancer?
Proteins produced by the viral genome upregulate DNA replication and proliferation by the host cell. Accidental integration of the virus into the basal epithelial cells can result in too much proliferation and is the first step in malignant tumour formation
What virus causing genes do papillomaviruses contain several of?
oncogenes - Viral genes (E6 and E7) bind to regulatory host proteins (Rb, p53) which control proliferation and inactivate them, releasing constraints on DNA replication
What is a retrovirus?
A retrovirus is a type of RNA virus that inserts a copy of its genome into the DNA of a host cell that it invades, thus changing the genome of that cell.
How do viruses exit the cell?
Either when it lyses (dies) or by budding in the case of enveloped viruses
Viral oncogenes are not involved in viral replication. Why do viruses have them?
Retroviruses usually cause cancer by incorporating human proto-oncogenes into their genome - thought to occur when mistakes are made during integration of the viral genome into the host genome.
What are proto-oncogenes often?
Proteins involved with cell proliferation
How is v-src different to c-src?
Normally the cell down-regulates c-src activity by phosphorylating one end of the protein to fold in on itself to become inactive. The viral form (v-src) does not have the c-terminus, creating an oncogenic form of c-src.
What are the benefits of the immune system?
Protect against infectious pathogens
Eliminate modified or altered self
What are the downsides to the immune system?
Collateral damage from inflammation
Damage to self (hypersensitivity or autoimmunity)
What is the immune system (in simple terms)?
A system of specialised cell types, mostly derived from the bone marrow, which are spread out to virtually every tissue in the body to protect us
Immune cells act as sentinels looking for pathogens, for example…
Dendritic cells (the only immune cell in skin) detect antigens and migrate via lymph vessels to elicit an immune response)
Immune cells congregate ‘lymphoid organs’, which are:
Primary: Spleen, thymus, bone marrow
Peripheral: lymph nodes
What are lymph nodes for?
Lymph nodes are centres for immune cells to trade information on encounters with pathogens and to organise an appropriate response
Who discovered innate immunity in 1883?
Ellie Metchnikoff
What is the innate immune system?
Designed to act against components shared by all pathogens - fast, no memory required
What is the adaptive immune system?
Detects antigens specific to individual pathogens - slower with lag phase, memory used
What is the first line of defence of the innate immune system?
Physical barriers:
- lysozyme in tears and secretions
- Skin (barrier) with flora on it
- Acidic pH of stomach and vagina
- Flushing of urinary tract
- Mucus and cilia (e.g. lining trachea)
What lines of defence of the innate immune system come after the physical barriers?
Cellular and humoral defences:
- Macrophages and neutrophils
- Macromolecules , cytokines, anti-microbials
How do macrophages phagocytose?
They recognise and attach to microbes using receptors, engulf the pathogen in a membrane (phagosome), this phagosome fuses with a lysosome to form a phagolysosome, the pathogen is killed and degraded by the lysosomal digestive enzymes.
How do cells sense pathogens?
Using Pattern Recognition Receptors (PRRs) - toll-like receptors
What are the four major classes of innate immune PRR receptors?
- Nucleotide oligomerisation domain (NOD)-like receptors (NLRs)
- Toll-like receptors (TLRs)
- C-type lectin receptors (CLRs)
- RIG-like receptors (RLRs)
What do PRRs sense on pathogens?
Pathogen Associated Molecular Patterns (PAMPs) - specific to each micro-organism and usually essential for pathogen viability
PAMPs bind to PRRs, activating a…
signalling cascade, leading to a protective (inflammatory) response
What are defensins?
Anti-microbial peptides produced by epithelial cells and phagocytes which bind to pathogen phospholipid bilayers and form pores
What does complement refer to?
A system of inactive soluble proteins in blood vessels. There are 3 activation pathways - lead to activation by proteolytic cleavage of component C3, which is split into C3a and C3b. C3 convertase amplifies C3 cleavage, so millions of C3b can deposit on the pathogen.
What do interferons do?
Interfere with the life cycle of the virus
What are natural killer cells?
NK cells are activated by intereron to kill virally-infected or tumourigenic cells - by exocytosis of granules containing perforin and granzyme, which induce apoptosis
Who discovered adaptive immunity in 1897?
Paul Erlich - coined idea of antibodies and their rlease from cells to neutralise microbial toxins + introduced lock and key concept
How many proteins make up an antibody?
4 (2 heavy chains, 2 light chains) - FAB region binds to antigen in lock and key manner
What is the antigenic determinant called?
The epitope
What does the Fc region do?
Mediates interactions with the immune system - directs effector functions
Triggers complement activation and cell lysis
Binds onto ‘effector’ cells
How can the binding of antibodies to antigens inactivate antigens?
