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Viral pathogenesis PowerPoint Presentation

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Description : Check out this medical presentation on Influenza (Flu), which is titled "Viral pathogenesis", to know about the mechanisms that viruses use to damage host cells, how the host contributes to damage resulting from virus infection, and how to design an experiment to determine what virus genes are involved in pathogenesis.

Tags : Influenza, Flu, Viral pathogenesis, host cells, virus infection

Published on : Jul 12, 2021 | Views : 2365 | Downloads : 3

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Slide 1-

Viral pathogenesis “No virus is known to do good. It has been well said that a virus is a piece of bad news wrapped up in protein.” Medawar and Medawar
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Learning objectives Describe mechanisms that viruses use to damage host cells. Explain how the host contributes to damage resulting from virus infection. Design an experiment to determine what virus genes are involved in pathogenesis.
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Clinical latency
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Viral Virulence The ability of a virus to cause disease in an infected host A virulent strain causes significant disease An avirulent or attenuated strain causes no or reduced disease Virulence depends on Dose Virus strain (genetics) Inoculation route - portal of entry Host factors - eg. Age SV in adult neurons goes persistent but is lytic in young
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Virulence is a relative property Quantitation of virulence to compare strains LD50 - lethal dose for 50% kill ID50 - infectious dose for 50% of symptom Virus conc % alive 100 50
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How is HIV/polio/influenza transmitted? Why are these the only ways? What would it take to make HIV airborne?
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Viral genes that affect virulence may Affect the ability of the virus to replicate Enable the virus to spread within host or between hosts Defeat host defense mechanisms Produce products that are directly toxic
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Attenuation - polio vaccine 3 serotypes of Sabin virus (attenuated) changed in 5’ NTR Affects ability to replicate in neurons Affects translation of mRNA in neuronal culture cells but not other cells Replicate poorly in gut so less is produced to spread
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What damage do viruses do? Direct damage to cells due to cell death/apoptosis Paralysis Immune deficiency Disruption of normal cell functions (eg protein synthesis, secretion, membrane trafficking) Immune response to virus infected cells Immune cell release of cytokines Virus hijacking/expressing host genes
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Evoking an autoimmune response that affects uninfected cells Mimicry Exposing protected sites Infecting immune cells - B cell antibody production against variety of proteins Hyperexpression of MHC
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Adenovirus and apoptosis Binding to Fas receptor triggers apoptosis (even ab) RID is Ad protein that internalizes epidermal growth factor receptor Hypothesis: RID internalizes Fas receptor and protects from apoptosis
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Adenovirus infection followed by treatment with anti-fas ab E1b is a bcl2 homolog - inhibits fas mediated apoptosis
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How could you measure whether RID internalizes Fas?
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West Nile virus Flavivirus (like hepC) Vector borne Appeared in US in 1999 and spread across country Symptoms include neurologic and may lead to paralysis and death
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West Nile Virus and Apoptosis Hypothesis: Capsid protein expression in cells results in apoptosis through mitochondrial pathway Inflammation follows as a response to apoptosis How do you show apoptosis as a result of capsid expression? How could you show it is the mitochondrial pathway?
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Filovirus infection Ebola and Marburg Hemorrhagic fever, shock and death Hypothesis: Shock is often associated with release of cytokines by macrophage/monocyte What do you need to show?
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Antibody enhancement of infection Dengue fever/dengue hemorrhagic fever Primary infection - acute, self-limiting Secondary infection - non-protective antibodies bind and facilitate entry to monocytes through Fc receptor Causes cytokine release that leads to hemorrhage, shock and death Ebola/HIV similar affect Ebola pseudotyped VSV
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What part of genome is needed for virulence? Coxsackie virus can cause heart disease CVB3/0 - avirulent CVB3/20 - cardiovirulent Change in nucleotide 234
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Growth of Coxsackie in HeLa, murine fetal heart fibroblasts, adult murine cardiomyocytes
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Influenza Avian H5N1 appeared in 1997 Until then most H1, H2, H3 Fatal with distribution in several tissues HA determines binding to host and virulence Basic amino acids at cleavage site increase protease susceptibility
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Pathogenicity of transfectant viruses in mice
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Virulence of chimeric and single aa substitution PB2
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Foot and Mouth Disease Picornavirus OTai strain infects swine but not cattle; OCamp is virulent for swine and cattle Chimeric viruses used to infect BHK (same responses on porcine) and BK
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Molecular mimicry by HSV1 Herpes keratitis may cause blindness T cell destruction of corneal tissue Hypothesis: Damage is due to autoimmune response caused by molecular mimicry Disease elicited by CD4 T cells for corneal antigen in mouse model
