Viral Pathogenesis Overview PDF

Viral Pathogenesis:Overview Dr Rob Noad [email protected] For the exam you need to be able to: 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare a...

Viral Pathogenesis:Overview Dr Rob Noad [email protected] For the exam you need to be able to: 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare and contrast acute and persistent viral infection Learning Outcomes - > infect whole organism. 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare and contrast acute and persistent viral infection The generalised virus infection of a host: Routes of Transmission Entry into host Local replication in cells at site of entry Primary viraemia Replication at secondary site(s) Secondary viraemia Target organ replication (previous Lecture. ) Viraemia=circulation through the whole body (usually in blood or lymph) For blood borne viruses this is usually organs with high blood flow, for example the liver, spleen, heart or kidneys. During the secondary viraemia there is usually much more virus detectable in the blood. Site of major pathology An example: Canine Parvovirus Entry into an initial host (cell) Local replication at site of entry Primary viraemia Replication at secondary site(s) Faecal Oral transmission spread local replication of Oropharynx>tonsils cropharynx T lymphoid organs · permeability a o. blood vessels All lymphoid tissues (Thymus, bone marrow, lymph nodes, spleen, patches) Secondary viraemia Target organ replication All white cells (lymphocytes and macrophages)>immunosuppression. Plus Intestinal crypts (vomiting/bloody diarrhea). Y sites thatare rapla diveding (wI b , stem wells) bore marrow Intestinal crypts. -mucosal Routes of transmission/ Entry sites - breaks membrane in the - allow (resp , tract , alimentary canal) skin verus to get through Keatinized layer protective. Skin Gastrointestinal tract Respiratory system Blood Genital Transplacental View virusv as host vTruS does would somethingtotogee away change easter to infect other hosts Must overcome innate defences to enter body -Both physical & immunological Site/tissue specific e.g. keratinised layer of skin Site/tissue specific plus systemic & laut viral proteins) e.g. innate immunity at site of infection at a local level, Antibodies and Cytotoxic T cells at a systemic level. ⑳ ③ ↓ targetcells infected ol. virus Defences in the Skin: Is an effective barrier (keratinised) For virus infection this must be breached by abrasions or bites Innate immune system Macrophages, neutrophils, natural killer cells recruited to sites wh inflammation &. Coates M, Blanchard S, MacLeod AS (2018) Innate antimicrobial immunity in the skin: A protective barrier against bacteria, viruses, and fungi. PLOS Pathogens 14(12): e1007353. https://doi.org/10.1371/journal.ppat.1007353 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007353 skin lessons Examples of virus that enter via the skin Orf infection (parapox virus) Causes lesions around the mouth and teats of lambs and goats Oral crusting due to Orf in a sheep Rabies Papillomaviruses = Orf infection in a sheep farmer local replication 7 Blood Via haematophagous (blood biting) insects Virus Schmallenberg Virus West Nile Virus -sharing. meles Via blood products and/or sexual contact Hepatitis B Virus HIV premony replications in capellances Respiratory Tract Defences Mucociliary escalator (in URT and bronchi) Mucus and cilia Filters out large particles Coughing & sneezing Innate immunological defences Virus entry Via aerosolized droplets Spread by coughing or sneezing Respiratory Viruses Influenza, FMDV, Rhinoviruses, Adenoviruses, Coronaviruses Gastrointestinal (GI) Tract Defences low pH (~2) in stomach Denatures protein and kills most microorganisms V surfactants ↑ - break lipid envelope Bile and proteolytic enzymes in intestines High pH in the duodenum (rapid change) Mucous and secretory IgA in the intestinal tract > - lose attachment protein. Pathogens that infect the Gastrointestinal Tract Pathogens enter via the oral route (ingestion) Some infect oropharynx Canine Parvovirus, Classical Swine Fever Virus Primarily replicates in the tonsils, then spreads systemically avoids harsher downstream conditions Others survive passage through the harsh conditions of the GIT, mainly non-enveloped viruses E.g. Norovirus Enzymes in the GIT cleave capsid to allow infection E.g. Rotaviruses (also some coronaviruses) Norovirus Transplacental - Pregnant animals can transmit some viruses to the foetus across shedding placenta Examples: Schmallenberg Viral Diarrhoea Virus Swine Fever. : - Ill-thrift in calf persistently infected With BVDV (right) Pig chronically infected with CSF virus > - transmit to other cows differentrationlateof self & non-self in is gestation period : infected verus is In stageas earlyused Xvy , i Genital PRRSV Shedding Via infected semen Bluetongue re-emerged from from frozen bull semen Equine Viral Arteritis Shed for months/years