MCB 55 Part 2 Viruses (1) PDF

Lecture 14: A deep dive into the word of viruses Zoonosi Forever Viruses Viruses and cancers Viruses outnumber cellular life ○ They comprise the greatest biodiversity on Earth ○ Estimated that they are 1 x 10^31 viruses on earth Enough virus...

Lecture 14: A deep dive into the word of viruses Zoonosi Forever Viruses Viruses and cancers Viruses outnumber cellular life ○ They comprise the greatest biodiversity on Earth ○ Estimated that they are 1 x 10^31 viruses on earth Enough viruses to assign one to every star in the universe 100 million time over 95% ocean biomass is microbial ○ about 20%of ocean microbes are destroyed each day by viruses ○ Major players in carbo/oxygen cycles taht reguylate our atmosphere ○ The bacteriophages that infect vibrio cholera may be an important factor in regulating cholera outbreaks and apndemics. Viruses can infect all types of life forms ○ animal , plants, microorganisms (including bacteria and achara) ○ Every living organism studied to date has at least 1 virus associated with it. A long history of coevolution ○ Our genome is 8% ○ Syncytin - 1 An endogenous retroviral envelope protein Retained its original fusogenic properties Participates in trophoblast fusion and the formation of a symptom during placenta morphogenesis. ○ Tobacco Mosaic disease, a mysterious infection  1892 - the agent is capable of permeating porcelainChamberland filters, something which bacteria could never do. The electron microphotographs of tobacco mosaic virus was the first virus to be visualized by Wendell Stanley ( as in Stanley Hall) What is a virus ○ An infectious obligate parasite comprising genetic material (DNA or RNA) surrounded by a protein coat and/or an envelope derive form a host cell membrane. A virus is an organism with tow phases ○ virion ○ Infected cell Stages of viral infection ○ attachment ○ Penetration ○ Uncoating ○ Replication ○ Assembly ○ Release Hundreds of progeny visions can be produced from a single infectious virus particle. Viruses have about 1 million times less genetic information than the genomes of most plants and animals they infect Viruses tend to mutate a lot ○ The red queen hypothesis ○  ○ Viruses must do a LOT with only a little bit of genetic information ○ Take over cellular machinery and redirect it to mass-produce the viral proteins and replicate the viral genomes… ○ Avoid eradication by the immune system ○ Keep the infected cell alive long enough to complete its replication cycle Viruses are important to the study of molecular and cell biology as they provide simple systems that can be used to manipulate and investigate the functions of cells ○ Tumor suppressors ○ Proto-oncogenes ○ How DNA is replicated ○ How our genes are expressed ○ Vaccines ○ Splicing ○ Gene therapy ○ CRISPR Not all viruses bad? ○ IN mammals Bacteriophage shape gut microbial composition Hepesviruses provide protection against listeria infection Lecture 15: Zoonoses Zoonosis (singular) Zoonoses (plural) ○ Zoonoses refer to infections diseases that are transmissible from vertebrates animals to humans under natural conditions.  ○ The event in which a pathogen jumps from animal to human or vice versa - is called a zoonotic spillover, or simply a spillover Zoonoses represent a major public health problem worlwide ○ 60% of known infectious diseases in people are spread from animals Significant morbidity and mortality Impact on regional/global economies Zoonotic pathogens can: ○ Be stably established in animal populations ○ transmit from animals to people little or no subsequent person to person transmission. ○ Spread efficiently between people once introduced form an animal reservoir, leading to epidemic or pandemic Zoonotic Transmissions ○ Fecal Oral ○ Inhalation ○ Vector transmitted – mosquitoes and ticks ○ Penetrating wounds rabies virus ○ Contact with body fluids Reverse Zoonoses ○ Transmission of SARS-Cov-2 in free ranging white-tailed deer in the US Nipah virus ○ Endemic to fruit bats Live in southeast asia The virus does not affect them, but they carry it though their bodily fluids like saliva or urine. The disease ○ Most cases are symptomatic ○ Nipah virus infection often causes several rapidly progressive encephalitis which migh have a delayed onset or relapse months or years after initial infection ○ Some people with Nipah virus infection have respiratory involvement or respiratory illness alone, which can lead to acute respiratory distress syndrome. Contaminated food ○ The virus can spread through consuming contaminated food or fruit products such as raw date palm juice. Close contract ○ The virus can spread through close contact with an infected person’s body fluids, such as saliva, urine, blood, or feces ○ Can happen when caring for an infected person or when someone is near an infected person Frequent outbreaks of Nipah virus in India Some of the factors that influence spillover events ○ reservoir host identity  Hantavirus are a family of viruses that can cause serious illness and death. Spread mainly by rodents Eliminate or minimize contact with rodents to reduce risk. ○ Reservoir host distribution Geographic range overlap Consumption of meat from wild species Travel ○ Animal host associated factors The role of bats as reservoirs