Block 9 Week 3 Flashcards
Virus Diagram
- All RNA viruses are single stranded with the exception of ROTA VIRUS.
- All DNA viruses are double stranded with the exception of PARO VIRUS ( single stranded DNA virus).
RNA vs DNA
+sense vs - sense
Naked vs Envelope
Virus Nucleic acid: + Sense vs - Sense
Sense strands only applies to single stranded RNA. It can either be positive sense or negative sense.
- For most viruses once they get into a host cell their number one goal is to go through a host ribosome. This is because once it has gone through the host ribosome it will be able to make viral proteins. Viral proteins help the virus to further replicate itself.
+sense RNA strand has a sequence of nucleic acids so that when it goes through a ribosome it will make a functional protein.
-sense RNA strand is a complement of the +sense RNA.
-The nucleic acids code for stop codon.
- viral RNA polymerase uses the -sense strand to create a +sense RNA which can go through the ribosome to make a protein.
- All -sense RNA viruses have a envelope.
Virus: Nucleic Acids: Reverse Transriptase
- Some Viruses have an enzyme (reverse transcriptase) which can convert RNA back to DNA.
- Most common is HIV virus. It gets into host, converts it RNA to DNA, inserts itself into the host genome so that the virus can become latent for many years.
- Another example HBV (hepatitis B virus)
Virus: Nucleic acids
- nucleic acids can be linear or circular or linear segments
- Mutations are common in viruses becuase they have no proof reading capabilities. So its often the viruses reproduced have errors
- Because of this its difficult to make medication against viruses because they are constantly mutating
Viral proteins
- Protein capsid: surrounds viral genome
- Replicative proteins: polymerase and trasnscriptase
- Protein antigen: bind receptors and antibodies
Viral envelope
- lipid layer around capsid.
- Not present in all viruses. But is always present in RNA single stranded viruses
Envelope has 2 functions:
- Protective membrane
- fusion onto host cell
Mechanisms of viral infectivity ?
TRANSMISSION
Attachment - Tropism is the tendency of virsues to attach to specific host receptors. E.g. HIV attached to CD4 (t-tropic), CXCR4 and CCR5 (m-tropic)
ENTRY
- endocytosis or fusion ( if have envelope)
- uncoating - genetic material released into cytoplasm
- bacteriophage genetic injection
REPLICATION (host machinery to replicate)
- RNA viruses replicate in cytoplasm
-DNA viruses replicate in nucleus
RELEASE
- cell lysis - virus busrt out of host cell
- budding - more with virsues with envelopes. buds off and takes host cell membrane as new envelope.
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Antiviral classes
Currently used antivirals
Characteristic infection
- The time period between transmission of the virus and the patient showing symptoms is called the incubation period.
- It can last days to months and varies between viruses
- On a cellular layer you may be able to see things happening to the host cell like cytolysis, bodies, synctia.
- Table (dont learn) but shows examples of things that happen to different viruses.
Chronic infection: viruses replicate over time eg. with HIV, HBV and HCV
Latency: virus is inactive/sleeping but during times of stress virus will replicate
Viral Genetics
REASSORTMENT: (s for segment)
- when 2 seperate viruses with segmented genomes swap segmented genomes with each other. This produces a new virus with new viral protein antigen.
RECOMBINATION: (c for crossing)
-gene exchange via crossing of chromosomes. New virus has viral protein antigens from both viruses.
- normally only happens in double stranded DNA viruses
PHENOTYPE MIXING:
- Coinfection with viral hybrid production
- Second generation progeny = genome of the original virus
- 2 viruses mix.
-New progeny 1 has genome from virus A and protein capsid from virus B. But when it reproduces it uses original genome.
- New progeny 2 - virus B genome
COMPLEMENTATION:
- Nonfunctional virus benefits from functional virus.
- E.g. Hep D only works with surface antigens from Hep B
POINT MUTATIONS:
- Genetic change altering a single nucleotide.
- Happens a lot in RNA viruses because there is no proof reading
GENETIC DRIFT vs SHIFT:
- Point mutations causing a change in viral antigens is called Antigenic drift . So Influenza virus antigens can change in a year so no one is immune to ‘new’ virus as antibodies dont compliment - leads to an epidemic.
- Antigenic shift
2 segmented viruses.
Influenza A ( affects Pigs)
Influeza B ( affects human)
They undergo reassortment to create a completely new virus Influenza C which can infect humans. Immune system may not be prepared for this completely new virus. This could cause a Pandemic.
- This happens commonly with Influenza.
