Viral Diseases

Viral Diseases Viruses are: Obligate intracellular parasites – considered intermediate state between living and non-living entities: -unable to replicate without infecting host cell -unable to generate own source of metabolic energy (ATP) -unable to translate mRNA into protein Basic principles of viruses: -they are bundles of genetic material (nucleic acid) – surrounded by protein capsid -some contain lipid membranes + carbohydrates in form of glycoproteins *do not contain any organelles of living cells *Means of Transmission Viruses can get into body via mucousal membrane-bound entries (rectum, eyes, mouth/gut, nose/airway, uro-genital tract, skin through cuts/abrasion/intravenous or superficial puncture) Respiratory Faecal-oral transmission Body fluid transmission (Blood- Sexual Transmission Animal/insect vectors -Influenza, Rhinovirus (smallpox -Enterovirus, Poliovirus Borne) -HIV, Hepatitis C virus -Rabies virus, Lassa fever virus, virus), Cytomegalovirus, *usually a route for -Hepatitis B virus, Ebola virus, Yellow fever virus, Dengue virus parainfluenzaviruses, herpes gastrointestinal viruses (listed Smallpox virus (use anthropods – biting simplex viruses, coronavirus, below) Blood-borne viruses: insects/mosquitoes) Varicella-zoster *Arboviruses -Rhinovirus (4,NE) – most -Rotavirus (3,NE) – cause of -Lassa Virus (5’E) – zoonotic -papillomavirus(1,NE) -most -tick-borne encephalitis virus frequent pathogen found in gastroenteritis in babies and viral haemorrhagic fever = prevalent viral sexually (4,E) = causes encephalitis and common cold children – immunity develops spread to humans and nontransmitted disease – causes meningitis in humans – also -Influenza Virus (5,E) – causes after multiple infections with humans from genital warts and precursor for infects dogs, causes seizures, flu – has caused pandemics + decreasing severity of disease rats(multimammates) – cervical cancer tremors, death, in other millions of deaths -Enteric adenovirus(1,NE) – through urine and faeces -Herpes Simplex virus(1,E) animals – lethargy and -RSV(5,E) – causes bronchiolitis Ad40 and Ad41 subgenus F = ingestion – predominant in causes genital lesions -virus can respiratory symptoms in infants + infection causes causative agents in enteric West Africa – also transmitted lie dormant and will -Dengue virus (4,E) – clincal nd development of asthma infections – 2 in importance by blood products and needles periodically re-emerge + cause manifestations range from -Measles(5,E) – pulmonary after rotavirus in infantile -Nairovirus (5,E) – causes new acute infections subclinical to dengue fever, infections in gastroenteritis Crimean-Congo haemorrhagic -Hepatitis C virus (4,E) –acute dengue hemorrahgic fever immunocompromised children -Noravirus and Sapovirus (4,NE) fever = transmitted to people infections result in chronic (DHF), and dengue shock -Adenovirus (1,NE) – massive – cause diaarhea in humans from ticks and animals – human disease- results in cirrhosis and syndrome (DSS) group of DNA viruses – causes and animals (cows, pigs), to human transmission occurs hepatic carcinoma -Blue tongue virus (3,NE) – nonupper and lower rt infections – Noravirus = causes billions of from contact w blood, -immune deficiency virus (6,E) - zoonotic (doesn’t spread to mild symptoms except in food-borne illnesses secretions, organs/body fluids causes HIV, also feline, simian humans) disease of cloven transplant patients -Astrovirus (4,NE) – childhood -HIV, Hepatitis B, C, Viral and bovine variants, and AIDS hoofed ruminants and camelids diarrhoea in animals+humans haemorrhagic fevers – severe in sheep and white tailed deer – causes severe viral -Ebola Virus (5,E) = causes acute, serious illness – if untreated = fatal *Respiratory Viruses Rhinovirus – NE ss positive sense RNA virus -contains RNA that looks like messenger RNA in our bodies – virus = 30nm in diameter (very small) -has icosahedral symmetry within the capsid *3 separate species of rhinovirus (A, B,C – C= most rare) – combined = have 150 different serotypes in total = which is why there are not many good vaccines *Rhinovirus A and B = bind to ICAM-1 (inter-cellular adhesion molecule 1)- Rhinovirus C however uses Cadherinrelated family member 3 (CDHR3) = mediates cellular entry -virus = spread via respiratory droplets and fomites (coughs, sneezes) -infects upper rt -symptoms = mild – increased mucous production, sore throat, headaches, mild cough The Common Cold -Rhinovirus = site of infection = nose - does not cause death of epithelial cells (unlike other respiratory viruses e.g. Influenza), instead = disrupts tight junctions between cells -causes rhinorrhea and nasal obstruction (due to neutrophilic inflammatory responses), increased vascular permeability + stimulation of mucus hypersecretion – pathogenesis of cough = irritation from posterior pharyngeal drainage/direct infection of large airways How it infects: -RV capsid = recognised by TLR2 on epithelial surface -RV-associated ssRNA and dsRNA = recognised by endosomal TLR3, TLR7, TLR8 -dsRNA = also recognised by MDA-5 and RIG-I *Even though common cold = minor disease, lots of money is spent on developing effective anti-rhinovral drugs as rhinovirus = most common pathogen responsible for exacerbations of asthma and COPD Gastrointestinal Viruses – referred to as stomach flu haemorrhagic fever like ebola in humans -Yellow fever virus (4,E) Respiratory Syncytial Virus (RSV) – E, ss negative sense RNA Virus -RSV = generates syncytia (fused cells) – start to appear hours after infection with RSV = loss of function of cilia and death of cells = sloughing off of epithelial cells + inflammatory infiltrates = blockage of lower airways -RSV = between 120-200nm in diameter (pleomorphic – shape isn’t set) -major cause of respiratory disease in infants – bronchiolitis in preterm infants + makes more likely for secondary bacterial infections (e.g. Haemophilus influenza, S. aureus, Streptococcus pneumonia) = leading to pneumonia *Spread- via respiratory droplets – infects upper and lower rt epithelial cells -Formalin inactivated virus = used as a vaccine but caused enhanced disease + overstimulation of immune system -experimental inolculation with RSV = caused reproduction of disease of different degrees of severity Rotavirus – NE, ds RNA virus (11 separate segments) Sexually transmitted virus -8 species (A-H) + multiple serotypes -size = 80nm in diameter -spread via faecal-oral route *has a segmented linear dsRNA genome – 11 segments coding for 12 proteins -segment size range from 667-3302nt (genome size = 18,550bp long) *viral mRNA produced contains 5’-methylated cap structures – but lacks polyA tail -co-infection of different rotavirus strains belonging to same serogroup A,B,C = mixing of genome segments (virus sex) *there are 2 mechanisms in which rotavirus causes diarrhoea: 1. virus induced enterocyte lysis occurs = causes disruption of intestinal villi and maladsorption 2. non-structural protein 4 (NSP4) of virus = stimulates calcium release = stimulates enteric nervous system = release of chloride ions and water from intestinal lumen *Rotavirus effects morphology of intestinal villi -rotavirus = infect mature absorptive villous epithelium of upper two thirds of small intestine – after replication in upper small intestine, infectious particles = released into intestinal lumen + undergo further replication in distal areas of small intestine -infection remains within intestinal mucosa -loss of enterocytes leads to villus blunting Herpes Simplex Virus – E, 1, linear dsDNA virus - icosahedral symmetry with layer between the protein capsid and lipid envelope called tegument *there are 2 separate species – HSV1 and HSV2 – both have large complex genomes w around 74 ORFs -after entering the cell – viral DNA = inserted into nucleus -host cell RNA polymerase II = responsible for transcription of viral genes -DNA replication occurs using virus encoded enzyme How it infects: 1. Infection of epithelial cells in mucosal surface = production of progeny virions + spread to additional epithelial cells -virus = enters innervating sensory neurons + capsids = transported to neuronal cell body -viral DNA = released and circularizes – circular viral DNA persists in neuronal cell nucleus – latency associated transcript = expressed 2. upon reactivation, viral lytic gene expression = initiated + newly formed capsids = transported to axon terminal -infectious viruses = released from axon + infects epithelial cells = causes recurrent infection and virus shedding Arboviruses -group of viruses that are transmitted by arthropod vectors Yellow fever virus (4,E), positive sense ssRNA -40-50nm in