viruses / prions

• non-living entities as they do not have own metabolism

• dependend on metabolism of other cells, can interfere with it

• can have physiological role in supporting other cells (e.g. bacteriophages) and in regulating the coexistence of several types of microorganisms and of microorganisms and the IS

• often also part of microbioma (virioma)

• mostly found inside other cells, where the different particles of the viruses, which build the virus are distributed within the cell at different places

  -> thatwise it also escapes the IS!!!

  -> only narrow time frame to act against viruses

  -> mainly problem for adaptive IS, which needs longer time to build antibodies as it has to take up these substances in a first step

• very small!!! (ebola with almost 1 micrometer is the biggest; other viruses with 100-200 nanometers are called large (in comparison, bacteria are measured in micrometers); and some small viruses only 20nm)

  -> only seen under electronmicroscope

  -> identification not easy

1) protein coat (CAPSID)

-> the sheath that is formed around the genetic material

• symmetric and mathematically described 3d-strcts

• only small amount of cytoplasm, as capsid is almost filled up with genetic material

  -> advantage, as they are resistant against

  temperature differences

2) lipid envelope

-> from the host cell, which the virus “grabs” leaving the cell, and only adds some membrane proteins

• mostly lipid bilayer

• some don’t use lipid bilayer as protective tool

  -> NAKED VIRUSES (are rare)

3) genetic material

-> 7 different types of primary genetic material

-> classification through these different kinds

3 DNA-classes;

4 RNA-classes

-> interesting, as this does not occur in eucariotic or

procariotic cells

-> viruses can build double-stranded RNA, which is also a

unique feature

class I

• double-stranded DNA, can be used directly to be transcribed into mRNA

class II

• single-stranded DNA; has to be doubled before it then can be used directly to be transcribed into mRNA (otherwise cannot be read by host cell)

class III

• double-stranded RNA; ‘original’ strand can be used directly to be transcribed into mRNA (negative copy also produces mRNA, which will not be used further)

class IV

• positive single-stranded RNA, has to be read first, to be switched to a negative copy, which then can be used directly as mRNA (equal to mRNA)

class V

• negative single-stranded RNA -> direct use as mRNA

class VI

• single-stranded reverse transcriptase RNA, has to be converted into a single DNA or a classical RNA without reverse transcriptase first, then into a double-stranded DNA in a second step, before out the ds DNA the mRNA can be formed

class VII

• single-stranded DNA - reverse transcriptase; can be used directly but is read in the ‘wrong’ direction (from end to beginning instead of from beginning to end)

1) attachment to the host cell (via specific markers, which induce the cell to form vesicle/phagosome) and entering

2) ‘uncoating’ -> freeing of the elements of the virus, that genetic information can enter nucleus

3) reading (3a) and replication (3b) of the genetic information

4) synthesis of proteins outside the nucleus (golgi-

apparatus); golgi-apparatus induces cell membrane to build up signals (proteins, lipids), which accumulate in the region where the underneath the gen inf and coat proteins are assemblied (see 5) )

5) accumulation of the proteins in the cytoplasm

6) replicated genetic information reaches the rim

7) assembly of virion, and then separation form the host cell by using the cell membrane (for lipid bilayer envelope)

• normal prion protein (PRc) is ubiquitous present on cell membranes in our body

• made of 209 amino acids, one disulfide bond, alpha-helical structure

• ‘prion’ nowadays used for the ‘misfolded prion’ (PRsc)

• the infectious isoform is able to convert the normal protein by conformation change

• normal function: repair of neuronal myelin sheaths? support long term memory? support stem cell renewal? support innate immunity?

• replication theory:

  -> induced by the PRsc which gets close to a PRc

  • inducing the PRc directly to change into PRsc

  • producing an enzyme which stimulates the PRc to change into PRsc

• how do misfolded proteins occur?

