Virology Flashcards
Mucociliary Flow
cilia that line the bronchi and trachea - forcing mucus from lungs and sinuses toward pharynx to be swallowed!
Infection
relationship between microorganism and human host; good or bad relationship; stable and transient
Infectious disease
an infection that results in a disease state
Communicable disease
infection that can be transmitted from person to person
Etiologic Agent
organism responsible for disease manifestations - direct or indirect (immune response)
Koch’s Postulates
criteria for proving that a certain organism is associated with disease 1) specific microbe is present in specific disease lesion 2) microbe can be isolated and grown in vitro 3) microbe can be infected in animals and cause disease 4) can re-isolate from animals and infect new animal host.
Limitations of Koch’s Postulates
some ID do not have characteristic lesions, some cannot be grown in vitro, ID is complex interaction between microbe and host
Pathogenicity
capacity of microbe to damage host
Pathogenicity
microbe causing host damage can be classical or opportunistic
Frank pathogen
cause disease to normal host
Opportunisitic pathogen
disease to immunocompromised patients
Virulence
relative capacity of a colony of microbes to cause a disease - often synonymous with pathogenicity
Virulence Factor
component of pathogen that facilitates damage to host.
In what ways doe microbes differ?
Same bug might have vastly different concentrations depending on route of infection, genetic differences, whether administred with bicarbonate.
What does administering microbe with bicarbonate do?
reduces stomach acidity, causes more virulence.
Stages of infection
1) encounter - how agent meets hosts - endogenous/exogenous, route dose 2) entry: colonization or adherence 3) spread: cross musical surface or spread within tissue 4) multiplication 5) damage - caused by agent of immune response 6) outcome - who wins?
Routes of spread
1) bodily fluids - saliva, blood, respiratory 2) fecal-oral 3) venereal 4) Zoonses - Vector (biting arthropod), Vertebrate Reservoir (contained within animal population) and Vector-Vertebrate Reservoir - arthropod infecting humans and animals
Entry of Microbes
globlet cells produce mucus and normal flora and pathogens are able to penetrate the tissue by: 1) disruption of tight junctions 2) infect the cell with phagocytosed material and transported via vesicles to other side.
what factors affect the microbiome?
Diet (breast or bottle feeding, solid food), suppression of microbial flora with antibioties, anatomic abnormalities, genetic differences.
Physiologic Importance of micro biome
Effect on tissue/organ differentiiaton, production of vitamins by gut flora, biochemical conversions, competition with pathogens for colonization.
Cholera is an example of a…
toxin mediated disease.
Pneumoccal Pneumonia is an example of…
acute inflammation caused by invasion, extracellular bacteria
TB is an example of…
infection by facultative intracellular bacterium
Rheumatic Fever is an example of..
pathology mediated by an immune response.
What is a virus?
filterable, sub-microscopic, obligate intracellular parasite. They are not alive, or do not undergo division. Genetic material enters the host cell and directs host to build new virus, which are then transported to another cell to carry out another round of replication.
Capsid
small proteinacous particle that contains DNA or RNA genome with the information to initiate and complete the infectious cycle.
How do viruses vary?
particle architecture, size, nature, topology of genes, protein coding strategies, cell/tissue tropisms, pathogenesis.
Two different classification of viruses
Classical and Baltimore
Classical Viruses
grouped according to shared physical properties - name derived from sort fo disease they are associated with
Properties of classical viruses
nature of genetic material, symmetry of capsid (helical or icosahedral), Naked or eveloped, dimensions or vision and capsid.
Baltimore Viral Classification
understanding how the virus replication and infection works. Based on central dogma.
Minus RNA
bottom strand of DNA (3’ to 5’), NDA from which mRNA is copied from
Positive RNA
top strand of DNA (5’ to 3’), contains open reading frame that is ribosome ready and able to be translated into protein.
Two principles of Baltimore Classification Scheme
1) genomes severe as template for synthesis of progeny genomes 2) function of viral genome is to make mRNA once inside the cell.
DNA Viruses
must use minus strand of DNA as genome template. RNA Pol II fills in the gaps of the DNA genome. Process takes place in the nucleus and produces an mRNA that is capped, poly A tailed.
dsDNA viruses
polyomaviruses, herpes, pox virus
Gapped Circular dsDNA
looks like normal DS, but has a portion of ssRNA, so this requires viral reverse transcriptase to bet to mRNA.
ssDNA
parvovirus, ssDNA is copied by host DNA Polymerase to make dsDNA and then to make mRNA and viral proteins.
RNA Viruses
have a negative or plus strand that dictates whether the genome alone is sufficient to be replicated. Some require additional proteins.
RdRp
RNA dependent RNA polymerase is a noval protein in the RNA viruses that produce both the RNA genome and mRNA from RNA template.
dsRNA
contain both + and - strands, can be turned into mRNA immediately; not reliant on host machinery as much
+ ssRNA
+ strand is translated directly by host ribosomes into protein, but need RdRp to amplify mRNA numer of subgenomic mRNA.