apparently healthy carrier animals commonly spread by the respiratory system Porcine Reproductive & Respiratory Syndrome Virus (PRRSV) Entry into host Local replication in cells at site of entry Examples: ORF, bovine papillomavirus Primary viraemia Replication at secondary site(s) Secondary viraemia Target organ replication Entry into host Local replication in cells at site of entry Example: ORF Primary viraemia Replication at secondary site(s) Secondary viraemia * Virus O Target organ replication can ② Can : it it get into the cell replicate (appropriate to in that well i stors supported virus produce an & permissive replication ).. infection Most do cause a systemic infection but demonstrate tropism towards particular cells/organs. For virus infection to occur, the cell must be: Susceptible Entry receptors Permissive Appropriate host factors to complete viral replication. Particular cell type Papillomaviruses needs differentiated cells Canine parvovirus needs rapidly dividing cells Sometimes the same virus species can have a different tropism when it infects different hosts. Example: Low path Influenza A virus is mainly a gastrointestinal pathogen in birds but a respiratory pathogen in mammals. Wahlgren (2011) Infection Ecology and Epidemiology 1: 6004 - DOI: 10.3402/iee.v1i0.6004 Sometimes changes in tropism can affect disease severity. : change In achment potem - > - Logic actorious buses generic protease present Example: Low pathogenicity and high pathogenicity strains of avian influenza 3 prote cleavage of birds gut in - facilitate fusion lots : actory of wells spreads in more of h attache birds elfictrng Spread via Nerves: Rabies - - neurotrophic - Introduced via bite - Primary replication in muscle cells - Uses motor nerves to reach CNS - Further replication in spinal cord & brain - Enters salivary gland for onwards transmission # ! under > - : verus in saleva stuck X :. in good reduced slower immune infection in brain for surveillance host ↑ teme of survival shedding travels back to sensy & replication ↑ chance of Trans- missionby saliva prevent. nerves of muscles through pharyngeal neares > paralyze : excess swalking muscle. salevation. Shedding:Key Points Critical step for transmission to new hosts Generally, virus reaches highest titre in organ tissues from which it is shed faecalAutre ina salivary gland Often, the sites of entry & exit are the same g. e. but not always e.g. FMDV sheds in vesicular fluid FMDV - vesicles Learning Outcomes 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare and contrast acute and persistent viral infection lyses Why do viruses cause pathology? - symytea. Pathology may be necessary for transmission Viral fitness is determined by survival & transmission g. e measles. respiratory syncytial , vers overreacts > Pathology may be a side effect hypersensitive response pathology > Often the pathology is a host response to the virus rather than something the virus actively does to the host. I g inflammation al of sermeability endothelial T essie But in general virus does not benefit from killing host - > - -. e -+. > Leakage vascular - - Emerging viruses do not have to evolve to become less pathogenic! H5 avian influenza currently more pathogenic than in previous years Swellung. How do viruses induce pathology Direct Effects Cytopathic effects (CPE) damage to host cell caused by virus well death. effects (cell death) formation bodies apoptoter Cell stimulation > - stimulated. to devide Cell transformation Integration into DNA Indirect Effects Immune-mediated pathology Cytokine Storm Negri bodies in rabies virus infections of neurons (tumour formation). > I cause can of be cancerous. most verus pathology Cell stimulation Trensenof genemen DNA * Poxvirus-infected cells synthesise epidermal growth ORF factor-like protein of Stimulates cell cycle in neighbouring cells overgrowth epidermal cells ↳ Makes them ideal infection targets for viral form lumps replication in skin wells ·. a en I - >. -. FOWLPOX Cell Transformations Papillomavirus - enfects > - g through breakage ofskin base of epithelial layer - ets To cells ! - devidly Papillomaviruses: Bovine papillomavirus: warts Human papillomavirus: cervical cancer Early gene product E5 Primary transforming protein Stimulates proliferation of infected cells. Downregulate expression of (MHC) class I molecules (helps the virus evade the host immune system). G i e.. make well wells prote dysregulate cycle of layer of wells & base. skin ↓ : excessive cells growth of skn Transformation by Retroviruses of of i n tegrated host Insertional Mutagenesis verus when its genome Provirus integrates into host DNA all interups gene Upregulates growth Viral Oncogene Expression - virus a carry that it & version dysregulates integrated is of cellular host well into gene plication re most into batt genome. * Indirect Viral Effects Immune system can do more harm than good Immune cytolysis of infected cells Essential for