  -> maybe by feeding non appropriate substances to animals => cows which get meat (as it has been done in the US) being herbivores

  -> maybe manipulation of plants has some impact on us humans => that we get fed with non appropriate substances which might lead to further building of misfolded prions

I - adenovirus, herpesvirus, poxvirus

II - parvovirus

III - reovirus

IV - coronavirus, picornavirus, togavirus

V - orthomyxovirus, rhabdovirus

VI - retrovirus

VII - hepadnavirus

double-stranded DNA

• adenovirus

• herpesvirus

• poxvirus

• class I virus - double-stranded DNA

• 7 species (A-G) with 88 human-pathogen viruses, with prefered cells

  -> respiratory (B + C), prefer cilia carrying epithelium

  -> conjunctivitis (B + D), prefer humid, wet condition

  -> gastroenteritis (F + G), pefer epithelial cells with

  microvili -> GI tract

  -> obesity (A + C + D)

• part of microbioma (so it’s not really sure, if they are pathogenic or just present)

• viral vector -> often used in gene therapy, lately also for vaccines,

  => good size of about 80-90nm

• one can have symptoms of adenovirus infection (variety of mild diseases; not sure if caused by AV)

8 human herpes viruses, all with large impacts on human conditions

• HHV1 (herpes simplex virus 1)

• HHV2 (herpes simplex virus 2)

• HHV3 (varicella zoster virus)

• HHV4 (Epstein-Barr virus)

• HHV5 (cytomegalovirus)

• HHV6 (roseolovirus)

• HHV7

• HHV8 (rhadinovirus)

most of them perform disease at the beginning, which will lead to a long-lasting immunity against them; but have the ability to stay in niches, mainly in neurons; so well protected from IS

-> can be reactivated!!!

• have specific target tissue where they like to stay

HHV 1 (HSV1)

• human-human transduction, also during silent time, as virions get released from time to time

• prefer trigeminus nerve in the face region; transported from the axons to the soma, where they stay and proliferate

  -> weak condition at end of nerve fibre

  • reactivation, release towards the skin, building of efflourescences (can happen again and again)

HHV 2 (HSV2)

• similar to HSV1; prefers the sacral region with sacral nervesm, which are mainly projecting towards the genital system

  -> usually sexually transmitted

  -> dependend on sexual practices, can occur also in

  face region

=> both viruses widely spread in our population

=> usually skin efflorescences

=> severe reactions can lead to encephalitis!

• children: chicken pox (varicella)

• incubation time: 10-21 days

• disease: 3-4 days

• usually performs a rush on the skin

• problem: infectious 2 days before skin lesions!

• rare complications: pneumonia, encephalitis (mainly adults, if not infected with HHV3 in childhood)

• persists in a quiescent form in neurons

• weakening of the immune system leads to reactivation

  -> shingles (herpes zoster)

  -> neural pain + skin blisters, typically dermatomal

  distribution

• vaccination (since 1995) to prevent from outbreak/

  severity of symptoms

  (so also recommended for elderly)

• KISSING DISEASE (Pfeiffersches Drüsenfieber)

• infectious mononucleosis:

  fever, inflamed throat, swollen lymph nodes, spleen,

  liver; postinfectious fatigue syndrom

• typical age: 15-24 years

• associated with lymphoma and autoimmune diseases!

• can persist in B-cells and epithelial cells

• number of lymphoma associated with HHV4 not high enough for industry to produce vaccine

two problematic conditions:

1) severe immunesuppression

-> as with HIV, organ transplants, newborns

2) infection during pregnancy of the mother (even then a

normal IS should be stable enough)

• if infection is developed and CMV is within the blood, it can pass the placental blood-barrier and infect the fetus

  => high number of severe infections of the major organs which can lead to abortion

• in newborn hepatitis, colitis, retinitis, mental disorder, etc.

=> vaccination for at-risk population?

often brought together as one virus

• also called SIXTH DISEASE

• neurovirulent group:

  increased in multiple sclerosis, Alzheimers disease

  -> discussed, if it produces these diseases as it is also affiliated to the nervous system as all HHV

• roseola (sixth disease):

  -> mainly in small children

  -> first 5 days with high fever (up to 40°; seizures!)

  -> after fever, an exanthema (rush) shows up

  immediately => EXANTHEMA SUBITUM

  -> lasts for up to three days

• only active in immunosupressed people (AIDS)

• Kaposi‘s sarkoma -> tumerous affection of the skin

• Castleman‘s disease (lymphoproliferative disease; quite similar to HHV 4)

• primary effusion lymphoma (after HHV 4, also HHV 8 can cause lymphoma!!!)