+ ssRNA with DNA intermediates
+ssRNA in virion is a real mRNA, but it is never used. Instead it is converted to dsDNA by viral reverse transcriptase and the sDNA intermediate integrates into host DNA and becomes a permanent part of the host genome.
- ssRNA
very deadly virus, Virus’s can’t be made directly into protein. First copied to make positive strand, always used viral encoded RdRp found inside caspid.
How do we study viruses?
infecting eggs,electron microscopty, cell culture, quantification by plaque assay, ELISA, hemoglutination tests infecting susceptible animals, gene sequences.
Capsid definition
protective protein sturcture the delivers genome, assembles from components during an infection, two forms: helical and isosahderal; can be surrounded by a lipid envelope.
Nucleocapsid
Nucleic acid protein complex in virion that is a substructure of a complex particle.
Envelope
host-cell derived lipid bilayer
Spike
virus derived membrane bound glycoproteins
Virion
infectious virus particle
Helical Capsids
a caspid put down in an array that sounds the genome in a disc like fashion; looks like a long strand or bullet shape.
Icosachderal capsid
alternative structure where the proteins are arranged in a hollow, quasi-pherieral structure with the genome enclosed inside. Have 2, 3, and 5 fold axis of symmetry.
Envelopes
lipid bilayers acquired during viral particle assembly, have glycoproteins embedded. From from budding through host membrane through PM, ER
how do non-enveloped viruses leave the cell
lysis
Viral Glycoproteins
spikes; integral membrane proteins that function in entry, host range determinants, assembly and egression, evasion from immune system.
How do viruses replicate?
in a replication burst - not exponentially - a virus come in, dismantles, makes new viral components, then puts together a lot and buds them outside of the cell or lysis to release contents.
Eclipse Period
Period where virus particles are broken down after penetrating cell, releasing their genome as a prerequisite to replication. No longer infectious.
Latent Period
time it takes from infection to release of new infectious virus particles.
what are the steps that occur during latent period?
attachment of virus to cell; entry of virus into the cell and un-coating of viral genome; viral gene expression; genome replication; assembly of new viruses and release of virus from cell
Attachment
specific binding of a virus attached protein with a cellular receptor to epithelial and mucosal surfaces
Susceptible Cells
functional receptor that may or may not be able to complete viral replication cycle
Resistant Cell
No functional receptor, it may or may not be able to replicate virus
Permissive Cell
has capacity of replicate virus, but may or may not have function receptor
Suseptible and Permissive
is the only cell that can take up a virus and repllicate it
steps in virus attachment
non-specific electrostatic binding to bring in close proximity, and proteins interact to initiate fusion of endocytosis
what are receptors on surface that react with viruses made of?
carbohydrates and protein - carbohydrate is less specific
Entry of virus
follows quickly after binding to cell surface, is an energy dependent process (cell must be metabolically active)
How does a virus enter a cell?
1) endocytosis to form an endosome (with enveloped or non-enveloped viruses, with or without clathrin or caveolin) 2)fusion of virus envelope (enevloped) with cellular membrane
Uncoating
virus has entered he cell and virus capsid is completely or partially removed and virus genome is exposed.
Gene expression and viruses
all RNA viruses encode a RdRp; RNA viruses need strategy to switch from making mRNA to making genomes.
how does a virus accomplish task of making maximal function with minimal genome?
nested mRNA, splicing, ambisense coding, RNA editin
How do viruses make or process proteins?
polyproteins, IRES elements, leaking scanning of AUG, suppression of terminal codons, protein processing/conformation change resulting in new activities
Viral Assembly
depends on host machinery: cellular proteins to capable or assist in folding; cell transport to move viral proteins and NA to site of assembly; membrane proteins enter secretory pathway, nuclear proteins use nuclear import machinery, subunits more on cytoskeleton using cellular motors
How is helical nucleocaspids assempbled?
viral genomic RNA is coated during synthesis of genome
How are icoshedral capsids assembled?
around virus genome, or inserted into preformed caspids.
Viral Egression
viruses with naked capsids are released from infected cell by lysis.
how do we measure how a virus effects the host?
1) result of viral infection on target cell 2) balance with host is necessary for survival 3) innate or primary defenses 4) adaptive defenses are acquired over time
Three general outcomes of a viral infection
Abortive infection/failed - no apparent effect on cells
Lytic/acute infection
production of virus and death of infected cell
Persistent Infection
Chronic production of virus, latent, transforming
Latent virus production
no virus is actively produced
Indirect Cell damage by virus
Integration of viral genome, induction of mutations in host genome (oxygen radicals), inflammation, host immune response. (these could be by viral design or by accident)
Direct Cell damage by virus
diversion of cell’s energy, shut off of macromolecular synthesis, competition of viral mRNA for cellular ribosomes, competition of viral promoters and enhancers, inhibition of interferons
Cytopathic effects by virus
changes in cellular morphology: nuclear shrinking, nuclear membrane alterations, cytoplasmic vacuolization, cell fusion, chromosomal breakage, rounding and detachment of tissue culture cells, lysis; Formation of inclusion bodies: Virions and proteins in nucleus, protein and RNA inclusions, Virus protein and nascent virus in cyto, chromatin clumps in nucleus.
