week 6 - infection and immune response 2 Flashcards
examples of diseases caused by viruses
polio, hepatitis B, rotavirus, measles, mumps, rubella, influenza, human papilomavirus
positive-sense viral RNA
similar to mRNA and so can be immediately translated by host cell
negative-sense viral RNA
complementary to mRNA so must be converted to positive-sense RNA before translation
describe a viral genome
can be DNA or RNA
linear or circular
ss or ds
structure of a virus
genome protected by a capsid made from capsomeres = nucleocapsid
capsid can be helical or icosahedral
some viruses have an envelope on outside which is derived from host cell membrane and has virus proteins and glycoproteins inserted
what kind of virus causes hepatitis B
ds circular DNA virus
positive sense ss RNA virus examples
coronavirus poliovirus Zika virus norovirus rubella
ss negative sense RNA virus examples
Ebola virus
mumps virus
influenza virus
measles virus
viral tropism
ability of a virus to productively infect a particular cell, tissue or host
stages of viral infection and replication
attachment - viral proteins interact with specific receptors on host cell
penetration - attachment induces conformational change in viral proteins - results in fusion of viral and cellular membranes
uncoating - viral capsid removed and viral genome is released
replication - viral genomes replicated - process depends on if virus is RNA or DNA
assembly - viral proteins packaged with newly replicated viral genome into visions that are released
vision release - lysis or budding
DNA virus replication
viral DNA enters host cell nucleus (may become incorporated into host DNA)
transcription into mRNA is catalysed by host cells RNA polymerase
mRNA translated into virus-specific proteins
coat proteins assemble around viral DNA and visions are released by budding or lysis
RNA virus replication
dsRNA viruses - one strand is transcribed into mRNA
ssRNA - positive sense is used directly as mRNA - negative sense is transcribed into positive sense which can then be used as mRNA
mRNA is then translated into proteins
retrovirus replication
reverse transcriptase synthesises DNA from RNA which can then be integrated into host genome and is called a provirus
Provirus DNA is transcribed into both new viral genome RNA as well as mRNA for translation in the host into viral proteins
visions released by budding
how does HIV invade cells
HIV has a glycoprotein called gp120 which has a high affinity for CD4
infection of T cells is assisted by T cell co-receptor called CXCR4 - HIV also infects monocytes by interacting with CCR5 co-receptor
outcomes of a viral infection
virus is released and host cell is destroyed by cell lysis
virus can exit by budding
virus can be maintained in host cell cytoplasm
virus can become incorporated into genome
can become an oncogenic virus causing uncontrolled cell growth
three main mechanisms for antigenic variation
mutations
recombination - DNA strands break and covalently link the DNA fragments, either from a single gene or from two infecting viruses of the same kind
gene reassortment - viruses can exchange genetic material - extends gene pool
antigenic drift
small antigenic changes that are sufficient to reduce the effectiveness of b and t cell memory eg. Influenza virus and HIV
leads to new strains that go unrecognised by host
does not change the viral subtype
antigenic shift
exchange of genetic material between two pathogens making a new hybrid virus
sterilising immunity
innate and adaptive response
results in recovery
non-sterilising immunity
has a good immune response but fails to clear infection completely resulting in chronic infection
causative organism of tuberculosis
mycobacterium
pathology of TB
apex of lung is predominantly affected - normal spongy architecture replaced by caseous
In the middle of the granuloma is caseous necrosis - surrounding it is a layer of highly active macrophages – surrounding the macrophages are sheets of lymphocytes (predominantly t cells) – scattered around a typical TB granuloma are giant cells
triggers for reactivation of MTB
Immunosuppression (particularly a co-infection of HIV)
Age – reactivation later in life
how does mycobacterial survive in phagocytes
Subverts intracellular trafficking – bacteria alters constituents of phagosome so it becomes coated with host protein called coronin – coronin is an actin associated protein that forms around phagosome and effectively inhibits the ability of the macrophage to fuse with lysosome
If lysosome does manage to fuse with macrophage – microbacterial proteins can some what neutralise ability of lysosomal compounds to produce cell death of microbacteria
Lysosomes work at a low pH and the change in pH occurs after macrophage and lysosome fuse allowing the key compounds of lysosome to work – MTB can partially reverse that drop in pH by pumping out protons and resisting phagosomal acidification allowing survival of MTB in phagosome
the immune response to MTB
Key cytokines in this are production of interferon gamma and to some extent tumour necrosis factor alpha by helper t cells
These will act on macrophages and enhance phagocytosis
This t helper response is a classic TH1 response
In dendritic and other phagocytic cells, a large production, particularly of IL12 and IL18 and a number of other cytokines instruct the t cell response and lead to large output of interferon gamma with TNF which activates the macrophages and limits MTB spread
does not kill MTB
detection methods for detecting whether someone has previously been exposed to MTB
Mantoux reaction
t spot test
how does HIV avoid CD8 response
In early stages of HIV, there is an accumulation of mutations within the whole variety of genes encoding proteins within the virus – these mutations are centred around the epitopes (features of proteins that are targeted by CD8 cells) so that there is a great CD8 response – but during the early period, the virus undergoes very high levels of mutation on the areas of the virus that have been mutated to avoid being recognised by CD8 cells are selected for – pretty soon after infection the CD8 response to many of these epitopes is ineffective
how does HIV avoid antibody response
After 3-12 months you get some neutralising antibody – role in preventing further spread – however often the virus then has mutations in the surface proteins recognised by the antibodies to make antibody response useless
immune response to HIV
CD8+ response brings virus under control - cytotoxic T cells keep HIV in check