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Host Cell Defence: Interferons
- Infected cell releases Interferon - a and Interferon-B, the molecules interact with neighbouring host cells (paracrine signalling). The infected cell is warning its neighbouring cells which respond by shutting down their protein synthesis.
- When cell lysis happens and viruses burst out the they cant use the neighbouring cells machinery to replicate because are not producing proteins. This decreases viral transmission from host cell to neighbouring cells.
Host cell defence: Presenting viral antigens on MHC1
- can tell immune cells infected cells has viral antigens in it
Immune system defense to viral infection
CELL MEDIATED DEFENSE:
- CD8+ cytotoxic T-cell direct destruction of virally infected cells via MHC1 presentation
ANTIBODY MEDIATED DEFENSE:
- APC take up viral antigens and present to B-cells, which produce ANTIBODIES against antigens.
Neutralising antibodies and Antibody dependent cellular cytoxicty (ADCC).
NK CELL MEDIATED DEFENSE:
- Directly destroy virally infected cells
Inflammation
- Heat (calor)
- Pain (dolor)
-Redness ( rubor) - Swelling ( tumor)
and loss of function
External factors that cause inflammation
Internal factors that cause inflammation
- Damage Associated Molecular Patterns (DAMPs). Released when plasma membrane is injured and cell dies. DAMPs trigger inflammation.
- DAMPs are recognised by PRRs ( Pattern recognition receptors) on WBC. This actiavtes the cell and sparks a inflammatory response.
Leuokocytes
Inflammatory response:
- begins with macrophage and mast cells
- When there is inflammation these cells respond to the PAMPs and DAMPs
- Mast cells contain inflammatory mediators which act on endothelial cells of capillaries which makes the capillaries more permeable.
- increase in vascular permeability allows plasma proteins and fluids to leave circulation.
- Endothelial cells release nitric oxide which helps dilate the capillaries and make them more permeable.
- Neutrophils are attracted to site of infection, neutrophils leave capillaries and enter tissues (extravasation). They phagocytose pathogens and infected cells.
complement system involved
At the same time Dendric cells present antigens to T-cells. Activates adaptive immune system.
- Inflammatory response ends with tissue repair. Macrophages are recruited to eat up dead and dying cells so there is more room. Now have space for angiogenesis ( creating new blood vessels).
- The new blood vessels are temporary so once the wound heals these vessels regress.
- Fibroblasts synthesise collagen to help with wound healing.
Acute inflammation vs Chronic inflammation
Acute inflammation: short lived (minutes to days), neutrophil rich
Chronic inflammation: long lived (months to years);
lymphocyte, plasma cells and macrophage rich.
Accute inflammatory response:
- C3a, C4a = increased histamine released from mast cells - more vasodilation
- C3b - oppsonisation
-C5a - Increase in neutrophil chemotaxis and increase in histamine released from mast cells therefore increased vasodialation.
-C5b - membrane attack complex - pathogen cell lysis
Acute inflammatory response
Acute inflammatory response
Arachadonic acid pathway:
- LIPOOXYGENASE pathway - leukotrines - LTB4- Increase neutrophil chemotaxis
- CYCLOOXYGENASE pathway - increases prostglandins - increase TXA2 (helps cells come together).
Accute inflammatory response
Bradykinin, Hageman Factor XII:
- increases pain sensitivity
- increases vasodilation
- increases vascular permeability
Systemic effects of acute inflammation
Chronic inflammation
- Fibrosis and Angiogenesis two main characteristics of chronic inflammatory response.
- IFN-y = proinflammatory. Secreted by Th1 cells, activates macrophages which increases the inflammatory response.
- IL-4 and IL13 are anti-inflammatory. Secreted by Th2 cells, activate macropages to decrease the inflammatory response.
- FGF (fibroblast growth factor) and VEGF( Vascular endothelial growth factor) responsible for Angiogensis
- PDGF (platlet derived growth factor) responsible for fibrosis.
- TGFB (tumour growth factor beta) responsible for increasing angiogenesis and fibrosis. This is the most important growth factor for chronic inflammation.
Chronic inflammation: Granulomas
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HIV
Shingles (aka Herpes Zoster Infection)
- viral infection that causes a painful rash.
- can occur anywhere in your body.
-typically looks like a single stripe of blisters that wraps around the left side or right side of your torso. It does not cross the midline of the torso.
- caused by the varicella - zoster virus (same virus that causes chickenpox)
- Herpes Zoster Ophthalmicus (HZO):
is a viral disease characterized by a unilateral painful skin rash in one or more dermatome distributions of the fifth cranial nerve (trigeminal nerve), shared by the eye and ocular adnexa
Hutchingsons sign (nasocillary nerve): vesicles on the tip of your nose which is an early indicator of shingles.