How do viruses cause disease?
Oncogenic/transforamtion; lytic, persistent infection, latent (slow delay between infection and appearance of symptoms)
Innate Defense mechanisms from virus
natural barriers, certain cells, and soluble factors that bring a non-specific and immediate response to infection - primes the adaptive imune response.
Natural innate barriers to viral infection
skin, mucosal membrane, ciliated epithelium, gastric acid, tears, bile,
Cells involved in innate defense against viral infection
dendritic, NK, PMNs
Soluble factors in innate defense against viral infection
interferons, cytokines, complement, chemokines.
Intracellular restriction factors
cell factors that block/inhibit virus after entry into cell - widely expressed and potent, however viruses have evolved to antagonize these factors.
APOBEC/TRM
both intracellular restriction factors that bind to viral component *shared structure among viral family, and block viral replication
APOBEC
human protein that interferes with HIV by damaging viral DNA; not present in every cell - those that lack is are permissive; APOBEC transcription is induced by IFN signaling.
what is APOBEC inhibited by?
Vif - an HIV protein that blocks APOBEC from binding or targets it for destruction
TRIM:
an intracellular restriction factor that blocks retrovirus activity
Interferons
cytokines that are able to protect neighboring cells form viral infections
Type I IFN
Alpha or beta; antiviral factors that are made in most cell types
Type II IFN
gamma, produced in T cells and NK cells, more restricted than Type I.
Jak/Stat
signaling pathway that Type I and II IFN act through to cause the synthesis of antiviral
IFN gamma activates what genes
GAS
IFN Alpha and beta activate what genes?
IREs
What is the antiviral state?
induced by cells that have responded to IFN to alter transcription; is the optimal state to block viral replication
how does anti-viral state block viral infection?
temporary blocks cell proliferation, reduces cellular metabolism, potentiates NK acitvity by induction go IFN gamma, increase antigen presenting molecules, apoptosis
what triggers anti-viral state
IFN is triggered by dsRNA (which si produced in replication of RNA viruses, is an intermediate in replication of DNA viruses) and intracellular signaling of TLRs and RLHs
what is the result of a anti-viral state?
flu-like symptomes
what are the downstream mediators of IFN induced anti-viral state?
PKR and OAS
PKR
downstream mediator of IFN anti-viral state: phosphorylates and inactivates EIF2alpha translation to decrease protein synthesis
OAS
Downstream mediator of IFN anti-viral state; 2-5-oligoadenulate synthetase to activate cellular ribonuclease to degrade mRNA
what transcription is included in antiviral state?
adhesion molecules, MHC Class I, P21 for growth arrest, and procaspases (inactivated OAS and PKR)
why are inactivated forms of OAS and PKR formed?
inactive precursors that are activated by darn to shut down translation of both cellular and viral mRNA, induce gene products associated with CTL, and arrest cell cycle and induce apoptosis.
what TLRs are responsible for viral infection?
3, 7, 9 recognize Nucleic acids (dsRNA, ssRNA, CgP containing DNA)
RHL
Retinoic Acid Inducible Gene I: reocognize viral patterns like TLRs do..
what cells are involved in innate immune response to virus?
Mononuclear phagocytes, dendritic cells; NK, granulocytes.
Role of mononulcear phagocytes in viral infection
innate: phagocytosis, inflammatory mediator, antigen presentation
role of dendritic cells in viral infection
migratory cells found in every tissue except brain, present antigen to T and Stimulate B cell differentiation and proliferation, key modulators in development of adaptive immune repsonse, secrete cyotkines
Role of NK cells in viral infection
innate; active in response to IFN or macrophage derived cytokines, serve to contain virus infections while adaptive immune system is generated
Granulocytes in viral infection
innate: neutrophils, basophils, eosinophils
cytokines in innate defense
INF, IL-1, TNFalpha, IL6, IL12, Il18
Chemokines in innate defenese against virus
IL8
how does the transition work between innate and adaptive viral response?
viral pathogens are recognized by cells in which they replicate, leading to IFN production and inhibiting viral replication. Activation of NK cells. Innate either succeeds in clearing infection or containing it for adaptive response.
Adaptive Immune response to virus
activates microbicidal and cytokine secreting properties of macrophages, activate complement, stimulate NK cells, uses cytokines to induce inflammatory response and promote influx of antibodies and effector lymphocytes
what is the adaptive response most important in?
cleanup and prevention of infection - cell mediated and humoral immunity.
where are virus antigens present?
on virions, surface of infected cells, debris of infected cells, peptide fragments on MHC molecules
Humoral Response
adaptive immunity: using B-lymphocytes to make immunoglobin to neutralize and prevent infection. Critical in recognition of virion.
ab Affinity Maturation
selection of B-cell producing highest affinity antibody, binding can lead to isotope switching
what antibodies are made during a viral infection
lower affinity usually, and most often IgM isotypes.