pathology of dengue
Destruction of endothelial cell capillary barrier
Variety of inflammatory cytokines produced by virus infected macrophages can lead to this destruction
Fluid escapes from capillaries into tissue which gives rise to oedema and can fill up lungs or areas of brain
does dengue have a sterilising or non-sterilising immune response
sterling - can clear this virus
immune enhancement in dengue
In a second infection of a different strain we can get immune enhancement
Neutralising antibodies act as an opsonin – enhances uptake of virus into monocytes and macrophages leading to much greater viral replication and consequently greater cytokine activation and infection of epithelial cells
describe natural killer cells
Large granular lymphocytes that release lytic granules that kill some virus-infected cells - Help kill virus-infected cells and cancer cells
describe type I hypersensitivity
IgE antibody and mast cells are the underlying cause
-In an inflammatory response, mast cells release granules such as histamine – still does this in a type I hypersensitivity response - Release of histamine and other inflammatory factors is what drives type I hypersensitivity response
IgE binds to mast cell receptors - mast cell cross links antibody molecules which sends signals into mast cell causing degranulation
what are the different types of hypersensitivity driven by
Type IV is driven by t cells
Types I, II and III are antibody mediated
autoimmunity
a misdirected immune response that occurs when the immune system goes away and attacks the body itself
differences between organ specific and non-organ specific (systemic) autoimmune disease
organ specific - damage to organ structure and function - autoimmune attack on self-antigens of given organ
non-organ specific - widespread self-antigens that are targets for autoimmune attack - damage affects structures such as blood vessels, cell nuclei
examples of organ-specific autoimmune diseases
type 1 diabetes mellitus
goodpastures syndrome
multiple sclerosis
graves disease
systemic autoimmune diseases
rheumatoid arthritis
scleroderma
immune response against transplanted organs
T cells activated against donor transplant antigens
Stimulation in peripheral lymphoid tissues
Both CD4 and CD8 t cells involved – also macrophages, DCs, neutrophils, b cells, NK cells
Antibody production activates complement
types and mechanisms of transplant rejection
hyper acute rejection - preformed anti-donor antibodies bind to graft endothelium immediately after transplantation
acute cellular rejection - T cells destroy graft parenchyma
acute humeral rejection - antibodies damage graft vasculature
chronic rejection - dominated by arteriosclerosis, T cell reaction and secretion of cytokines proliferation of vascular smooth muscle cells
timeframes for the different types of transplant rejection
hyperacute rejection - minutes to ours
acute cellular rejection - days to months
chronic rejection - months to years
pathophysiology of asthma
Chronic inflammation of lower airways
Thickening of basement membrane
Increased goblet cell activity
Smooth muscle hypertrophy and thickening
Epithelial shedding
Airway occlusion (mucosal plug)
mucosal infiltration of T cell, eosinophils and others
the two types of immunodeficiency disease
primary - results from genetic defects
secondary - acquired as a result of other diseases or conditions
describe grave’s disease
normally - thyroid hormones regulated by thyroid-stimulating hormones (TSH). TSH bind to receptor and stimulate synthesis of THs. negative feedback switches off TSH production
disease - results in non-regulated “activity” auto-anitbodies that bind to the TSH receptor leading to overstimulation of the thyroid hormones
describe primary immunodeficiencies
most are recessive
can lead to cancer, abnormal lymphocyte proliferation, allergy, autoimmunity
can be b cell, t cell, combined or an innate immune deficiency
describe combined immunodeficiencies
affect both t and b cells
still a primary immunodeficiency
describe the abnormalities and common infectious consequences associated with b cell deficiencies
absent or reduced follicles and germinal centres in lymphoid organs and reduced serum Ig levels
pyogenic bacterial infections
describe the abnormalities and common infectious consequences associated with t cell deficiencies
may be reduced t cell zones in lymphoid organs
defective t cell proliferation responses to mitogens in vitro
viral and other intracellular microbial infections
virus-associated malignancies
examples of combined immunodeficiencies
T-B+ severe combined immunodeficiency - common gamma chain deficiency
T-B- SCID - adenosine deaminase deficiency (ADA-SCID)
CD40L deficiency is a less profound combined immunodeficiency
describe adenoside deaminase SCID
ADA is an enzyme required to generate energy that t, b and NK cells require - so when this enzyme is not functioning you cannot make proper t, b or NK cells - gives SCID
describe hyper IgM syndrome (CD40L deficiency)
high levels of IgM and low levels of other immunoglobulins cause - fault in class switching - b cells are unable to switch from IgM to other types of antibodies meaning quality of antibodies is not as good - susceptible to infection Although cause of this is from a fault in class switching of b cells, the fault actually lies on CD40L ligand molecule which is expressed on t cells – so is a combined immunodeficiency
describe humoral/b cell defects
lack of antibody leads to recurrent sepsis
bacterial infections often in airway
examples of humoral/b cell defects
bruton’s agammaglobulinaemia
IgA deficiency
describe bruton’s agammaglobulinaemia
mutation in bruton’s tyrosine kinase gene
prevents b cell development and get stuck in pro-b to pre-b stage
few follicles in lymph nodes
results in low serum antibody levels
describe IgA deficiency
most common immunodeficiency
b cells are unable to switch from making IgM to IgA but can still make IgG
examples of autoinflammatory disorders
familial mediterranean fever
IL-10/10R deficiency
describe familial mediterranean fever
inflammasome is a cellular structure that generates cytokines
inflammasomes cleave pro-IL-1 to IL-1 (activation)
in FMF - inflammasome regulators are mutated
inflammasome activated, increase in IL-1
causes of secondary immunodeficiency
HIV
protein-calorie malnutrition
irradiation and chemotherapy treatments fpr cancer
cancer metastases to bone marrow
removal of spleen - decreased phagocytosis of microbes