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Recognition of UV-irradiated extracts of HSV-1(KOS)-infected cells by cornea-specific CD4+ T cell clones. Cornea-reactive T cell clones (C1-6 and C1-15) or the OVA-specific clone O3 (2 x~ 104 cells per well) were stimulated with UV-irradiated extracts of HSV-1-infected or uninfected Vero cells in the presence of -irradiated syngeneic BALB/c spleen cells (5 x~ 105 cells per well). Proliferation was assessed after 2 days by 16 to 18 hours of exposure to 1 µCi of [3H]thymidine ([3H]TdR) and is expressed as mean counts per minute (cpm) ± SEM of triplicate cultures. Dose-dependent stimulation of cornea-specificCD4+ T cell clones by HSV UL6-(299-314) peptide. CD4+ T cell clones (C1-6 and C1-15) (2 x~ 104 cells per well) were incubated with the indicated peptides (0.2 µM) in the presence of irradiated syngeneic BALB/c spleen cells (5 x~ 105 cells per well): , p292-308 (IgG2ab)closed square; , p299-314 (UL6) open square; , p200-222 (MMTV).
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Mutant Ul6 A - T cell proliferation B - virus replication C - immunization and adoptive transfer of T cells to nude mice; infection with WT (open circle: control; closed circle: mutant virus; square: wt virus)
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Coronavirus neurovirulence Mouse hepatitis virus Neurotropic strains - acute meningoencephalitis then chronic demyelination; noneurotropic - acute meningitis Acute phase - virus replicates in neurons and glial cells; then low levels of viral RNA persist in glial cells and chronic inflammation Hypothesis: cytokine response of brain immune cells determines disease outcome
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Analysis of mRNA levels of cytokines 24 h following infection of astrocytes with a neurotropic (MHV-A59) and a nonneurotropic (MHV-2) virus compared with an uninfected control culture. The blots of mouse cytokine array assays are shown. The cytokine key is as follows: A, colony-stimulating factor granulocyte; B, gamma interferon; C, IL-1; D, IL-1ß; E, IL-2; F, IL-3; G, IL-4; H, IL-5; I, IL-6; J, IL-7; K, IL-9; L, IL-10; M, IL-11; N, IL-12 p35; O, IL-12 p40; P, IL-13; Q, IL-15; R, IL-16; S, IL-17; T, IL-18; U, lymphotoxin B; V, TNF-; W, TNF-ß; X, GAPDH; Y, ß-actin; Z, bacterial plasmid (pUC18).
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HIV associated dementia (HAD) Occurs in ~ 15 - 30% of cases of subtype B but only 1-2% of subtype C Migration of monocytes to brain correlated to HAD Extracellular Tat protein exhibits strong monocyte chemotactic properties Hypothesis: Differences in Tat between subtypes B and C may account for different rates of HAD
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Sequenced isolates to find differences
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Functional evaluation of Tat transactivation (A) expression vectors encoding the isogenic C-Tat proteins. Differences within the dicysteine motif of these vectors are highlighted.. (B) Transactivation of LTR-driven GFP expression by different Tat vectors in 293 cells. (C) Transactivation of LTR-driven SEAP expression by different Tat vectors in 293 cells. SEAP in the culture medium was quantified on day 1 (open bars) and day 3 (filled bars). (D) Rescue of the Tat-defective virus by isogenic C-Tat proteins. HLM-1 cells were transfected with different C-Tat variant expression vectors. Culture supernatants were collected on days 1, 3, 5, and 7 following transfection, and p24 levels in the culture supernatants were determined. Results of experiments using samples from day 3 are presented; similar results were observed for samples from other days. Abs, absorbance; -VE, parental vector. Contains integrated HIV with Tat defect Secreted AP
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Monocyte migration induced by isogenic Tat proteins. f-MLP peptide was used as a positive control at 10-7 and 10-8 M concentrations. Tat proteins were used at concentrations of 100 and 20 ng/ml (12 and 2.4 nM, respectively) as indicated. No grad, wells with 100 ng of CC-Tat protein/ml in both the compartments. Differences in the numbers of monocytes that migrated with Tat-CC and Tat-CS were statistically significant Taxis assay: membrane with monocytes on one side and test protein on other Count cells on filter
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Viruses and multiple sclerosis? Protein database search for virus gene products with similarity to myelin basic protein Used a variety of aa substitutions accounting for those that are not essential for function Why protein and not nucleic acid sequence?
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How to make a killer virus What characteristics should a biological weapon have? How can it be constructed?
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Ectromelia virus causes mousepox Recovery due to CTL death of infected cells via perforin pathway mousepox virus produces inhibitors of caspases Vaccinia virus does not inhibit caspases so they are killed by two mechanisms Il4 skews immune response to ab production and shuts down perforin pathway
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Viruses and obesity
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Canine distemper virus - hypothalamic damage? Rous associated virus, borna virus Chicken adenovirus - excessive fat accumulation but lower cholesterol and triglycerides Ad36 - human ad that causes obesity in chickens and mice and lower chol/triglyc
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Viruses and diabetes Mouse model B - decrease in diabetes with expression of Ad early genes square expressing all E3 genes), DL704/NOD (triangle expressing E3 apoptosis-inhibitory genes), DL309/NOD (x expressing E3 MHC class I suppressive gene), and nontransgenic controls - diamond
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Other diseases with possible viral involvement Coronary restenosis Behaviorial disorders