IgA - viral infections
inhibits attachment, neutralizes toxins and enzymes
IgG - viral infections
inhibit fusion of enveloped virus, opsonizes virons to engage phagocytosis, facilitate complement lysis
IgM - viral infections
opsonize virions to engage phagocytosis, coat and agglutinate virions, facilitate complement lysis
Types of antibodies
group or type specific
Group specific antibodies
see epitopes that are shared by all viruses in a group
Type specific antibodies
see epitopes defining a virus group subset.
Neutralizing antibodies
bind to virus attachment proteins that prevent productive infection (re-infection)
Cell mediated response
adaptive immunity: rely on CTL to kill virus once inside the cell. Utilize T cells (helper and Cytotoxic killer) that bind to MHC I and II on APCs
what do helper T- cells bind to?
MHC Class II and produce cytokines that regulate proliferation
what does CTLs bind to?
MHC class I and kill virus infected cells
Results of adaptive immune response
secrete IFN by helper and activated NK cells; CTL lysis of cells; NK and macrophage kill directly
Th1 activate moves towards…
cell mediated immunity
Th2 activation moves towards…
humoral response.
Memory Cells
antibody and T-cells decline over time after infection is cleared, reinfection at later time leads to rapid increase in antibody and effect T-cells and infection appears as mild or even inapparent.
how doe viruses evade host defense?
antigenic variation, immune tolerance, trestricted expression of virus genes, production of viral molecules that act as inhibitors or decoys, down regulation of host proteins, infection of immunopriveledged sites, direction infection of immune system, inhibition of apoptosis
antigenic variation in virus resistance
point mutation of genome shifting to make virus unrecognizable by immune system receptors
Immune tolerance in virus resistance
molecular mimicry or infection prior to immune system.
what barriers do airborne viruses overcome in respiratory route?
alveolar macrophages, ciliated epithelium mucus secretion, lower temperature
what barriers do viruses overcome in the GI tract?
gastric acid, bile salts
what barrier do viruses overcome in the skin?
requires a breach of physical integrity or a vector (tick, mosquito)
where do viral infections usually take place?
near epithelial surface or barrier
requirements for successful infection
sufficient virus, cells at site of entry are susceptible and permissive, local host defense is absent of insufficient.
viral infected cells that are released from apical side tend…
to remain a local infection
Viral infected cells that are released from basolateral side tend to..
gain access to underlying tissue and spread
hematogenous stread
viral spread by infecting endothelial cells or direct inoculation of blood or lymph
Tropism
virus likely to infect certain tissues but not others
why does tropisms occur?
access to tissue, receptors for virus entry, expression of host genes required of virus, production of virus progeny, relative failure of host defense.
Enveloped viruses - tranmission
fragile and sensitive to pH - only transmitted from close contact
Non-enveloped viruses - transmission
hardier, sustain dyring, pH, detergents, high temperatures, and are transmitted via fomites, respiratory, fecal/oral routes
Incubation period of small pox
twelve days
Incubation period of common cold
2-5 days
Incubation period of Measles
8-12 days
Incubation period of Chicken Pox
14-16days
incubation perio of Erythema infectiosum
13-18 days
Incubation period of rosella
9-10 days
Incubation period of rubella
14-21 days
Incubation period of influenza
1-2 days
Virulence definition
capacity of the infection to cause a disease; affected by ability of virus to replicate, modify host defense mechanism, facilitate virus spread in and among hosts, directly toxic to host cells
Host factors in viral disease
receptor, cell type, age of host, genetic background, exposure history and underlying health conditions, immune status
what is the optimal age of flu for host infection?
Elderly >65 or children
underlying predispositions for the flu
asthma, COPD, cardiovascular disease, obesity, diabetes
What viruses are associated with cancer
HepB, HepC, retrovirus, EBV, papilloma, papovavirus, JC, BK, Wu, KI, HIV1, KSHV
outcome of a viral infection..
acute, persistent, latent/reactivated infection
Localized infections
rhinovirus, rotavirus, papillomavirus
Rhinovirus
UPR
rotavirus
local insetinal epithelium
Papillomavirus
local epidermis
systemic viral infections
enterovirus and herpes virus
enterovirus
primary: intestinal epithelium, secondary lymphoid tissue and CNS
Herpse Virus:
primary: propharynx or GU tract; secondary: lymphoid cells of CNS
Acute Local infections
only infect epithelium, short incubation period 1-2 days, induces secretary IgA, often have many different serotypes that are dependent on host age, history, immune status, Reinfections are common due to short lived immunity.
Acute Systemic Infection
primary infection in epithlium, secondary: in spleen, lung, liver with viremia. Incubation period of 10-21 days, lifelong duration of immunity; secrete IgG and secIgA for antibodies.