- Neutralization (blocks viral binding sites, coats bacteria) -> enhances phagocytosis
- Agglutination of microbes -> enhances phagocytosis
Precipitation of dissolved antigens -> enhances phagocytosis - Activation of complement system, leading to cell lysis
Which antibody class are 75-85% of the antibodies in the plasma?
IgG (monomer) - activates phagocytosis, neutralises antigens
What are the 2 parts to the cellular components of the adaptive immune system?
1 - B cell production of antibodies
2 - Effector functions of T cells
What is an antigen?
Any molecule that can be detected by adaptive immunity
If a B cell receptor binds to an antigen, what happens next?
A T helper cell gives it a chemical signal. It then becomes a plasma cell and releases the complementary antibodies
The MHC-I presents the antigen found in the cytoplasm to…
Cytotoxic T cells
The MHC-II presents the phagocytosed antigen to…
Helper T cells specific for the same antigen, which then help the B cell produce more antibodies (as a plasma cell)
Activated T cells become…
Effector or memory T cells
What does naive mean in terms of blood cells?
Never previously exposed to antigen
What is a CD4+ cell?
Helper T cell
What is a CD8+ cell?
Cytotoxic T cell - kill by inducing apoptosis by releasing perforin and granzyme
When does inflammation occur?
- Tissue necrosis (trauma, injuries, temp extremes)
- Infections
- foreign bodies (splinters, stings, poisons, kidney stones)
- Immune reactions (e.g. self antigens, allergies)
What is inflammation?
A protective and innate response involving cells/molecules to infection/damage. The goals are to rid the cause, remove necrotic tissue and start repair
What are the main features of inflammation?
Vascular reaction and a cellular response, triggered by mediators
What collateral damage can inflammation cause?
Potentially injures bystander cells and can cause disease such as autoimmune disease or chronic inflamation
What are the 5 cardinal signs of inflammation?
- Heat
- Redness
- Swelling
- Pain
- Loss of function
What happens during inflammation?
- Recruitment of leukocytes
- vasodilation & increased vascular permeability
- -> leading to edema
- eliminatioin of microbes and dead tissue
What characterises acute inflammation?
- Stimulus
- Inflammatory mediators
- Influx of innate immune cells/plasma proteins
4! Repair!
How is inflammation initiated?
PRRs on macrophages and other sentinel cells recognise PAMPs (pathogen-associated) and DAMPs (damage-associated) and produce mediators. Release plasma proteins, e.g. complement system
What are the principal inflammatory mediators (derived from cells or plasma)?
- Vasoactive amine (e.g. histamine)
- Lipid products (e.g. prostaglandins)
- Cytokines
- Products of complement activation
What are phospholipid mediators activated by and what do the attract?
Activated by PRRs and attract neutrophils
What is TNF?
Tumour necrosis factor, a cytokine mainly produced by macrophages and dendritic cells
What is IL-1?
Interleukin 1, a cytokine
What are chemokines?
Small peptide chemoattractants for leukocytes
What are the local and systemic effects of cytokines and chemokines?
- Local inflammation - increased permeability of capillaries - increased expression of adhesion molecules - leukocyte activation - t-cell activation
- Systemic: Fever (brain), Acute phase proteins (liver), leucocyte production (bone marrow)
Neutrophils are activated by cytokines/chemokines. This causes the upregulation of what molecules for neutrophils?
Adhesion molecules
Integrin activation by chemokines occurs
When neutrophils migrate through the capillary endothelium after adhesion and rolling, what is this called?
Diapedesis
If injury is limited, what occurs?
Regeneration of epithelia
If injury is repeated or sever what can occur?
Fibrosis (fibroblast recruitment and differentiation, myofibroblasts and extracellular matrix)
Macrophages shift between…
Pro-inflammatory (M1) or anti-inflammatory (M2) type macrophages
How do macrophages shift between the M1 and M2 phases?
M1 phagocytose neutrophils which have undergone apoptosis (after 24hrs)
What is chronic inflammation?
Prolonged inflammation
Either follows acute phase or my precede without signs of acute inflammation
What are the 3 main causes of chronic inflammation?
- Persistent infection
- Hypersensitivity (autoimmunity, allergic reactions)
- Prolonged exposure to toxins, pollutants
What is COPD?
Chronic obstructive pulmonary disease.
Progressive airflow limitation with enhanced chronic inflammation in airways
Common causes are smoking, TB, dusty work environment
Obstructive brionchiolitis, emphysema and chronic bronchitis
How do the inflammatory cells differ between acute an chronic inflammation?
Acute - mainly neutrophils
Chronic - monocytes/macrophages and lymphocytes
M1 macrophages promote…
inflammation
M2 macrophages promote…
repair