of multiple viruses is due to the capacity of the immune system of these animals to deal with a wide variety of pathogens? The ecological habits of animals, and domestic livestock animals ○ Human host associated factors Immunological factors Genetic factors Behaviroal factors ○ Phylogenetic distance between host species Risk of spillover is higher among species with greate phylogenetic proximity (closer in evolution) ○ Characteristics of pahthogens Generalist pathogens as opposed to specialist with their ability to inject a broad host range More able to jump the barrier between species Different viral taxonomic groups have varied zoonotic potential Resistance of the pathogen in the environment. ○ Environmental factors The loss of biodiversity is associated with the emergenc e and spread of infectious diseases Change in land use Global warming (environmental factors the modify the behaviors of hosts as well as viability of pahtogens) Lecture 16: Zoonosis (continued) Animal Reservoirs of zoonotic pathogens ○ Many different viral families are found in bats most dont appear to make them sick What’s so special about bats? ○ Second most diverse mammalian order on Earth after rodents and they are gregarious (living in flocks or loosely organized communities.) ○ Large population sizes could sustain acute immunizing infections ○ Select for viruses that can adapt to novel hosts environment  ○ Interaction with human is frequent Peridomestic habits Bushmeat Deforestation ○ They have a relatively long lifespan for their body size (3-10x’s longer than equivalently sized mammals Facilitate viral persistence for chronic infections? ○ They fly long distances ○ Allow dispersal over long distances Special immune system in bats ○ The classical pathology caused by strong activation of the immune system in response to viral infection that is seen in humans (cytokine storm) does not occur in bats Weakened DNA sensing Some aspect of their innate immune system is always turned on Bats are not enemies ○ Bats provide considerable ecosystem services Pollination Arthropod suppression Seed dispersal Most animal viruses are not able to replicate in the human body ○ Human exclusive ○ Transmissible between humans ○ Replication competent in humans What are the obstacles to overcome to replicate in a new host ○ Two main ones A virus needs to interact with many different cellular proteins to enter a new cell and replicate A virus needs to evade immune responses of the host ○ Once inside a host, replicationg and spreading is a complex process for a pathogen Attachment Penetration Uncoating replication Assembly Release ○ Viruses exploit host cell machinery for all aspects of their manipulation Animal viruses will replicate in humans only if they interact with the proteins that are useful to them Viral Sensing ○ Cells monitor their extracellular space and intra cellular space for the presence of atypical necleic acid (the wrong location or unusual structure associated with viral infection.  ○ The interferon pathway play a critical role in the control of viral infections ○ When a cell is infected by a virus, viral PAMPS are recognized by specific receptors. ○ Initiates a cascade of events that results in infected cells releasing a small set of molecules called interferons (IFN). ○ Cells exposed to interferon will start making many proteins whose function is to combate viral infections. ○ Restriction of viral life cycle by different ISGs ○ Many viruses in humans are able to evade IFN response, and is rendered useless ○ To replicate withing a host, viruses need to inhibit the IFN response Hiding dsRNA is one strategy used by viruses to prevent being detected and eliinated ○ Often pathogens must adapt ot successfully infect a novel host Use different cell surface receptors Escape a novel tupe of immune response Ensure they are transmitted by the new host ○ Among the pathogens RNA viruses might be the most likely to be associated with spillover events High mutation rates High multiplication rates. ○ Disproportionate nimber of new zoonosis are being caused by RNA viruses Exceptionally shorter generation time and faster evolutionary rates Lecture 17: Coronavirus The human coronavirus ○ The 3 highly pathogenic viruses (all causing severe respiratory syndrome) SARS CoV1 MERS CoV SARS CoV2 ○ Four human coronaviruses (mild upper respiratory diseases in immunocopentent hosts) HCoC - NL63 HCoV - 229E HVoV-OC43 HCoV-HKU1 Coronavirus - Name ○ Coronavirus (CoV) A large family of viruses that cna cause disease in humans an danimals ○ SARS-CoV-2 (Severe Acute REspiratory Syndrome Coronavirus Disease) The strain of virus causing the current pandemic ○ COVID-19 The set of symptoms caused by SARS-CoV-2 ○ Corona Latin for crown Coronavirus structure ○ The Spike and ACE2  ○ The intial week ○ The virus finds a welcome home in the lining of the nose where the virus finds cells expressing ACE2, the cell surface receptor ○ Once inside, the virus makes myriad copies of itself and invades new cells. ○ As the virus multiplies, an infected person may shed copious amounts of it especially during the first week ○ Symptoms may be absent at this point or develop a feverm dry cough, sore throat, loss of smell and testm and head and body aches. The lungs ○ If the