Transforming Viral Infection
activate viral or host oncogenes, cause host DNA damage and activation of oncogenes or inactivation of tumor suppressor to cause inflammation and tumorgenesis.
what viruses are most susceptible to re-infection
local acute infections
Serotypes
a single infection that can result in a variety of syndromes - most often associated with local acute infections
Epidemic
local outbreak
Pandemic
global outbreak
Endemic
outbreak that occurs commonly and frequently in given population
Viral Gastroenteritis signs and symptoms
diarrhea, nausea, vomiting, intestinal cramps (muscle aches, fever, rarely headaches, malaise), dehydration.
Viral gastroenteritis incubation
1-2 DAYS
viral gastroenteritis duration
1-2 DAYS
site of infection for viral gastroenteritis
local inestinal epithelial cells
Viruses that cause gastroenteritis
rotavirus, adenovrius, astrovirus, norovirus
Norovirus
source is by contaminated water/food, shellfish, person to person spread and possible respiratory spread.
Norovirus incubation
15 hours to 2 days
Duration of illness of norovirus
1-2 days
Stool contaisn how many viruses - norovirus
10,000,000 viruses/ml
Infectious dose of norovirus
10 to 100 viruses
Attack rate of norovirus
up to 50% in 2 days
Examples of persistent or latent viruses
Rubella, HepC, HepB, rotovirus, herpes, papillomavirus, parvovirus
Latent virus definition
dormant state in which virus is not replication
examples of latent viruses
Herepes slimplex, EBV, HPV
Herpes virus lays dormant in..
dorsal root gangion
EBV lies dornant in..
the B lymphocytes
HPV lies dormant in..
basal epithelial cells
Hep B incubation time
60-90 days
Clinical signs of HepB
jaundice, chronic infection, incidence differs with age.
Fatality for Hep B
0.5-1% acute fatality, premature mortality due to liver disease in 15-25%
Spectrum of chronic disease with HepB
chronic persistent heptatits *asymptomatic), chornic active hepatitis, cirrohsis, hepatocellular carcinoma.
General outline of herpes viruses
Primary infection, latent period, reactivation
Structure of Herpes
Enveloped with glycoproteins, Tegument layer, icosahedral capsid with dsDNA.
What is the tegument
middle layer of herpes virus that contains proteins that control entry, gene expression and immune evasion; evasion is without cell lysis
Herpes Simplex Virus Manifestations
Painful vesicles on skin at sight of inoculation
Primary site of infection for HSV
most often silent, HSV1 is during childhood. Oropharyngeal for 1, Genital for 2
Which are more severe, primary or secondary lesion for HSV?
if symptomatic, primary.
Length of incubation time in primary HSV infection
1-3 days after exposure, if immunocompromised may spread
Secondary HSV
also known as recurrent, causes encephalitis, keratitis, mucocutaenous, labia and genitals
Latency period of HSV
inside sensory ganglia (trigeminal for Orofacial) and Sacral ganglia for Genital
What provokes reactivation of HSV?
Sunlight, stress, menstruation, immunosuppression.
Prognosis/outcome of secondary HSV infection?
more localized lesions and heal more rapidly; still infections; may even be silent (still infectious)
Diagnosis of HSV
for gum, oral, genital - clinically; but cal do a viral culture, direct IFA, PCR
Treatment of HSV
oral acyclovir for oral or genital; C-section for women with active lesions; for severe IV Acyclovir
Prophylaxis for HSV
antiviral suppression, but no vaccine
Gingiovostamitis
complication/symptom of HSV, oral secretions, mouth ulcers on lips, gums, tongue. Fever and enlarged nodes
Herpetic Whitlow
Innoculation of HSV from oral secretion onto finger - med professionals
Encephalitis
HSV complication, predilaection for temporal lobes to cause hemorrhagic necrosis, slow mental capabilities, hallucinations. Primary or reactivation
Herpes keratitis
HSV infection of cornea vie ophthalmic branch of trigeminal N. Primary or reactivation
Genital Herpes
HSV, 10-14 days duration, very painful. primary or reactivation
Neonatal HSV
Transmitted via materanal secretions of active lesion or asymptomatic viral shedding, more often primary than reactivated.
Forms of Neontal HSV
1) Skin, eye, mucous mem (SEM) 2) CNS 3) Disseminated
SEM
neonatal HSV, site of lesions, corneal ulcers, blindness
CNS - Neonatal HSV
severe encephalitis, 5% mortality with acyclovir
Disseminated HSV
neonatal HSV that is widespread - pneumonitis, hepatitis, intravascular coagulation, encephalitis, skin rash, eye involvement. Most lethal, 30% mortality with acyclovir
Varicella-Zoster Virus Transmission
Respiratory, aerosolized, lesion contact
VZV incubation
10-21 days
Symptoms of VZV
fever, malaise, headache, cough rash
Rash of VSV
vesicular of face/trunk that spreads to limbs, lesions appear in successive waves (crops). Multiple stages of lesions throughout body
Duration of VZV
1w
Pathogenesis of VZV
Respiratory entry, spread via lyphatics. Replication in lymph nodes (primary). Viral replication in liver, spleen, sensory ganglia, Secondary to cause rash
Complication of VZV
Strep, pneumonia, necrotizing fasciitis, encephalitis, encephalomyelitis, hepatitis
Treatment of VZV
self limiting, acyclovir accelerates resolution if given 48-72 hours of onset. Vircella zoster immune globulin for high risk individuals
VZV prophylaxis
Live attenuated varicella vaccine (varivax) 2 doses as 12-18 months and 4-6 years
Latency and Ractivation of VZV
latent in sensory ganglia; asymptomatic shedding DOES NOT occur ing reactivation. Leads to Herpes Zoster (Shingles in 30%)
Herpes Zoster
Singles, Radicular pain along dermatome that does not cross midline. Itchy, very painful, but heals in 2 weeks.