• 83 species among 22 genera

• only a small group of this viruses affect the human and lead to diseases

  -> smallpox virus

  -> vaccinia virus (leads to mild form of poxes)

  -> molluscum contagiosum virus

SMALLPOX VIRUS (and VACCINIA VIRUS)

• since 1986, smallpox virus exists only in two labs worldwide

• described since ancient times

• 16th century: inoculation in China (kind of vaccination)

• 1796: Edward Jenner introduces vaccination

• 1980: global erradication; typical example of herd immunity

• since then, vaccination has stopped; if there would be an outbreak of the virus out of the labs, that would become a major problem again!!!

MOLLUSCUM CONTAGIOSUM

• often seen in children as it is transduced human-human by smear contact

• adult: sport, (sex) -> as it likes humid conditions (change of clothes)

• very contagious! but stays on superficial skin layer, does not enter the tissue;

  -> builds molloscule like strcts (name!)

• clears up untreated within 9 months; then stable immunity -> one time infection!!!

single-stranded DNA

-> parvovirus

• single-stranded DNA

• 126 species among 26 genera

• useful vectors (dependoparvovirus)! -> gene therapy

  -> as they are very small in size (20nm)

• not problematic for humans, but numerous diseases in animals; only 2 parvoviruses with human related diseases

  -> parvovirus B 19

  -> bocavirus 1

PARVOVIRUS B 19

• infectious skin disease

  => ERYTHEMA INFECTIOSUM; FIFTH DISEASE

• incubation: 4-14 days

• prodromal (non-specific) stage: low-grade fever, headache, nausea, diarrhea

  -> at this time, the kids are highly infectious, where the skin rush is not (yet) seen

  -> facial rash ends infectious stage

  -> possible arthritis, anemia (both self-limiting, both occur with the infection and not somewhen in lifetime)

  -> one time infection, as first contact builds up good immunity

BOCAVIRUS 1

• not affecting the skin, but respiratory tract with a wheezing (Pfeifen/Keuchen), coughing, running nose or rhinorhea; or intestines with a diarrhea

• occurs more in children as adults due to better developed IS

  -> often not detected due to non-specific symptoms

double-stranded RNA

-> reovirus

• 97 species among 15 genera

• many reoviruses do not harm humans

• their role in pathology is mostly uncertain

• oncolytic properties! -> potential cancer therapists!

• two reoviruses discussed in disease conditions

  -> rotavirus

  -> orthoreovirus

• interic diseases

  -> diarrhea

  -> vomiting

  -> eventually fever and abdominal pain

  => all non-specific symptoms

• mostly seen in children between 6-24 months

• oral transduction by contaminated outer skin or tool; then can spread via the feces

• as it invades the endothelic tissue, it is self-limiting (renewal within 48 hrs)

• severe diarrhea can lead severe dehydration and therefore to other symptoms

  -> until risk of death!!!

• oral vaccination for small children; no revaccination necessary

• also in discussion to induce enteric diseases

• similar to adrenovirus mimics a lot of different diseases

  -> upper respiratory tract infection

  -> gastroenteritis

  -> biliary atresia

  -> hydrocephalus

  -> jaundice

  -> conjunctivitis

  => many asymptomatic infections

• morphologically has a nice appearance

  -> used as a research model

single-stranded RNA

• coronavirus

• picornavirus

• togavirus

• single-stranded RNA

• ubiquitous existing

• 4 species responsible for human conditions as common cold

  -> non-specific symptoms in the upper respiratory tract, mild fever, headache…

• three types responsible for more severe conditions

  • SARS-CoV1

  • MERS-CoV

  • SARS-CoV2

spike protein (S) -> sticks out, gave the virus its name

membrane protein (M)

nucleocapsid protein (N)

envelope protein (E)

• spike protein is the problematic part, since it is very similar to other proteins of eucariotic cells

  -> body could react against own body cells due to

  theses similarites => autoimmune disease

• due to single-stranded RNA switches easier (as seen in pandemic; first very virulent, later lost that high virulency and adapted to the environment)

• not restricted to the upper respiratory tract, can also reach the lungs, lead to an inflammatory reaction which forms a lung disease (which the physician in China then realised)

  -> from the lungs can enter the blood system, and can affect:

  • the muscles (skeleton and heart m.)