immune system doesnt beat SARS CoV-2 during initial phase, the virus goes down the windpipe into the lungs, where it can be harmful. ○ The thinner distant branches of the lung’s respiratory tree end in tiny air sacs called alveroli. Each alveroli is lined by a single layer of cells that are also rich in ACE2 receptors. ○ Normally oxygen crosses the alveorli into the capillaries Capillaries are tiny blood vessels that lie beside the air sac The oxygen is carried to the rest of the body The Pneumonia ○ The virus replicate the alveoli. Dying cells release inflammatory cytokines and other mediators  Viruses are sensed by immune cells which release inflammatory cytokines and chemokine. ○ This leads to the recruitment of more immune cells that target and kill virus-infected cells. Leaves a stew of fluid and dead cells - pus - behind ○ This is the underlying pathology of pneumonia - with corresponding symptoms Fever Coughing Shallow respiration] ○ ○ Some COVID 19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs. Acute respiratory distress syndrome ○ Other people deteriorate, often quite suddenly Develops a condition called acute respiratory distress syndrome (ARDS) ○ Oxygen levels in their blood plummet and they struggle ever harder to breathe ○ On x- rays and computed tomography scans, their lungs are riddled with whit eopacities where black space (Air) should be ○ Many end up on ventilators and a lot of them die ○ Autopsies show their alveoli became stuffed with fluid , white blood cellsm mucus and the detritus of destroyed lung cell ACE2 is expressed thoughout the body ○ Does that accounts for some of the symptoms observed in COVID-19 patients? ○ Order of infection Nasal Initial infection Spread Loss of smell? Lung pneumonia ARDS Heart  Direct infection and inflammation? Lack of oxygen? Formation of blood clots? Ileum Gastrointestinal sumptom Virus cna be shed in feces Get to know EBMUD’s wastewater treatment plant! Concentration of SARS CoV-2 in Wastewater Samples ○ ○ Studies have shown that both sumpomatic and asymptomatic patients infected with SARS CoV-2 shed the virus in stool. ○ Can use the watewater to monitor and use as an early warning of future COVID outbreaks A delicate balance ○ Between viral response phase and host inflammatory response phase ○ ○ Anti virals +Monoclonal antibodies vs Anti-inflammatory drugs Lecture18: SARS CoV-2- COVID was sequenced in about 5 weeks Cumulative confirmed COVID-19 cases  ○ The toal number of confirmed COVID-19 cases globally has reached over 700 milllionst ○ There have bene reported 7 million confirmed COVID induced deaths worldwide. 19-36 million deaths likely COVID induced deaths are taken in account ○ The US only has 4 % of population but 15% of COVID cases COVID-19 Hospitalization and Death by age compared to 18-29 years ○ Way more likely to dies form covid when older ○ Long standing systemic healht and social inequities have put many people from racial and ethnic minority groups at increasesd risk ○ Risk for hospitalization if you have any other underlying conditions and get COVID 19 Asthma Hypertension Obesity Chronic kidney disease Long Covid ○ Long cvid is defined as a chronic condition that occures after SARS CoV-2 infection and is present for at least 3 months ○ Long COVID includes a wide range of symptoms or conditions that may improve, worsen or be ongoing. ○ The incidence is estimated at 10-30% of non hospotalized cases ○ 50-70% hospitalized cases ○ 10-12% of vaccinated cases SARS CoV-2 Vaccines ○ Pfizer mRNA vaccine ○ Johnson & Johnsons ○ Human adenovirus ○ Sinovac and Sinopham Inactivated /killed SARS CoV2 virus ○ Approximatedly 14 billion doses of COVID 19 vaccine have been adminitered worldwide ○ Vaccination have prevented 15 to 20 million death worldwide in one year In Vitro Transcribed mRNA is formulated into lipid nanoparticle using a cell-free production pipeline ○ Seqience design ○ In vitro transcription ○ Purification ○ mRNA +Lipids ○ Nanoprecipitation ○ Filtration ○ mRNA Vaccine COVID vaccinee ○ Injected mRNA vaccines are endocytosed by antigen presenting cells.  ○ After entering the cytosol, the mRNA is translated into protein by ribosome. ○ The translated antigenic protein stimulates the immune system. Neutralization by antibodies ○ Is done faster with the vaccines RNA from viruses are recognized by innate sensors and elicit the release of cytokines. A vaccine in a year ○ Coronaviruses were already a concern ○ The technology was ready ○ Worldwide collaboration ○ Funding for COVID19 vaccine research ○ Close collaboration between pharmaceutical companies and governmental agencies ○ Very high infection rate in the population and no difficulty recruiting volunteers. Lecture 19: Rabies Rabies have been around since a long time ago Origins of Rabies ○ 2300 BC first written record of rabies causing death in dogs and humans. ○ AD 79: Pliny the Elder includes in a alist of rabies cures, a recipe for inserting the ashes from a biting dog’s tail into the wound ○ 1753: first documented case in the US ○ 1804: recognized as an infectious disease ○ 1885: first Rabies Vaccine by Pasteur ○ The infection would affect your spinal cord Rabies ○ Rabies is cause by the rabies virus Type species for the Lyssavirus genus in the Rhaboviridae