Viruses

1. Viruses

2. What are Viruses? • Viruses are pieces of RNA or DNA enclosed in a protective coat(s) • Viruses are parasites • Evolved to reproduce inside cells they infect • Evolved to survive outside cells they infect • Can do much with little and do it elegantly • Hepatitis B is smallest known human virus • has only four genes • over 1 million people die each year • Hepatitis B associated liver disease

3. Structure of Viruses • Very small • 20-300 nanometers • Contain either DNA or RNA (the genome) • which codes for the few proteins necessary for replication • Proteins assembled to form a tight shell “capsid” • Capsid made up of protein subunits called capsomeres • The # of capsomeres is characteristic for a particular virus • Nucleocapsid = genome + capsid • Some viruses acquire an outer lipoprotein coat by budding through host cell membranes “enveloped”

4. Structure of Viruses (cont.) • All viral proteins have reactive epitopes • Epitope aka antigenic determinant, part of macromolecule (protein) that is recognized by the immune system • The host’s defense mechanisms • Cellular and humoral mediated responses are directed against these epitopes • Viruses gain entry into host cells by binding to specific receptors

5. Specific receptor examples • HIV binds to CD4 receptors • Can infect cells with these receptors • Monocytes, macrophages, T-helper cells • EBV (Epstein-Barr) binds to receptor present for CR2 • CR2 = Complement receptor type 2 found in B cells • Influenza binds to glycophorin A • Glycophorin A is found on many cell types • Rhinoviruses use ICAM receptors • Have the capacity to infect many different cells

6. Replication • Adsorption • Uptake/Entry • Uncoating • Genomic activation • Assembly • Release • (animation)

7. 3 Problems human viruses must solve • How to reproduce • How to spread from person to person • How to evade host defenses • These solutions must fit together in an overall plan of infection • Wouldn’t make sense for a virus that reproduces only in liver cells to be spread by coughing • It wouldn’t do for a virus to evolve to reproduce in the intestines, yet not evolve a strategy that protects the virus from acidic conditions present in the stomach

8. How to reproduce • Gain entry to cell via specific receptors • Hijack machinery • Turn cells into factories that make many copies of the virus • Make both genome (DNA or RNA) and the proteins • DNA viruses use bits and pieces of the cellular DNA replication machinery to copy their own genomes • Problem in cells that are mature and not actively replicating their own DNA “resting” • Figure out how to turn infected cell back on (give it a kick) • Bring its own substitutes for parts of cellular copy machines not active at the time of entry

9. How to reproduce (cont.) • RNA viruses • Bring their own copy machines • RNA-dependent RNA polymerases • Or have genes which encode the proteins required to assemble these copy machines within the infected cell • By “bringing their own” many RNA viruses are able to replicate their genomes in resting cells • animation

10. How to spread • Viruses have solved “transmission” problem in ways that take advantage of human behavior as varied as coughing or having sex • Once it reaches its new host, traveling virus must locate cells in which it can reproduce • Cell must have appropriate receptors • Humans have abut 200 different types of cells & a given virus usually will be able to infect only a few of these many different cell types

11. Viral Pathogenesis • Most human viruses cause some form of disease in their hosts • although some pathological conditions affect only a small subset of infected humans, or are so mild that they are virtually undetectable. • The disease that viruses cause are the consequences of the way each virus has chosen to solve the problems of reproduction, spread, and evasion

12. Viral Pathogenesis (cont.) • Viral pathology can result from: • Actions of the virus itself • Killing the cell it infects • Host’s reaction to the virus • Host immune response • Most of the host’s defenses against viruses are not finely focused resulting in collateral damage • A host’s “shotgun” approach to defending against a viral infection is somewhat like trying to kill a mosquito with a machete • You may kill that mosquito, but most of the blood on the floor will be yours

13. Adsorption • Viruses have reactive sites on their surface with interact with specific receptors on suitable host cells • Usually passive (doesn’t require E) • Specificity of reaction defines and limits the host species as well as the type of cell that is infected • Damage to binding sites (disinfectants, heat) or blocking (specific Ab) can render a virus non infectious

14. Uptake/Entry • After adsorption, uptake/entry can occur in different ways: • the coat of enveloped virus may fuse with host cell membrane & release the nucleocapsid into host cytoplasm • Endocytosis-invagination of the cell membrane to form vesicles in the cytoplasm

15. Uncoating • Release of the viral genome from its protective capsid • enables the nucleic acid to be transported within the cell and transcribed to form new progeny

