Organ Tissue infections Flashcards
Hepatovirus A (HAV)
STR:- icosahedral,naked,27nm ss+RNA class IVa FGV- Picornaviridae (non-lytic), heparnavirus, Hepatovirus A.
VPg is attached to the 5’ end of of RNA, replicates in Kupffer’s cells and hepatocytes without much pathology.
stable withstands heating and disinfectants stomach Ph, salt water, solvents and detergents
Sensitive to Chlorine and Formalin, UV light.
Route- Fecal Oral, food or water, under-cooked meat, shellfish, oysters clams. Blood, maybe sexual. usually from water, restaurants and daycare centers.
Incubation- 15-40 days(short) Shedding in feces before symptoms appear, stops before cessation of syptoms, 2 weeks viremia with possibility of blood borne infection. Recover complete in 8-12 weeks.
Symptoms- abrupt, fever, nausea, vomiting jaundice(due to necrosis) most pediatric cases mild and undiagnosed. doesn’t initiate chronic infection or liver cancers
Diagnosis-detection of antibodies by ELISA- no virus isolation
Treatment/Control- Passive immunoglobulins in severe cases. sanitation, hygiene, hand washing, vaccination(inactivated vaccine)
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Hapatitis B Virus
Structure– 42nm, spherical, complex protein envelop, partial ds DNA
Replication: core enters hepatocyte with coat outside–>DNA released from Core. –> viral enzymes compelte circular dsDNA–> DNA moves into nucleus–> Transcription of DNA into many species of mRNA and one full length pre-genomic RNA–>All RNA moves back into cytoplas–> mRNA translate viral structural/nonstructural proteins(RT)–> iral core assembled with pregnomic RNA and RT inside–>
RT (Viral coded DNA polymerase) changes into DNA-RNA hybrid–> RNase H of RT digests RNA to leave nucleotides as primer. DNA polymerase portion of RT makes complimentary strand. –> no space for RT to complete two strands of DNA–> core gains coat and moves towards cell membranes.
FGV- Hepadnaviridae, Orthohepadnavirus, Hepatitis B virus (HBV
Route- zoonotic-Chimps. (other members of families can infect)ducks, woodchucks, ground squirrels. Blood borne, serum (needles syringes). Oral and sexual transmission. Chornic carriers and IVDAs- major source.
Incubation- 50-180 days. ,
Symptoms: Fever, rash, and arthritis begin insidiously with variation in severity, mild cases are anicteric duration rarely over 8-10 weeks. Mortality 1-2%
Acute: Jaundice, dark urine, pale stool, nausea
Chronic- result of limited cell mediated immunity- infected cells survive can turn ito fulmiinant hepatits(w/HDV), Primary hepatocellular carcinoma, Cirrhosis.
Chronic Persistent and Chronic active can lead to Polyartheritis Glomerulonephritis.
- viremia starts 1 month before symptoms,
- viral shedding happens after 1 month.
Diagnosis: Dane particles and viral surface antigen in serum
If they have both anti HBs and anti-HBc then the person has recovered from the infection.
During latter half of incubation period Urine, semen, vaginal secretions, breast milk, feces, and nasopharyngeal secretions contain HBs Ag present for 6 months, greater than 6 months means chronic
Major determinants of acute and chronic hep B virus infection.
presence of Cell mediated immunity leads to acute Hep B due to cel damage, will have jaundice, dark urine, pale stool, nausea, the person usually recovers
if there is limited CMI then it will lead to the chronic disease- this means that some infected cells survive.
- if there is a superinfection of HDV it will lead to fulminant hepatitis
- can lead to primary hepatocellular carcinoma
- can also lead to cirrhosis.
Clinical outcomes of acute hep B
acute hep B can lead to complete resolution in 90% of cases, fulminant hepatitiis(with HDV infection or 10% will go to chronic if you see HBsAG for more than 6 months
If you have HBsAG for more than 6 mopnths it can lead to complete recovery, they can be asymptomatic carriers or they can become chronic active or chronic persistent.
Chronic persistent leads to polyartheritis glomerulonerphirits
chronic active leads to polyartheritis glomerulonephritis, liver cirrhosis or hepatocellular carcinoma
Infection cycle of HBV
HBV enters the blood, antibodies neutrilize the virus and attempt to prevent disease and spread, the virus goes to the liver,
In the liver it can have:
antibody response- this leads to immune complexes and type III hypersensitivity
Cell mediated response can lead to cell damage, symptoms, resolution or viremia,
with viremia it enters the blood, breast milk, saliva, semen, vaginal secretions.
Unique features of Hepdnavirdae( HBV included)
- glycoprotein coat
- partialy ds circular DNA
- replication through circular RNA intermediate
- associated with RT
- surface and core antigens share sequences but have different IN FRAME start codons
- strict tissue tropism (Liver)
- Genome can integrate into host chormosome.
- infected cells release HBsAG particles lacking DNA
Heb B antigens
Surface antigens- HBsAG-
- start showing at around 1 month, is what the vaccine has. during 5th month there is a window period where there is no HBs or anti-HBs antigen. this is because Hbs and anti HBS are equal.
- if anti Hbs is detected, it means acute infection , if HBs is longer than 6 months, it is in a chronic state.
- used to investigate nosocomial infection.
- detected in large quantities (sometimes clogs vessels) in infected serum, PLEOMOROHIC in shape, found in a small 22 nm from and a filamentous form of up to 700 nm
- S, M, &L glycoproteins with a common c- terminal AA sequence.