Herpes zoster oticus
- Ramsay Hunt syndrome (herpes zoster oticus) occurs when a shingles outbreak affects the facial nerve near one of your ears.
- In addition to the painful shingles rash, Ramsay Hunt syndrome can cause facial paralysis and hearing loss in the affected ear.
How does Herpes (shingles) present?
- Seen in immunocomprimised patients (patients who use steriods, HIV, sickness)
- Symptomatic during times of stress
- Primary infection: systemic and accompanied by fever
- Secondary infection: Localised and less severe (more just rash)
Microbiology of herpes infection viruses ?
- Herpes simplex 1
- Herpes simplex 2
- Varicella zoster
- Enveloped double stranded DNA viruses
- Multinucleated giant cells
- Intranuclear eosinophillic Cowdry A inclusions
Herpes Simplex Virus 1
- An estimated 3.7 billion people under age 50 (67%) globally have herpes simplex virus type 1 (HSV-1) infection, the main cause of oral herpes.
- childhood transmission (saliva).
- Most people are asymptomatic however when they get ill, stressed, malnutritioned or get too much sunlight.
- Most common symptom is ‘cold sore’ on lip.
- Can also occur on mouth, eye, finger, esophagus, temporal lobe.
Herpes Simplex Virus 2
- An estimated 491 million people aged 15–49 (13%) worldwide have herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.
- Transmission from genital contact.
- Anal or genital ulcers
- Inguinal lyphadenopathy
- Dysuria - pain or burning when urinating
Management of Herpes virus ?
- Antiviral medications:
FAMCICLOVIR - Prevention: Recombinant zoster vaccine
How is it spread ?
- Spread the virus when the rash is in the blister phase (DIRECT CONTACT). The blister fluid is filled with virus particles.
- Or through breathing in virus particles.
- Virus remains dormant in neurons.
Pathophysiology of shingles
- Varicella virus causes chickenpox. After primary infection the varicella virus remains dormant in the dorsal root ganglia of spinal nerves or the trigeminal ganglion.
- In times of stress or immunosupression of the virus can reactivate and travel down the the sensory neurons causing herpes zoster (shingles)
Microbiology of herpes virus
- Herpesviruses have a unique four-layered structure: a core containing the large, double-stranded DNA genome is enclosed by an icosapentahedral capsid which is composed of capsomers.
-The capsid is surrounded by an amorphous protein coat called the tegument.
-It is encased in a glycoprotein-bearing lipid bilayer envelope.
Epidemiology of herpes virus ?
- An estimated 3.7 billion people under age 50 (67%) globally have herpes simplex virus type 1 (HSV-1) infection, the main cause of oral herpes.
- An estimated 491 million people aged 15–49 (13%) worldwide have herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.
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Malaria ?
- Serious infection spread to human by some types of mosquitos.
- Symptoms: high fevers, shaking chills, flu-like illness.
Malaria ?
- caused by a few different types of plasmodium species. There are 100s of species of palsmodium but only 5 cause malaria:
- P.falciparum
- P. Vivax
- P. malariae
- P.ovale
- P. knowlesi
- once plasmodium enters the bloodstream it infects and destroys mainly liver cells and RBCs, which can eventually cause death.
- Mainly effects tropical countries : malaria belt
Having sickle cell anemia is protective against having malaria.
- P.vivax uses a specific RBC receptor which attaches to a antigen called Duffy atigen present on RB
Cs. - Some individuals particulary those with sickle cell anaemia lack this receptor. meaning P.vivax cant get into their cells.
- Other diseases which decrease malaria infection is thalassemia and G6PD Deficiency
How is malaria spread ?
- Spread via female mosquitos which are looking for a blood meal.
- Plasmodium is in a state of development called SPOROZOITE in the moquitos salivary gland.
- 1-2 weeks later: Sporozites go from bloodstream to liver. The Plasmodium multiply to form merozites and liver cells die (EXOERYTHROCYTIC PHASE)
Some plasmodium species go dormant causing a long delay before symptoms.
How is malaria spread ?
- The merozoites then go into the blood and invade the RBCs.
- Once inside the RBC the merozite undergoes asexual reproduction and transformational changes (ERYTHROCYTIC PHASE)
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- In the replicative phase the merozites in the RBC undergo mitosis and differentiate into lots of merozoites. The RBC ruptures and the merozoites are released into the blood.