16. Genomic activation • DNA viruses (replicate Io in the nucleus) • mRNA is transcribed from viral DNA and codes for viral proteins that are translated by host cells • RNA viruses (replicate Io in the cytoplasm) • Most carry a protein, RNA-dependent RNA polymerase which directs both transcription & replication of viral RNA genome • During this process the “foreign” proteins are recognized and incorporated into the major histocompatibility complex I molecule (link) • Nucleic acid replication produces new viral genomes for incorporation into progeny viral particles

17. Assembly • Assembly of viral nucleocapsids occurs primarily in the: • nucleus • For DNA viruses • Cytoplasm • For RNA viruses

18. Release • Final stage of replication • Release of new infectious viral particles (progeny) • May occur by budding-many enveloped viruses • Carry with them a piece of host’s cell membrane • Lysis (disintegration) of infected cell can also release new infectious viral particles

19. Retrovirus • contain viral RNA and several copies of reverse transcriptase • reverse transcriptase (DNA polymerase) is used to make the initial copies of viral DNA from viral RNA. • Once a DNA strand has been synthesized, a complementary viral DNA strand is made. • These double strand copies of viral DNA are inserted into the host-cell chromosome • host-cell RNA polymerase is used to make virus-related RNA. • These RNA strands serve as templates for making copies of the viral chromosomal RNA and serve also as mRNA. • mRNA is translated into viral proteins that are used to make the virus envelope. • New viral particles are assembled, bud from the plasma membrane, and are released. • HIV (human immunodeficiency virus) is a retrovirus

20. Oncovirus • Virus associated with cancer • Can be a DNA virus • Adenovirus • Can be a RNA virus • T-cell Leukemia • Oncogenic mechanisms (link) • Insert additional oncogenic genes in host DNA or • Enhance already exsisting oncogenic genes in the genome • Viral DNA incorporates a section of the host DNA which contains genes for growth promotion • Proto-oncogenes

21. Influenza (flu) • Infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae (influenza virus) • Influenza from the latin influentia meaning influence (link) • Two types that cause epidemic human disease • Influenza A • Further categorized into subtypes on the basis of 2 surface antigens • Hemagglutinin (H) • Neuraminidase (N) • Influenza B (not divided into subtypes)

22. Influenza (cont.) • New variants result from frequent antigenic change aka “antigenic drift” • Results from point mutations that occur during viral replication • Influenza A > B (with regard to antigenic drift) • A person’s immunity to surface antigens (e.g. hemagglutinin) reduces: • Likelihood of infection • Severity of disease if infection occurs • Antibody (Ab) against one strain confers limited or no protection against another strain

23. Epidemics of Influenza • development of antigenic variants via antigenic drift is the basis for seasonal epidemics • Epidemics typically occur during the winter months • About 36,000 deaths/year in U.S. (1990-1999) • Pandemics- dramatic  in rates of illness/death • Due to antigenic shift • Morbidity highest among children • Mortality highest among elderly (> 65 years) & individuals with pre-existing medical conditions

24. Symptoms of Influenza • Coryza –acute rhinitis; • Fever • Body aches • Malaise • Generalized muscular aches • Loss of appetite • A lot of different illnesses can have similar symptoms (including common cold)

25. Complications of Influenza • Guillain-Barre Syndrome • Nerve damage, polio-like paralysis, coma. Usually follows recovery from disease or immunization to the disease • Reye’s Syndrome • Fever, protracted vomiting, lethargy, sleepy, disorientation, incoherence. Liver & brain damage. Elevation in blood ammonia. High mortality. May be associated with aspirin use during disease.

26. Vaccine for Influenza • Vaccine contains the inactivated virus • Several strains of both A and B are included

27. Manual treatment for influenza • Some historical perspectives from the osteopathic profession. • Letter one • Letter two

28. Rhinovirus • Non-enveloped positive-stranded RNA virus belonging to the family “picornavirus” (pico = small) along with enteroviruses. • Most common viral infective agents in humans • cause of common cold • Icosahedral (20 faces) in structure • Replicate in the secretory mucous membranes • Transmission • Person to person • Via aerosols of respiratory droplets • Contaminated surfaces

29. Rhinovirus (cont.) • Can lead to (sequelae) but highly unlikely. • Secondary bacterial pneumonia • Otitis media • Sinusitis • Prefer lower temperature (33 deg C.) • Tend to stay in nose

30. Coronavirus • RNA virus belonging to family coronaviridae • Cause respiratory infections (common) • Enteric infections primarily in infants (occasionally) • Neurological syndromes (rarely) • Transmitted by aerosols of respiratory secretions, or by fecal oral route, or by mechanical transmission • Usually localized to the epithelium of URT

31. Coronavirus (cont.) • Most infections cause a mild, self limited disease • Classical cold • SARS (Severe Acute Respiratory Syndrome) • Viral pneumonia associated with the LRT • Very common worldwide • Incidence is seasonal, highest in winter in children • # of serotypes & extent of antigenic variation ??