family Rabies virus is an enveloped, RNA virus with a helical capsid Rabies can be from cat, dogs, raccoons, bats ○ They originate form teh lyssavirus carried by other animals ○ Form the genus lyssavirus Lyssa is derived form the greek word for “rage” and “fury” Transmitted by rabid animals Saliva Biting 60,000 people that die from rabies each year ○ All mammals can get rabies mammal s which are not carnivores could get rabies Much rare Small rodents liek squirrels and rabbits are rarely carrying the virus Non mammal pets never transmit rabies Transmission  ○ Virus cann enter intact skin ○ Transmission is almost always a bite ○ Non bite transmission Saliva from a rabbit animal comes into contact with someone’s mucus membranes or fresh skin lesions ○ Rare Inhalation of virus containing aerosols Human to human transmission through transplantation ○ Number of deaths from Rabies 55000 death worlwide Many of them in India ○ Have been trying to control it. 98% are caused by dog bites Indian vulture crisis ○ India had a lot of vultures ○ Many of the cows that died were left in the streets and fed the vultures ○ Now, barely any vultures inhibit india This is because of widespread use of drugs like diclofenac, s nondteroidal anti-inflammatory drug (NSAID) commonly given to livestock ○ The loss of vultures caused an increase in feral dogs Grew from 5 million to 38 million dogs. cause d estimated 47000 more deaths from rabies 40-60% of animal bites occur on children ○ Due to short stature, they are susceptible to bits on face ○ Children are more likely to play with animals in open streets ○ Children cannot ward off animals as easily Control of animal vectors is the primary strategy for the prevention of ravies in humans. ○ Management of stray dog populations Vaccination Neuter the dog before releasing Rabies rates ○ In 1938, msot cases of rabid animals reported were domestic, and some were wild ○ Now, it is reversed. Most rabies exposure in the US are from infected bats ○ The bite wound is so small that the person may not know they were bitten ○ May not seek medical attention since not noticed ○ The only way to know if an animal has rabies is to kill the animal and check their brain for repsonses Whya bats are insanely attracted to wind turbines? ○ Use echolocation to travel ○ The wind turbine messes that up ○ End up crashing into the tower Rabies pathogenesis after animal exposure  ○ The virus travels through the muscles, infiltrating the brain ○ Will infect salivary gland which creates a lot of salive, making it easier for the virus to transmit. ○ Does a good job avoiding the immune system ○ Could take months to year for the virus to travel to the brain Disease course ○ Incubation period about 2-3 months ○ Unspecific initial symptoms Fever with pain Tingling Burning sensation ○ Two forms of rabies Furious rabies Hyperactivity Hydrophobia (death happens after a few days due to cardio respiratory arrest) Paralytic rabies 20% Coma slowly develops, with eventual death Often misdiagnosed Hydrophobia - an unusual symptom of Rabies ○ Rabies increases spit production ○ Painful spasms makes it harder to swallaow and breather ○ Feel like they are drowning, hence fear of water Preventative immunization in people ○ Any person who could be exposed ot the live rabies virus. ○ Children traveling ot or living in a rabies endemic area Post exposure prophylaxis ○ (PEP) is the immediate treatment of a bite victim after rabies exposure Prevvents viral entry into the central nervous system ○ PEP includes Extensive washing of the wound Effective rabies virus Administration of rabies immunoglobin Lecture 20: Ebola Virus Ebola Virus ○ Filoviridae fmaily ○ RNA virus but ubusual structure and genetic sequence ○ Virions are variable in length on average are 1000 nm ○ A very aggressive virus ○ It is on the maximum biosecurity level  BSL 1-4 ○ Varying levels of security ○ Ebola is the highest at BSL 4 ○ Geography of virus ○ Predicted geographical distribution of the three species of Megachirooptera (bats) suspected to reservoir Ebola virus ○ Took all the animals in areas of Africa to see which ones could carry the disease without dying quickly From animal reservoir to human ○ The ebola virus is foudn in fruit bats, it is also detected in chimapnzees, gorillas and antelopes ○ Transmission Occurs through the handling of these animals ○ The gorilla population is dying becuase of the ebola virus, reaching a 90% mortality rate First Ebola Outbreaks ○ The first outbreak of Ebola was in Democratic Republic of Congo, 1976 ○ 318 cases, with 218 deaths. 