Complication of Herpes zoster
skin infections, Ophthalmicus, encephalitis, never palcies, Post-herpetic neuralgia
PHN
complication of things - Post-herpetic neuralgia- debilitating neuropathic pain that lasts weeks to months
Immune response to VZV
depends on cell mediated immunity - why is occurs in immunocompromised and elderly
Treatment of Herpes Zoster
acyclovir within 48-72hours and NSAIDS, steroids for PHN
Prophylaxis for HZ
live attenuated vaccine (Zostavax) for >50
Diagnosis of VZV/HZ
clinical signs; possible direct IFA, PCR, Culture
Cytomegalovirus
type of herpes that is generally asymptomatic except in immunocompromised - opportunistic infection of most organs
Transmission of Cytomegalovirus
infected body fluids, in untero, organ transplants
body fluids of cytomegalovirus transmission
saliva, breast milk, sex, blood, tears, urine
Infection rate of cytomegalovirus
high, almost 80% in >40
Pathogenesis of cytomegalovirus
infects epithelial cells in salivary and genital tract, persistent infection and viral shedding - distribution to other organs and tissues
Latency of cytomegalovirus
latent in monocytes and lymphocytes, reactivated virus occurs in urine and saliva. Usually asymptomatic reaction unless immunocompromised
Pregnancy and cytomegalovirus (CMV)
3-5% tranmission, 1/3 are infected in utero, 10-15% symptomatic
Congenital CMV
congential Cytomegalovirus that causes low birth weight, microceohaly, hearing loss, mental impairment, HPM, blueberry muffin spots, jaundice
Immunocompromised CMV
severity parallels cell mediated immunity, pneumonia, colitis, retinitis, hepatitis, encephalitis
Diagnosis of CMV
Serology IgM or IgG, culture, PCR,DFT
CMV histoloty
intranuclear inclusion bodies and intracytoplasmic inclusions
Treatment of CMV
no treatment for normal; IV gancyclovir or oral valcancyclovir for immune compromised, IV gancyclovir for congenital; high titer for CMV antibodies (CMV-IG) for pregnant and transplant patients
Prophylaxis for CMV
no vaccine, CMV-IG
Herpes viruses
HSV, VZV, Cytomegalovirus, HHV6, HHV-7, HHV8/KSHV, EBV
Influenza Virus scutures
RNA virus with segmented genome, 8 different single stranded RNA pieces, enveloped. Hemagglutinin, neuraminidase glycoproteins
Hemagglutinin
glycoprotein on influenza virus used for cell entry
Neuraminidase
glycoprotein on influenza virus used for cell except
Pathology of Influenza
binds to sialic acid, enters cells, replication, release
Type A Influenza
severe illness, epidemics and pandemics, rapidly changes in lots of aniamls and humans
Type B influenza
less severe symptomes, epidemics only, only in humans
Type C influenza
mild or asymptomatic, minimal public health impact. Only in humans
Naming of Type A
Virus Type/geographic origin/strain number/year (virus subtype)
Naming Type B
same, but lacks subtypes
Antigenic Drift
grandual minor change (point mutations) in DNA that changes hemagglutinin or neuraminidase surface antigens. Creates a new strain and cause ongoing flu vaccine changes. creates epidemics
Antigenic Shift
type A influenza virus with a completely novel hemagluttinin or neuramidinase segment introduced into humans (from other species) - due to two infections in a being. Less frequent but more dramatic impact. Pandemic
waterfowl transmit flu to..
aquatic mammals, horses, poltry, humans, pigs.
What transmits flu to humans
waterfowl, poultry, pigs
Transmission of flu
droplet, aerosols, fomites, hand and feet
how long does flu virus live on hand
5m
how long does flu virus live on cloth/paper
8-12 hours
how long does flu virus live on plastic
24-48 hours
how does flu cause symptomes
desquamation which leads to upper and lower airway inflammation, high rates of secondar infection
Flu symptoms in neonates
Fever, lethargy, decreased eating, mottling, apnea
Flue in infants/tollders
GI, fever >103, anorexia, respiratory, malaise, headache, sore throat
Flu in children/adutls
rapid onset, high fever, cough, chills, muscle aches
General drugs for flu treatment
Matrox protein inhibitors and neuraminidase inhibitors
Matrix Protein inhibitors action
diable M2 proteins to prevent uncoating useful for A viruses
Neuraminidase inhibitors action
inhibit release of visions and promote clumping, Used on A and B
Swine Flu
H1N1, started in mexico and spread around the world. Highest incidence in 5-24 years olds , then 0-4 year olds; caused Acute respiratory distress in humans
Bird Flue
domestic poultry most effected. H5N1 is high virulence in poultry and occasionally humans, high pathogenic, most prevalent in asia.