  • nervous system (brain stem)

• single-stranded RNA

• oncolytic properties, therefore of high interest in research

• 4 groups with affection to the human system

  1) enterovirus (poliovirus/rhinovirus/coxsackievirus/

  echovirus)

  2) aphthovirus (FMDV)

  3) cardiovirus

  4) hepatovirus (HV-A)

• class IV viruses

• part of picornaviruses

• present in the enteric system, from the gut they develop their fct

• 4 subgroups

  1) poliovirus

  2) rhinovirus

  3) cosackievirus

  4) echovirus

• class IV virus - single-stranded RNA

• picornavirus > enterovirus > poliovirus

• usually oral upatake

• replicates in the epithelium of small intestine

  -> in the first stage non-specific symptoms such as

  fever, nausea, headache

  -> from there enters the tissue and reaches the blood

  via the lymphnodes => distributed in t whole body

  -> most dangerous site => CNS (esp. spinal cord)

  • destroys nervous fct, leads to a paralysis

  • loss of contact of the nervous system with the skeleton muscles (mainly arms and legs)

    => poliomyelitis

• oral vaccination possible as it enters the intestines

• almost erased -> 2022 only 30 cases worldwid

• class IV - single-stranded RNA

• picornavirus > enterovirus > rhinovirus

• responsible for the common cold

  -> with coughing, sore throat, running nose, fever

  -> in 80% of common cold infections, rhinovirus is

  detected

  => comes - stays - goes

• socially important

  -> main reason for work incapacity!!!

• class IV - single-stranded RNA

• picornavirus > enterovirus > coxackievirus

• two different types with quite an impact on human health

  1) COXACKIE A VIRUS

  2) COXACKIE B VIRUS

COXACKIE A

• really severe infection of the throat -> hepangina

• can lead to hemorrhagic conjunctivitis

• HAND-FOOT-MOUTH-DISEASE

  -> can spread to the palm, to the foot and within the

  oral cavity

  -> only symptomatic medication, IS is able to cover

  the virus

COXACKIE B

• more aggressive

• infections include:

  -> heart muscle cells (myocarditis+ pericarditis)

  -> hepatitis

  -> pancreatitis

  • leads to a disturbance and destroying of the beta-cells of the langerhans islets

    -> causes diabetes type I

  • as the virus does have the ability to mimic some surface elements of the beta-cells in the langerhans islets, there is an autoimmune reaction -> antibodies act against the beta-cells

• class IV - single-stranded RNA

• picornavirus > enterovirus > echovirus

• enteric symptoms are predominantly present, but can also cover respiratory part

  -> coughing but even skin affections can appear

  -> one side effect might be the infection of the sheath

  of the brain => meningitis

• mostly self-limiting and asymptomatic

• class IV - single-stranded RNA

• picornavirus > aphtovirus

• mainly a disease in animals

• foot and mouth disease

• class IV - single-stranded RNA

• picornavirus > cardiovirus

• can lead to

  -> myocarditis

  -> can involve the brain and the nervous tissue

  => encephalomyocarditis

  -> is discussed if destroys also beta-cells of

  langerhans islets and leads to diabetes

• very similar to coxackie B virus

• class IV - single-stranded RNA

• picornavirus > hepatovirus (HV-A)

• distributed around the world, mainly around the equatorial region (warmer countries with higher infection rate)

• fecal-oral transmission

  -> hygienic standard

• symptoms: fatigue, fever, nausea, jaundice, diarrhea

  -> mainly dsyfct of the liver => hepatitis A

• vaccination since 1992:

  especially for children, exposed travellers

• class IV - single-stranded RNA

• togavirus > chikunguna virus

• in small regions in France and Italy; mainly in africa, south and north america, in china and asia

• non-specific symptoms:

  -> headache

  -> chilling

  -> nausea

  -> joint pain

  -> fever

  -> back pain

  -> vomiting

  -> eventually a rash on the skin

• most of infections human-human,

  but can also be spread from mosquitos (or to humans or to animals - wild/domesticated) and other animals

• hard to erase it

• negative single-stranded RNA

• orthomyxovirus

• rhabdovirus

• among them INFLUENZA virus

• classification always starts with virus type

  -> besides this, it gives the origin

  -> then strain number

  -> year

  -> subtype (like with neuraminidase and

  hemagglutination)

• as single-stranded RNA virus, no control mechanism, and variations easily possible

  -> switches often

  -> vaccinations have to be adapted each season; only to prevent severe forms, not possible to prevent influenza at all; yearly revaccination necessary

• why so effective?