- S-glycoprotein is associated with the 22nm particle. all S,M,L, are contained in the FILAMENTOUS form,
- L-glycoprotein- in the attachment protein and also binds the envelope to the core,
- most useful marker group sp. a type sp. (d,y,w,r)
- 8 subtypes have been identified as adw, ary, adr, ady,etc
Soluble antigen- HBeAG
-shows for 2 months starts 1 month before symptoms.
associated with REPLICATION- high HBV titers, indicates infectivty becasue it indicates ACTIVE virus. every secretion of body is infective. THis means that the virus is replicating.
CORE antigen- HBcAg
starts showing at 2 months and continues, must ask for anti HBc everytime.
-observed in infected heptocytes,
- has protein kinase activity,
- very highly immunogenic, so you won’t find free HBcAG inthe serum.
- you will find the ANTI- C body first, it is the first to rise in the serum in an infection.
Acute hep B antigen amounts over time
HBs starts at 1 month, continues down until 5months, where it has window period then goes down again
anti HbC starts at 2 months, and goes up continuously and then tapers off after about 9 months
anti Hbs starts a little after HBs and goes up until window period and then continues upward.
Development of chronic HBV carrier state
viremia continues for years(virus alway sshedding, symptoms go away after 6 months, , both HBs and HBe detected for years, Anti Hbc always present. NO WINDOW period.
HBV virus persistence
5-10% continue to have HBsAG in serum for life, 8-10 % carry high concentrations of Dane particles
- all carriers ahve anti HBc and some anti HBe, those without anti HBE have high levels of circulating HBe,
- chronic active infection correlates with hepatocellular carcinomas- exact mechanism unknown but cells obtained from liver contain HBV DNA
Proposed mechanisms of oncogenicity
Virus DNA attaches next to a vrial growth gene dna- cis,
Viras DNA attaches farther away from viral growth Gene, -trans
Constant activation because of growth promoters have been activated.
Control of HBV
screen of all blood for HBs and use both inactivated and recombinant subunit HBs vaccines for high risk individuals.
Hep C virus
enveloped wtih icosahedral nucleocapsid
- flavivirus, 40-60 nm in diamter
- SS+ RNA
- INFECTS humans and chimps, hepatocytes, CD81 and lymphocytes are susceptible to infection.
TRANSMISSION- by sex or IVDA
- INCUBATION PERIOD is 40-120 days,
- MAJOR LAB VALUE is high ALT value
- COMPLICATIONS half of the post transfusion patients develop chronic liver disease and many develop cirrhosis and HCC(Types 1b, 2 a/c)
-Continental prevalence- Americas- 1a, 2b - europe- 1b, 2b, 2c -Aftica- 4c, 5a, Asia- 1b, 2a, 3a, 4a, 6a, 7a, 7b, 8a, 8b, 9a, 10a, 11s, Australia- 1a, 3a
PATHOGENESIS- coats itself with LD and VLD lipoproteins and utilizes the hepatocyte cll receptor to enter into the cell
- virus buds into the ER and remains there
Virulence Factors- inhibits apoptosis and INF alpha by binding to TNf receptor and protein kinase R, to establish persistence.
- HCV core leads to marked cell proliferation through Wnt/Beta-catein dependnet pathway.
- nuclear accumulation of beta catenin activates Cmyc, cyclin D and WISP-2 genes which dictate cell proliferation.
- core proteins decrease the amount of cyclin dependent inhibitor -21 WAF1 through inactivation of -53
- this results in imbalance between cell proliferation and apoptosis, contributing to malignant cellular transformation leading to cirrhosis and primary HCC.
OUTCOMES- depends on complex virus host interactions.
- Quasispecies- complex of genetic variants within individual viruses.
- host factors- sex, initial immune response, presence of virus specific neutralizing Abs, host genetics (strongets factor- polymophism in IL28B gene, involved in virus clearing.
acute infection of Hep C- only 15 % have complete recovery
- 70% persistent infections which can become chronic infections or asymptomatic infections . Chronic infectiosn can lead to liver failure, HCC and cirrhosis.
- more persistent than Hep B because of it’s evasion techniques.
IL28 B genotype
active normal gene leads to icteric, or non icteric virus clearance
inactive or altered gene icteric leads to virus clearance( is due to cell necrosis, nonicteric leads to little or no virus clearance- leads to chronicity and HCC
HCV persistence
virus damages the hepatocyte, cells recognize the damage and recruit proteins to eliminate the damaged area
- the virus stimulates the production of Drp1 that induces viral damaged mitochondria to undergo assymetric fragmentation. This results in one healthy mito and one damaged mito, the damaged mito is quickly broken down and dissolved in the cell cytoplasma
- fragmentation excises the damaged area from the mitochondrion however the ehalthy mito is necessary to keep the virus infected cell alive, so the viru sutilizes the mitochondrial remains to help fuel its continue replication and virulence.
higher DRP1 also produce less interferon so less likely to undergo apoptosis,
HCV control
no vaccines, prescreening of blood donors,
treatment use PEGylated interferon Alpha, genotypes 2 and 3 respond better than 1b to the this therapy, you can also use small molecule protease inhibitors like boceprevir and telaprevir also ribaviron.
Combined oral therapy- Daclstavir afects viral NS5A (no enzymatic activity- inhibits viral RNA synthesis and viral assembly secretion
-sofosbuvir is a nucleotide analogue uridine, binds to highly conserved active site of NS5B (HCV polymerase), causes chain termination.