Pandemic Flu Requirements
1) new virus subtype 2) must infect humans and cause serious illness 3) sustained transmission and spread easily
Inactivated Flu Faccine
IM or ID, killed; >6 months. Trivalent and quadrivalent.
Live Attenuated Vaccine
intranasal, live, >2 years-49 years, quadrivalent.
Efficacy of flu vaccines
70-90% effective in well matched years, less for elderly (but reduction in hospitalization and death)
CDC Flu vaccine recomendations
> 6 months or older who do not have contraindications
RSV
Respiratory Syncytial Virus
RVS epidemiology
infants and young chilldren, LRI annually during winter and spring
RVS spread
large lipid droplet spread - lives on surface for 1 hour (no vaccine)
Structure of RSV
singled stranded non,segmented RSV, antigenic variablity, drift,F-protein and Gprotein
F-protein
Fusion of viral envelope to host or fusion of membranes of infected cells taught syncytia (RSV)
G protein
initial binding of RSV to host
Subtypes of RSV
A and B, A is usually worse
Pathophysiology of RSV
invades conjuctivat and nasopharynx, spreads to lower respiratory tract by inhalation of secretions. Constriction of smooth muscle bonchioles to get edema/inflammation, hypoxia, emphysema, hyper expansion by mucous plugging
RSV incubation
3-5 days
Clinical signs of RSV
Respiratory distress, wheeze/rhonchi, hypoxia, copious secretions
Testing of RSV
culture - not practial, Direct antigen detection - not sensitive, PCR
RSV Immunology
recurrent infections are common, immune proetextion is complete, drift occurs, may be associated with wheeze or asthma later in life
RSV treatment/prevention
Formalin-inactivates RSV vaccine of 60’s did not provide immunity and was worse off, new vaccines on horizaon. Palivizumab and motavizumab are prophylaxis.
Palivizumab
human pooled antibody of highh RSV titers to decrease severity and hosptializations. IM injection during season to high risk
Motavizumab
higher affinity RSV titer that binds tighter to F protein - inferior to palivizumab and very expensive
Mechanisms of Anti RSV
do not inhibit pre-fusion to hairpin formation, questionable to inhibit pre-hairpin to hairpin, confirmed inhibition of hairpin to post-fusion formation
steps in antivirals
Block attachment and entry; blocks uncoating; blocked NA syntehsis, Blocks protein synthesis and process, Blocks viral release
Pathophysiology of Influenza
Binds to airway epithelial and is endocytosed and forms endosomes. Acidified to promote conformation change in hemagglutinin to medial fusion between Flu viral envelope and endosome membrane. Proton influx through viral M2 proton channels elects RNA genome release for replication and assembly. New visions are tethered to PM via Hemagglutinin and sialic acid. Nueroaminidases cleave silica acid and release
Oseltamivir and Zanamivir- Action
Inhibition of Neuraminidiase to cleave Sialic acid to prevent egression. Causing aggregation on PM surface.; impairs viral penetrate through mucin
Types of NA inhibitors
Oseltamivir (tamiflu), Zanamivir, Peramivir
Oseltamivir resistance
rare from mutations in Hemagglutinin or NA
Pharmokinetics of Oseltamivir
Oral prodrug, eliminated as renal secretion
Pharmokinetics ofZanamivir
Inhalation renal elmination, but be over 7 YO
Pharmok of Peramivir
single IV dose
Use of Oseltamivir or Zanamivir
48 hours of symptoms to decrease severity and duration of A or B in adults and children. Can be prophylactic in contacts
Adverse reactions to Oseltamivir
N,V, headache, fatigue, diarrhea
Adverse - zanamivir
bronchospams, ough, nasal and throat discomfort
Adverse Peramivir
GI, diarrhea, neutropenia, skin reactions
Drugs that inhibit flu uncoating
Amatiadine, Rimantadine
Amatiadine and Rimatadine actions
Blocks M2 (H+) channel to prevent intracellular changes for uncoating
Resistance to Amatiadine and Rimatadine
Occurs due to muataions in M2
PK of Amatadine
Oral, excreted in urine (unchanged, requires renal function dosage change). Excreted in break milk too
PK for Rimatadine
Oral, elemianted in liver; excreted in breast milk too
Use of Amatadine and Rimatadine in flue
Prophylaxis for Flu A, give 1-2 days prior, and 6-7 durings to reduce insidence and severity. Only slightly effective after 48 hours of symptoms
AR to Adatadine
Insomnia, difficulty concentration, lightheadded, headache
AR to Rimatadine
better tolerated, poor CNS penetration
Drugs for Herpes target
DNA polymerase (viral) and penetration
Herpes mechanism
Cell attachment, uncoating, transfer DNA to host nuclei for transcription and syntethesis, Assmbly and packaging, budding
Inhibitors of Viral DNA polymerase