88% fatality ratio ○ In a small remote village ○ No hospital or electricity ○ Jean Jacque Muyembe - key to handling the ebola outbreak ○ Named after a river near the village Ebola Virus Disease ○ The symptoms show 2-21 days after exposure ○ Onset of 8-10 days ○ Symptoms stage form “dry” to “wet” ○ 1st stage: Dry Headache Fever Sore throat  Aching muscles Extreme weakness Not very different from the flu or COVID ○ 2nd stage: Wet Nose bleeds Impaired liver function Rash Vomiting Impaired kidney function Diarreah Internal and external bleeding Die becasue of organ failure ○ Ebola Hemorrhagic Fever (Ebola Virus Disease) EVD Ebola infects the macrophage primarily in the liver Infection in liver may be important cause of fluid loss or hemorrhaging by by leading to liver dysfunction Low blood pressure Less blood clotting, meaning mor einternal bleeding ○ How does Ebola cause mortality The pathogenesis of the virus is tied closely to triggering vigourous inflammation to the infection Typical course of Ebola Virus ○ Exposure ○ Incubation 2-21 days ○ Symptoms Begin Dry -> wet stage ○ Recovery or death Virus clearance might be delayed in a few immunologically protected body compartments and fluids. ○ Someones eye turned green after he was told he was cured of ebola The Ebola virus is transmitted by direct contact with Blood, organs, or other bodily fluids Contaminated objects Infected animals Human to human transmission occurred via: ○ Close family contacts or care givers in households ○ Burial ceremonies where mourners have direct contact iwht the deceased ○ Transmission in hospital settings Ebola virus has occured in Affrica ○ UsuallyL one to a few hundreds people infecteed ○ Case fatality ranges from 25%-90% ○ Most often it is Ebola Zaire The 2014 pandemic  ○ Initial sequence data showed that the Guinea outbreak was Ebola Zaire, one of the common strains. ○ AFter 8 weeks, the Ebola outbrak seemed to resolve ○ Suddenly exploded and spread to other countries Why did Ebola virus cause a large outbreak in 2014? ○ Total number of of identified cases from 1976 to Jan 2014 were 1850 with 1200 deaths. ○ 2014 epidemic had about 30,000 cases with 11,310 deaths adn definite human-human pread. ○ This epidemic had a 40% mortality rate but more spread of infection Challenges with 2014 epidemic ○ Took a long time for government aid to be involved ○ Big structures had to be built which scared the people ○ Nonspecific treatment Immune response to Ebola ○ The adaptive immune response is activated and helps resolve infection in those who survive. ○ Thos who surevivie infection are thought ot be protected from re-infection ○ IgG antibodies seems to be key to protection There are significant antibody responses to the Ebola virus in people who recover from re-infection Passive transfer from people who recover to people with active infection seem to help ○ Two piece virus ○ They recognize the spike protein and attack the spike equivalent to the ebola. Then produce IgG antibodies Vesicular stomatitis virus (VSV) ○ infected people may be asymptomatic or may experience mild symptoms lasting 2-5 days Lecture 21: Ebola Virus Part 2 Vaccine trial during 2014-2016 outbreak ○ Ring vaccination method 3500 people recruited Separated into tow groups One immediate vaccination One delayed vaccination group No case were observed in the immediate cluster group ○ Vaccine approved in 2019 Ebola outbreak monitoring ○ When small outbreaks occur they must be followed up immediately with treatment and contact tracing  Treatment ○ Sumptoms of Ebola virus disease are treated as they appear Fluids and oxygen Using medication to support blood pressure, reduce vomiting and diarrhe Treating other infections ○ Antiviral Drugs Severe drugs have been developed and approved for the treatment of Ebola virus disease. Drugs are being developed to treat EVD work by stopping the virus from making copies of itself. (Remdevisir) Also used towards SARS CoV2 Lecture 21: West Nile Virus Arboviruses (Arthropod borne viruses) ○ Viruses transmitted primarily by arthropod vectors Flies, mosquitoes ticks, and fleas Common types of mosquitoes ○ Over 3000 mosquito species ○ The most dangerous are the anopheles, aedes, and culex Culex Typically bite at night both indoors and outdoors Prefer avian hosts but will bite humans Carry: ○ west nile virus ○ Western equine encephalitis ○ Eastern equine encephalitis anopheles Bite indoors and outdoown between dusk and dawn Prefer both humans and mammals Carry ○ Malaria Aedes Active day biters Prefer humans Carry Zika Chikungunya Yellow fever Dengue Only female mosquitoes bite Mosquito Anatomy and feeding  ○ Female mosquito’s mouthparts form a long piercing poboscis ○ Males have feathery antennae and a proboscis that is not equipped for piercing skin ○ Both genders feed on nectar ○ Female also take blood meals ○ Females inject saliva into the host, acting as a anticoagulant (also induces inflammatory response) Most female mosquitoes must blood feed on a vertebrae host to produce eggs ○ The virus circulates and multipies the the mosquito’s heolymph for several days. The virus then penetrates and infects the slaviary glans ○ After incubation of 1-2 weeks the infected mosquito can transmit viruses an danimals while taking blood meals. Arbovirus transmission ○ In general, arthropods have no apparent diseases ○ The infection persist for live in vector ○ Virus can be transmitted transovarially Can be transmitted to eggs ○ Birds, rodents reptiles can be reservoir hosts ○ Mammals can be dead end hosts WNV (West Nile Virus) ○ Isolated form feverish patient from the west nile district ○ Since the 50’s several large outbreaks. WNV Transmission cycle ○ Birds are very susceptible to the virus ○ Replicate in mosquitoes and given to birds. ○ Might accidentally bite into humans and horses  West Nile recently arrived in the US ○ In 1999 the virus first came ○ Then it grew a lot until 2002 ○ It followed the migration of the