  -> enzymes have ability for hemagglutination or neuraminidase activity, which increases the ability of the virus to survive and to interact with the host cell and to produce different kinds of pathologic infection types

• severity depends on immunological stage of a person and age

• symptoms:

  -> mainly respiratory system with running or stuffy nose, sore throat and aches

  -> able to enter the body, then can affect

  • brain with headaches and fever

  • muscular system with tiredness of muscles, aches

  • joints

  • gastroenteric system with vomiting

• cycle

  -> up to 4 days of incubation time

  -> peak of symptoms around 6-9 days

  -> two whole weeks needed by IS to cover it

  completely

• negative single-stranded RNA

• two viruses with really an impact on the human due to toxin production

  -> rabiesvirus

  -> vesiculovirus

RABIESVIRUS

• distributed in nature, in different animals

• transmission through bite of infected animal, as distribution of virus in the body is within the saliva; mainly dog bites

• enters the nervous system and disrupts major fct of the nervous system (CNS)

  -> animals lack normal fear mechanisms, are rather

  aggressive and attack

• no local reaction at the site of the bite; takes days up to weeks until symptoms of rabies encephalitis starts

  -> so enough time for the IS to act against the virus

  -> IMPORTANT ISSUE

  => vaccination effective also after exposure to

  prevent encephalitis (if diagnosed correctly); in

  doubting, better one more than one less, because

  of time dependency

• if encephalitis starts, only way to start the therapy

  -> artificial coma, and then wait until the body and the

  nervous system have reacted against the virus and

  stopped the viral disease

  => CRITICAL POINT

  • number of side effects of artificial coma

  • lethality after contact very high

VESICULOVIRUS

• affects also the nervous system and leads to an encephalitits

• symptoms and therapeutic strategies similar

• but not globally spread

• single-stranded reverse transcriptase RNA

• human T-lymphotropic virus (HTLV)

• HIV-1

• HIV-2

research found that there are numerous retroviruses in our bodies; they can modify the genome; estimation says that 5-8% of the human genome consists of this retrovirus information

not known, in what way exactly the affect the body….

• single-stranded reverse transcriptase RNA

• transmission:

  -> breast feeding

  -> sex (male to female)

  -> blood

• direct reaction

  -> cardiovascular system

  -> dermatological and respiratory elements

• later stage

  -> digestive system: stomach, liver, group of

  immunological lymphnodes

  -> genital tract, mainly the cervix in woman

• association with cancer development in these sites is known

• single-stranded reverse transcriptase RNA

• transmission:

  -> sex and blood (placenta is a barrier)

• very high affiliation to the CD4+ cells (t-helper cells)

  -> interferes with the immunological response, leads

  to dysfct of the IS

  -> during time, the numer of CD4+ cells decreases

  and weakens the immunological response until

  high immune deficiency

  => these secondary diseases are the problem and

  mostly long-lasting

AIDS

• secondary infection with variable symptoms

• in the beginning it was a lethal disease, but nowadays, with more understanding of the virus and new therapeutic strategies, many people live with HIV/AIDS; no longer life-limiting disease, but still no curative disease

• single-stranded DNA - reverse transcriptase

• hepatitis B (only virus in this group)

• single-stranded DNA - reverse transcriptase

• one virus with a very rare combination of DNA

• very aggressive in the human system

• transmission by body fluids

  -> blood

  -> via sex

  -> saliva of infected people

• vaccination since 1982

  -> very effective as no other sources as humans

  -> does not only stop the outbreak within the person

  but also stops transduction to other persons

• one of the most dangerous viral liver diseases

• three major antigenic elements

  1) HBs

  2) HBe

  3) total HB core

  => HBs and HBe can be seen quite rapidly