diameter – closely related to dengue and zika virus icosahedral virus from Flavivirus genus -virus incubates in body for 3-6 days – followed by infection that ca occur in phase 1 or phase 2 -1st phase (acute) – fever, muscle pain with backache, headache, shivers, loss of appetite, nausea (most symptoms disappear after 3-4 days -2nd phase (more toxic – 15% patients enter this phase after 24hrs of initial remission – 50% who enter this phase die within 10-14 days – rest recover) = high fever returns and several body systems = affected – patient rapidly develops jaundice w abdominal pain and vomiting -bleeding may occur from mouth, nose, eyes, stomach etc – blood appears in vomit/faeces + kidney function deteriorates How it infects the cells: -virus enters cell by binding to receptors including TIM & TAM receptors – virus can also enter cells by antibody dependent enhancement (ADE) – positive sense RNA genome of virus can be immediately translated into protein in the ER -maturation of virus required cleavage of polyprotein by host cell proteases such as furin *this causes changes in liver, kidneys, cardiac muscle, spleen , brain: Liver = swelling and necrosis of hepatocytes in midzone of liver lobule – nucleic acid hybridisation shows the viral antigen and RNA in these cells, and cytopathology = mediated by direct viral injury via apoptosis – inflammatory changes = minimal – patients who recover from hepatitis = do not have scarring or cirrhosis Kidneys = acute tubular necrosis – due to reduced perfusion of blood rather than direct viral injurt Muscle cells in heart = focal degeneration Spleen and Lymph nodes = necrosis of B-cell areas Brain = oedema and petechial haemorrhages – but viral invasion and encephalitis = rare *Haemorrhages = occur due to decreased synthesis of clotting factors by liver *Blood-Borne Viruses Ebola Virus – ss negative sense RNA virus(19kb) – has a classical sheppards crook/worm-like filamentous appearance -RNA = divided into 7 genes – code for 8 proteins – proteins = divided into 7 structural proteins, 1 non structural) -80 nm in diameter – varying length but can be up to 1.1um -virus has envelope w spike glycoproteins -ss negative sense RNA = complexed w viral RNA-dependent RNA polymerase = enclosed by a helical nucleocapsid -this is surrounded by a matrix coat + a host cell derived lipid envelope (contains viral spike glycoproteins) Symptoms of Ebola haemorrhagic fever = fever, fatigue, dizziness, muscle aches, loss of strength, exhaustion -sever cases of Ebola = bleeding under skin, in internal organs, from body orifices (mouth, eyes, ears)- patients rarely die from blood loss – die from internal haemorrhagic shock Ebolavirus Reston – in 1989 – outbreak of haemorrhagic fever in crab-eating macaques(monkey) in animal handling facility in Reston Virginia – Simian Haemorrhagic fever symptoms = similar to Ebola in humans – causes breakdown of endothelial cells, inhibition of clotting factors = shock and organ failure *Oncogenic Viruses -there are tumour viruses(viruses linked to cancer), evidence for this: -presence of part of a viral genome within tumours + expression of some viral genes in tumour cells -invitro infection of cells leads to transformation (makes cells immortal so they keep dividing) -viral genes = identified that transform cells in a culture(uncontrollable cell division) -infection of animals results in tumours = not possible for human viruses + vaccinations prevent tumour formation Mechanisms of oncogenesis on a broad scale: 1. DNA viruses negate(turn off)tumour suppressors (tumour suppressors are genes that stop cancers from forming- stop cells from dividing uncontrollably) – this is advantageous for the virus as it can continue replicating 2. RNA viruses activate oncogenes (oncogenes drive cells into cell division) Epstein Barr Virus -member of herpes family of viruses – closely associated w infectious mononucleosis (glandular fever/kissing disease) -able to infect both acutely and lies dormant within lymphocytes (B-lymphocytes) *EPV causes cancer (Burkitt’s Lymphoma)- fastest growing human tumours(most in African countries, due to EPV or malaria) -solid tumour = formed of B-lymphocytes = results in impaired immunity and can be disfiguring *however, Burkitt’s Lymphoma = treatable w chemotherapy – long term survival in over 50% patients