birds WNV pathogenesis ○ Infection from mosquito ○ Migration to lymph nodes ○ Migration to spleen ○ Crossing the blood brain barrier ○ Infection of neurons  ○ There is a WNV vaccine for horse, why not for humans? ○ Unpredictable outbreaks ○ Economic considerations ○ Lack of progression to phase 3 trials Enrollment, low cause counts, target population Reducing West Nile Virus Vector management ○ Finding and monitoring places where adult mosquitoes lay eggs ○ Tracking mosquito population and the viruses they may be carrying Can buy mosquito dunks ○ Place in water where mosquitoes may lay eggs ○ Bacteria Ingested by larvae, killing them Lecture 22: Herpesviruses The age of Pangaea and the emergence of herpesvirus ○ 250 million years ago The virion ○ Relatively large virus  ○ Genome is made of DNA ○ Encode 70 to 200+ proteins Generalities ○ They are successful pathogens, extremely well adapted to their hosts No or little clinical symptoms High infection rates within their host population ○ Herpes will last for life ○ To persist in their host herpesviruses have adopted two different modes of life cycle; the latency and the lytic cycles Latency Dormant ○ Very little expression nor virions produced Reactivation ○ Virions are made - cell death Afte primary infection herpesviruses persist for life in their hosts in a latent stage ○ upon infection, virla DNA is transported to the nucleus where it circularizes ○ The circular form is called an episome ○ The episome is maintained in the nucleus of the infected cell ○ No (or little) viral expression ○ ○ The latent stage can be interrupted by periods of lytic replication termed reactivation ○ ) Maintenance of the viral reservoir in the host Viral spread to new hosts Reactivation is not associated with disease but under certain circumstances it may be accompanied by clinical symptoms Stimuli leading to reactivation is not well understood. ○ They excel at evading immune responses innate and adaptive A large fraction o genomes are dedicated to immune evasion The human herpesviruses  ○ 8 different kinds from 3 different subfamilies Apha herpes viruses Herpes simplex virus (HSV1) Herpes simplex virus 2 (HSV2) Varicella Zoster Virus (VZV) Beta herpes virus Cytomegalovirus (CMV) Human Herpes virus 6 (HHV6) Human Herpesvirus (HHV7) Gamma herpes virus Epstein-Barr virus (EBV) Kaposi’s sarcoma-associated herpesvirus (KSHV) ○ Herpes viruses to not survive long outside a host: Transmission usually requires intimate contact like kissing Lecture 23: Herpesviruses Human cytomegalovirus ○ ○ Seroprevalence and transmission ○ HCMV congenital infection ○ Treatment Human cytomegalovirus ○ HCMV seroprevalence is high worldwide Transmission ○ The virus isspread through body fluids, including: Blood Urine Saliva Breast milk Tears Semen Vaginal fluids CMV is generally asymptomatic ○ CMV primary infection and reactivation episodes are generally asymptomatic ○ People are unlikely to know they have been infected or shedding virus CMV in immunocompromised patients ○ Those with weak immune systems ○ May have serious symptoms the affect eyes, lungs, liver,, esophagus, stomach, and intestines Relative burden of congenital CMV ○ More children are affected with CMV infection than several more familiar congenital disorders. A pregnant woman can pass CMV to her fetus  ○ 1 in 150 babies is born with CMV ○ 10 % are symptomatic, and will develop long lasting problems ○ 90% are asymptomatic, but some will still develop some problems ○ CMV is the most common congenital infection in the US Outcomes of symptomatic congenital CMV infection ○ Visual impairment ○ Epilepsy ○ Premature birth ○ Coordination disorders Tips to help prevent CMV ○ Do not share food utensils or drinks ○ Avoid contact with saliva when kissing a child ○ Do not share a toothbrush ○ Wash your hands Antiviral drugs ○ They inhibit the viral polymerase ○ They are given to immunocompromised patients with active HCMV replication ○ They may improve hearing and developmental outcomes for babies with sign of congenital CMV infection at birth ○ They can have serious side affects CMV vaccine development ○ CMV vaccine rankes as teh highest priority by the US institute of medicine ○ Women of child bearing age and transplant recipients coild benefit most ○ Vaccination of toddlers would offer strong indirect protection to women Herpes simplex virus 1 & 2 HSV 1 and HSV2 ○ Type 1 causes sores around the mouth and lips ○ Can also cause genital herpes ○ HSV are also associated with recurrent eye infection and in rare cases encephalitis Transmission ○ Transmitted through intimate person-to-person contact ○ HSV is transmissible when areas of skin with the virus come into contact with mucous membranes. These are moist linings in certain parts of the body, including the mothm vagina and anus ○ Kissing can also transmit ○ HSV-2 can be contracted through vaginal, anal or oral sex HSV seroprevalence ○ 3l7 billion people under age 50 have HSV-1 ○ 417 million people between ages 15 and 49 have HSV-2 Latency establishment ○ Approximately 75% of patients with primary genital HSV infection are asymptomatic  ○ ○ HSV establishes latency in the ○ Trigeminal ganglia (TG) ○ Lumbar and sacral dorsal root ganglia Asymptomatic shedding is frequent ○ HSV-2 shedding is detected in ~20% of the days in symptomatic individuals and 10% of the dyas in persons with asymptomatic infection Drugs and vaccine ○ Vaccine candidates are currently being evaluated For therapeutic purposes: intended to reduce viral shedding in people who are already infected with HSV Fr preventative purposesL designed to prevent infection Anti-herpesvirus drugs ○ Incomplete suppression of lesions (70-80%) Testing for genital herpes is recommended for people who have sumptoms ○ To confirm they are infected ○ To discuss what is expected in the future ○ To learn which medication are available to help manage any symptoms ○ To learn how to lower the risk of spreading the infection to sex partners.  