for herpes, most are nucleoside analogs that target viral genome replication and inative viral DNA pol and viral RT; purine and pyrimidine analogs covered to triphosphates forms by intracellular kinases
Highest degrees of selective toxicity in Viral DNA polymerase inhibitors
is due to necleoside analogs that are activated by viral kinases rather than host kinases
Types of nucleoside analogs
Acyclovir, vidarabine, foscarent, ganciclovir
Mechanism of Acyclovir
Phosphorylation of analog is mediated by viral thymidine kinase to convert to Triphosphate form. TP competes for binding with DNA polymerase and is incorporated into viral DNA strand. Termination. DNA with acyclovir TP irreversibly binds and inactivates viral DNA pol
Resistance to acyclovir
reduced expression of viral thymidine kinase, alters thymidine kinase substrate specificity, altered viral DNA pol acitvity - rare only in immunocompromised
PK of acyclovir
oral is poor (15-30%), but also available in topical or IV
PK of valacyclovir
Prodrug of acyclovir, given orally for higher plasma levels (3-5x)
PK of peniciclovir
Acyclic guanosine analog, poor oral abosprotion, topical only (better than acyclovir topical)
PK famiciclovir
pinciclovir prodrug that increase oral bioavaliability
Elimination of Acyclvir
renal, neonatal under 1 year is 1/3 f clearance
Use of acyclovir with HSV
oral shortens symtomes for primary and recurrent and reduces pain duration of recurrent labialis. Topical is not effective. good secondary prevention.
when is acyclovir HSV used?
HSV encephalitis, neonatal HSV, serious HSV or VZV infections
Treatment of VZV antivirals
oral acyclovir decreases number of lesions and duration for varicella and zoster, but higher dose required. Zoster: increases lesion healing, decreases pain, lessens incidence
AR to acyclovir
Headache, nausea, vomit, renal dysfunction.
IV acyclovir AR
tremors, hallucinations, seizures, coma (encephalopathy)
Inhbiitors of Herpes penetration
Ducosonal (abreva))
Ducosonal Mechaism
long chain sat alcohol that inhibits rep of lipid enveloepd virus and prevents fusion for viral entry.
Ducosanol PK
topical begun within 12 hours of symptomes to reduce healing time.
RSV drugs
Ribavirin, purine nucleoside analog
Mechanism of Ribavirin
not understood. Covered to TP by cellular kinases, inhibits 5’ capping of viral mRNA to decrease stability, increase viral mutation.
Resistance in ribavirin
none yet
PK ribavirin
oral, with fatty meals. Eliminated via hepatic and renal excretion. Other routes inhalation for kids
AR to ribavirin
conjuctival or bronchial irritation when inhaed, Oral: Hemolytic anemia, should not ge given during pregnancy or administered by pregnant HC workers
Use of Ribavirin
for RSV and penuomia, but only severe or immunocompromised patients
Palivizumab action
human monoconal antibody to RSV F glycoproein used for immnoprophylaxis in infants and children with heart disease. exepnsive, mostly IM
Drugs for cytomegalovirus
Canciclovir, Valganciclovir, Foscarnet, Cidofovir
Methods of treating CMV
viral DNA pol inhibition
Ganciclovir mechanism
uptake regulated by viral protein kinase UL97 (selectivity), cellular kinases convert MP to TP binds to viral DNA polymerase, terminates strand.
Resistance to Ganciclovir
UL97 mutations, mutation in viral DNA pol
PK of Ganciclovir
Poor oral, but good IV. excreted unchanged via urine
Valganciclovir PK
prodrug of ganciclovir that is converted to active ty GI and hepatic esterase’s
Clinical use of ganciclovir
CMV retinits HSV keratits in immuncompromised and for transplant patients.
AR in ganciclovir
Myelosuppresion, neutropenia, thrombocytopenia, N/D, fever, rash, HA, isnomia, GI headache, seizures.
Cidofovir
does not require activation by viral kinases, so can be used against acyclovir or ganciclovir resistant strains; nucleotide analog
Cidofovir PK
IV only, long half life, renal excretion. must be administered with probenecid to block secretion and decrease nephrotoxicity.
Cidofovir AR
nephrotoxicity, neutropenia
Foscarnet mechanism
inorganic pyrophosate analog, very unique. Does not require cellular activation. Noncompetitivey binds to pyrophosphate BS of RNA and DNA pol and inhibits cleavage of pyrophosphate from TPs to block viral replication.
Resistance in Foscarnet
alterations in DNA polymerase, combines use with ganciclovir is useful
PK of Foscarnet
poor oral, good IV. Eliminated unchanged in urine
Clinicical use of foscarnet
CMV retinitis in immunocompromised patients, used in Gancyclovir or acyclovir resistant infecitons
AR of foscarnet
nephrotoxicity, hypocalcemia, heachace, tremor, seizure.