recovery but can damage host Clinical signs often consequence of immune response Immunopathology I cytotoxic 7 verue wells infected recognise cells of itneuron well CTLs: Myocarditis caused by coxsackievirus B infection of mice is caused by CTLs ↳ O - CD4+ peptides kill those on surface of wells regenerate inflammatoryresponse byscolgera lending T cells: induce cytokines & activate effector cells. Recruited neutrophils and mononuclear cells release proteolytic enzymes, free radicals & cytokines Antibody: Dengue virus Summary Direct Effects Cytopathic effects (CPE) Visible damage to host cell caused by virus Cytocidal effects (cell death) Syncytia formation Inclusion bodies Cell stimulation Cell transformation (tumour formation). Indirect Effects Immune-mediated pathology Learning Outcomes 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare and contrast acute and persistent viral infection Disease as the tip of the iceberg cytobeme storm - Disease is determined by host, viral and environmental factors ENVIRONMENT HOST PATHOGEN Host factors influencing disease outcome g parvovirus e in. ↑↑ 6 poppies dividing herdevelope immune system status ? WRE fight off infection Species/ breed resistance or susceptibility status (from vaccination/ previous infections) stress (e.g. weaning/high productivity animals/ pregnancy/movement of animals) Co-infections with one or more pathogens to - 7. - pregnant nemunosuppressed eng : X regent fetry as object. African horse sakness - fatal to horses but X freeg - donkeys Viral properties that impact disease Infectivity (R0 how many onward cases does each case cause) Geographical origin of virus: endemic or exotic Transmission route: Insect vector, air-borne, faecal-oral Immunosuppression Tropism for immune cells (HIV/FIV in CD4+ cells) Viral Virulence Factors > - genaten markers associated wl & disease Viruses can differ in their pathogenicity Non-coding virulence factors of Tick-borne encephalitis virus, of poliovirus Protease cleavage site in the Influenza virus Haemagglutinin Protein Alter spread within host (LPAI ->HPAI) Papillomaviruses differ in their ability to cause cancer usually virus Xencode toxins : benefit from host Rotavirus D NSP4 Enterotoxin released from infected cells Responsible for fluid secretion by altering plasma membrane permeability - structural ↓ gut pathogen in protein young 4 animals ↳ T.. e Marrhoea.. surviving Environmental Factors that Influence Disease Outcome Contamination of the environment (e.g. water supplies/habit) wind -> facilitate Climatic Conditions flying of midges high rainfall-* larvae impacts insect- borne viruses to high growthborne disease. ⑦ of nutrition (pasture/ feed) arthropod Stocking density (impacts ease of transmission & dose) practices (e.g. imported animals/new feedstuff) Veterinary policy (e.g. vaccination programs) · · Learning Outcomes 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease 4. Compare and contrast acute and persistent viral infection i b Infectious type I O local 8 systemiz contagious ? ? Acute Vrs Persistent Infections Acute infection Virus causes a rapid, self limiting infection Infection cleared by immune system leading to recovery Persistent infections I: Latent Infection Virus persists at very low levels following recovery (Quiescent/Latent state) Virus replicates in immune privileged sites g neurones No viral protein synthesis/ infectious virus production Limited recognition of molecules on infected cells Latency associated transcripts: (reduce MHC expression, block apoptosis). Potential to reactivate (i.e. switch from latent to productive infection) Occurs in certain circumstances (e.g. Immunosuppression / stress). e. Intermittent episodes of recurrent disease and virus shedding (allows for transmission to naïve host) I stell : carries is it it it was is others verus infections an more , anothe or enfection , immune than Persistent infection II: Chronic Infection -local. replications > chicken pox FMDV when X acute * X export hard to chicken pox elderly or : as a child - > Immunosuppressed X die. shedding tell now expose -> recover expose > - vs shedding Slow progressive disease of FeLV Maedi Visna or Jaagsiekte sheep Retrovirus infection (JSRV) Virus detectable for years/lifetime > - recover shingles from chuchen pox. Factors involved in persistence Replication in immune- Privileged Immune suppression Immune evasion (though seen for acute infections also) Tolerance (e.g. avian leukosis virus, BVDV) Virus variants with antigenic variation (RNA viruses e.g. HIV) HIV within-host phylogeny For the exam you need to be able to: - where does it how does how get -itsbread dies If 1. Describe the stages of viral infection in a host 2. Describe the mechanisms by which viruses cause disease 3. Define viral and host factors that influence whether infection results in disease (serenity 4. Compare and contrast acute and persistent viral infection an affect pop. level/hardlevel