CDC recommends against screenign asymptomatic adolescents and adults for HSV infections ○ Blood test to detect the presence of HSV antibodies is not very accurate ○ Whether infection is oral or genital can not be determined Kaposi’s sarcoma ○ Until the early 1980’s kaposi’s sarcoma was a rare disease found mainly in older men, patients who had organ transplants or african men ○ With the AIDS epidemic in the early 1980’s docotrs began to notice more cases of Kaposi’s saecoma if Africa and in gay men with AIDS At the peak, 20 of every 100 gay men with AIDS develops KS KS is caused by a virus other than HIV ○ By 1990, scientitsts built a compelling case for KS being caused by secually transmitted infection in people with AIDS - but not caused by HIV ○ KS was more common if a person had contracted HIC through secual contact than by any other way The discovery of Kaposi’s sarcoma associated herpesvirus ○ Compared teh DNA from healthy tissue agains the DNA isolated from Kaposi’s sarcoma lesions ○ They obtain two small pieces of BNA that were not huan Analysis of the two pieces indicate that it’s a new herpesvirus Karposi’s Sarcoma associated Herpesvirus (KSHV) Human Herpesvirus (HH8) ○ Also related to the Epsteub Barr Virus EBV and KSHV are associates with cancers ○ Like other herpesviruses, EBV and KSHV are usually asymptomatic ○ Epstein Barr virus mononucleosis(or kissing disease) Burkitt lymphoma (B-cells) Nasopharynx Carcinoma (B-cells) ○ Kaposi’s sarcoma herpesvirus: Primary effusion lymphoma (B-cells) Kaposi’s sarcoma (endothelial cells) Like all other herpesvruses, KSHV and EBV go latent ○ They face a challenge They infect dividing cells They need to tether their episomes to the DNA of the host. Otherwise teh episome would be lost during cell division. During latency EBV encodes EBNA-1, KSHV encodes LANA. These protein are required for ○ Episome maintenanc ○ Episome replication ○ Cellular division Lecture 24: Hepatitis C Hepatitis C ○ Causes inflammation in the liver ○ Liver tropic Likes to move to the liver and infect that area HCV Transmission ○ HCV us transmitted via blood contact Intravenous drug use Blood transfusions Contaminated madical/dental From mother to bay at birht (about 5% risk) risk are higher if mother is HIV + Secual transmission that involve bloo overall the risk of secual transmission is very low Unregulated tattoos or body piercings Sharing personal items ○ Egypt has the highest prevalence of HCV Hepatitis C virus causes both acute and chronic infection ○ 70% of HCV infected individuals will develop chroinic HCV infection They will have the virus for life ○ Of those with chronic HCV infection, the risk of cirrhosis (liver disease) ranges between 15% and 30% within 20 years Liver transplantation ○ Live failure due to hep C is one of teh most common reasons for liver transplantation in the US ○ An estimated 1 to 5 out of 100 people with chronic hap C will of cirrhosis or live cancer. The last estimates ○ About 60 million people ○ 1.5 million new infections per year ○ 80% of people infected with HCV dont know their status No clinical sign until severe damage ○ Less than 10 millions are currently being treated ○ There is currently no effective vaccine against hep C There is new treatment that can cure, but very low access Viral quasispecies ○ Hepatitis C virus exhibits significant genetic variability and exists as quasispecies within infected individuals Quasispecies are population of closely related but genetically divers viral variants that coexist within and infected host ○ HCV has high mutations rate ○ Rapid viral replication ○ Selective pressures from the host immune system  ○ (makes different quaispsecies) Immune system is overworked and is always chasing the pool of viruses that keep mutating and evading the immune system. Direct acting antivirals ○ 1990’s Ribavirin and IFN-I ○ 2011: DAAs are a newer class of drugs used to treat hapatitis C. DAAs wirj by targeting the virus directlym making them more effective than older treatment. DAAs that can cure hep C in more than 95% of people infected Short treatment duration Little to no side affects Toward the eilimination of HCV? ○ World health organization have committed to eliminate viral hepatitis by 2030 Only 11 countries are on track to meet all HCV ELIMINATION TARGETS BY 2030 Another two dozen are expected to meet these targets between 2031 and 2050 Most countries including the USm are unlikely to achieve ahaptitis C elimination untl after 2050 In the US, the number of people infected with HCCV has increased dramatically ○ From 1700 in 2011, to 41000 in 2016 In the US ○ An estimated 40% of those chronically infected with hep C ○ One major limitation is that testing for hep C requires 2 steps Check for prior infection Then RNA test to determine whether infection is active Can take days or weeks A third visit to begin treeatment ○ Among those diagnosed hep C treatment coverage is far below what is needed to achieve elimination goals ○ ⅓ of HCV infected individuals with insurance are treated High cost of DAAs Requirements for patient sobriety Requirements to document evidence of liver fibrosis Access to treatment only to those seen by specialists Low rates of treatment may also reflect the complexity of teaverisn the full cascade of care in our health care delivery system Lecture 25: Hepatitis B A fourth of teh worlds population has been infected with hepatitis B virus ( HBV) and an estimated 250 million peeople have it chronically How is it spread?  ○ Hep B is spread when blood semen or other body fluids from an infected person enters the body of someones who is not infected ○ Methods Sexual transmission Intravenous drug Blood transfusion Vertical transmission ○ Hep B is not spread through huggin kissing or sharing food Likelihood that acute hep B will become chronic ○ 5% of adults will become chrinically infected ○ 25% - 50% of children infected between ages 1 to 5 will develop chronic hep B ○ 90% of infeants will develop chronic Post exposure prophylaxis of newborns ○ Approx 90% of children who are infected at birth or during teh first year of life will become chronically infected Only 5% of newly infected adults become chronically infected ○ Post exopsure prophylaxis of newborns born to chronically infected mothers is 85-95% effective when administered within 12 hours of birth Spectrum of liver disease after HBV infection ○ Acute or Chronic From there it branches The first time was seen is in 1971 and surprisingly it was discovered that it can adopt multiple shapes. The Dane particles being the infectious particles ○ Small spherical most abundant ○ Dane is sphere is the virus itself ○ Tubular forms HBV vaccine represents the first licensed vaccine of any kind produced by recombinant technology ○ Used in millions of individuals with outstanding safety ○ Reduced from high to low prevalence in many countries Availabel therapies for the TReament fo Chronic HBV infection ○ Intererons The exact mechanism through which have an antiviral effect against HBV is not fully understood. ○ Nucleoside analoguesThey mainly act by inhibition of HBV polymerase activity resulting in decrease of viral replication oral medication Liver cancer is one of the leading causes of cancer deaths worldwide ○ About 800,000 deaths annuallu ○ Primary liver cacner is the eith most common cancer ins the world more than 50% are related to HBV ○ Liver transplantation is consideredgold standard ○ Viral reactivation in the graft can be detrimental Human Papilloma Virus (HPV) Papilloma viruses maek up a group of more than 300 viruses ○ About 200 different papillomavirus types infect humans Asymptomatic Causes genital or skin warts Carry a risk of becoming cancerous HPV is the most common sexually transmitted infection in the US ○ HPV infection is commonly spread during vaginal or anal sex ○ 80% of men and women will be infected with at least one type od HPV in their lives Most people infected with HPV are asymptomatic and will clear infection on their own ○ Usually within two years Sometimes the virus persists and results could lead to complication, including genital warts and cancer. In fact HPV causes virtually all cases of cervical cancer 95 percent of anal cancer and about 70 percent of throat cancers Low and hish risk papilloma ○ Low risk papllomavirus Infection with most low risk genital HPV Strains doesnt cause symptoms ○ High risk HPV Infection wiht high risk HPV can lead to extensive cervical dysplasia and certain types of cancer. 90% heal in 2 years Prevention ○ Safe sex practices Not 100% effective ○ Pap test and HPV test To detect abnormal cell proliferation in the cervix and to determine the HPV type involved The virion ○ Small viruses ○ Their capsid is made of the protein L1 ○ The genome is DNA HPV vaccines ○ Teh vaccine is made of the L1 proteins ○ The protein naturally assembles to form virus like capsids ○ HPV 16 and 18 cause 70% of te cervical cancers Types of genes linked to cancer ○ Proto oncogenes Proteins tha tnormally contribute positively to cell proliferation Mutations might alter the regulation of these proto oncogenes preventing them to be turned off ○ Tumor suppressor genes Proteins that prevent the unwanted proliferation of mutant cells  Mutations might render these tumor suppressor genes ineffective E6 and E7 is expressed in tumor cells ○ HPV are found integrated in most cancer cells ○ Intergration is a genetic accident ○ Integration is a dead end for the virus as it is no longer able to forma a small circular genome that can be packaged and transmitted to a new host ○ Integration results in dysregulation of expression of the viral E6 and E7 oncogenomes HPC infection lead to cervical cancer ○ It take s15 to 20 years for cervical cancer to develop The virus cause cancer by accident ○ Not part of their life cycle