- The virus can either go into the Erythrocytic Phase however some merozoites undergo Gametogony. This is where they divide and give rise to gametocytes.
- The gametocytes remain inside a RBC and may be sucked up by another female anopheles mosquito. The gametocytes fuse into a zygote in the mosquitos gut. This part of the plasmodium lifecycle is called SPOROGONY (sexual reproduction).
- The zygote will eventually mature into a Ookinete then a Oocyst which will rupture in a mosquitos gut. Releasing sporozoites which make their way into the mosquitos salivary gland.
- The cycle repeats itself.
Symptoms of malaria
- Fever
- Extreme Fatigue
- Headaches
- Jaundice
- Splenomegaly
P. FALCIPARUM causes the worst malaria infection
- P. Falciparum generates a sticky protein that coats the surface of the infected RBCs.
- This causes RBCs to clump together and jam up blood vessels.
- This can cause hemolytic anemia and ischemic damage and
eventually ORGAN FAILURE. - When the brain is affected it is called CEREBRAL malaria and can cause altered mental status, seizures and coma.
- When liver is affected it is called BILIOUS MALARIA. This presents as diarrhea, vomiting, jaundice and liver failure.
- Other organs that can be affected are lungs, kidney and spleen and together create a sepsis like clinical picture.
Diagnosis of malaria
- With thick and thin blood smear.
- may also see Thrombocytopenia, elevated lactate dehydrogenase, normochromic and normocytic anemia.
Treatment for malaria
- Depends on what stage of the infection you are at.
- Suppresive treatment / Chemoprophylaxis: kills sporozites before they infect hepatocytes. Given to travels who are going to a country with endemic malaria.
- Therapeutic treatment: Aimed at eliminating merozoites in the erythrocytic phase given during an active infection.
- Gametocidal treatment: aimed at killing gametocytes.
- Radical treatment: Kill Hypnozoites in the liver.
- Most cases of uncomplicated malaria resolve with treatment.
Recurrent Malaria
Can be because of one of three reasons:
- Recrudescence
- Relapse
- Reinfection
Prevention of malaria
- A vaccine is being developed against malaria the RTS,S/ASOT vaccine.
pathophysiology of parasitic infections
A variety of mechanisms have been suggested to explain the immunosuppression observed in protozoan infections. The most common mechanisms proposed are (1) the presence in the infected host of parasite or host substances that nonspecifically stimulate the growth of antibody-producing B cells, rather than stimulating the proliferation of specific antiparasite B-cells; (2) proliferation of suppressor T-cells and/or macrophages that inhibit the immune system by excretion of regulatory cytokines; and (3) production by the parasite of specific immune suppressor substances.
Travel safety and prevention of disease ?
- clean water preparations
- vaccinations
- mosquito avoidance
- Personal protective equipment
Mechanism of fever in the body ?
Typical fever has 4 stages:
- The ascent phase
- The peak
- The beginning of the decrease
- Normalisation: end of decrease
Ascent phase:
- Heat production increases: muscles become tense, may be accompanied by trembling, shivers, and muscle tremors.
- Increased heat retention: small blood vessels in the skin contract, reducing heat release (heat radiation), hands and feet cool, face pale; as sweat secretion decreases, evaporation also decreases.
The end of this phase is usually the most uncomfortable, and may be accompanied by chills, head and muscle pains and malaise.
Peak:
- Heat production and heat dissipation are in balance, as the body has reached its target, optimal, set point temperature.
- Heat production is reduced.
- Heat dissipation increases: as the temperature of the blood (core temperature) flowing through the thermoregulatory centre is sufficiently elevated, the signalling of the cooling centre expands the skin’s vessels (accompanied by flushing), and the skin’s temperature elevates again.
The skin and limbs of the person become warm.
- At the end of the decrease, at normalization
The operation of the thermoregulatory centre will increase again.
Heat dissipation decreases.
This creates the new, normal temperature balance.
These four stages may rhythmically repeat for a few days.
The height of the fever is not in proportion to the pathological factors that produced it.
This means that fever height, in and of itself, does not indicate grave illness (in children older than six months). The very same virus may cause in the same child very high fever on one occasion, and on others no fever at all. Low fever may disguise illnesses that have to be taken seriously (pyelitis, for instance); but simple teething may cause very high fever. We discuss these in detail in the chapters „Accompanying symptoms of fever” and „How dangerous is the febrile condition
HIV
- discovered 1983
- ## 100,000 people living with HIV in the UK
Routes of transmission
Pneumocytis jirovecii