32. Adenovirus • DNA virus belonging to family of adenoviruses • A few types serve as animal models for cancer induction (some are oncogenic) • 42 known human serotypes • Cause URT or LRT infection • Bronchitis (Types 1,2,3,5) • Resembles whooping cough-pertussis syndrome • Signs • Fever, HA, myalgia, pharyngitis, hoarseness, conjunctivitis

33. Adenovirus (cont.) • Clinical presentation varies based on serotype • Bronchitis (1,2,3,5) • Sore throat • Tonsillitis • Conjunctivitis • Pneumonia • Hepatic disorders (3,7) • Gastroenteritis (9,12,13,18,25-28, 40-42) • Musculoskeletal disorders (7) • Genital infections (19) • Skin infections (32, 34-35)

34. Respiratory Syncytial Virus (RSV) • negative-sense, single-stranded RNA virus • Paramyxovirus Family • Family contains viruses that cause mumps & measles • RSV most common cause of bronchiolitis & pneumonia among infants (< 1 yr.) • Onset fever, runny nose, cough (wheezing) • During 1st RSV 25-40 % of children have S/S of bronchiolitis or pneumonia • .5-2% require hospitalization (most < 6 months) • Most recover in 1-2 weeks

35. RSV (cont.) • Repeat infections common throughout life • Moderate-severe cold symptoms • Severe LRT infection may occur • esp. in compromised individuals • Compromised cardiac, pulmonary or immune systems • Spread from respiratory secretions • Close contact with infected individuals or contaminated surfaces/objects • Sneeze/cough (aerosol particles) • Route of entry • Mucous membranes (eyes, mouth, nose)

36. Metapneumovirus • Negative sense RNA virus (paramyxovirus fam.) • Discovered in the Netherlands in 2001 • Very common cause of colds in adults • more severe symptoms in children (severe cough & wheezing) • 12% of severe illness • 15% of common colds • 33% of colds complicated by middle-ear infections • Diminished severity in repeat infections • Second to RSV as a cause of severe LRTI (2/3)

37. Fifth Disease/Erythema Infectiosum • DNA virus-Human Parvovirus B19 (link) • Not the same as animal parvovirus (no interspecies transfer) • Affects primarily children • Grows in stem cells, lyses cell to spread • Rash produces a “slapped cheek” appearance • Proceeds from face to trunk & limbs (like measles) • Mild systemic & respiratory illness • Aplastic crisis in individuals with chronic anemia • Virus infects erythroid precursor cells (reduced Hgb) • Hydrops fetalis –spontaneous abortion as fetus infected

38. Varicella (chickenpox) • Double stranded DNA virus (Herpesviridae fam.) • Prior to mandated vaccine: • 3.2-4.0 million cases/yr. ⇒ 9000 hospitalizations ⇒ 90 deaths (mortality rate 2.25 X 10-5) • Among the most communicable of all diseases • Transported by respiratory droplets & skin contact • Incubation period 14-21 days • Begins in the respiratory tract, symptoms of fever, HA, malaise, passes via the blood localizing in peripheral nerves & skin (fluid filled vesicles)

39. Varicella (cont.) • Varicella (latin for “little vessel”) • Vesicles form crusts eventually falling off with or without a scar • Reye’s syndrome may occur during recovery (linked to aspirin use during illness) • Complications (increase with age) • Pneumonia, encephalitis, secondary bacterial infection of the skin, fetal damage in pregnancy • (link)

40. Herpes Zoster/Shingles • Caused by the varicella virus that remains in the nerve roots after chicken pox • Contagious to people who have not had chickenpox, however you cannot catch shingles from someone else. • Common after age 50, risk withage • Numbness, itching, severe pain followed by clusters of blister-like lesions in strip like pattern • Pain can persist for weeks, months, or years after rash heals  post-herpetic neuralgia

41. Herpes Zoster/Shingles (cont.) • May experience headaches, facial paralysis, • One of the more devastating conditions that is likely to recur due to: • physical/emotional stress • Suppressed immune system • 10-20 % of adults will experience at least one attack during lifetime

42. Poliomyelitis/Polio • RNA-picornaviridae (Greek- gray matter) • Three antigenic types • Type I/Brunhilde strain • Causes a major # of epidemics • Type II/Lansing strain • Occurs sporadically, but invariably paralytic • Type III/Leon strain • Usually remains in intestines, but can cause paralysis • Enters body via mouth, multiplies in tonsils, then lymphoid tissue of GI tract causing nausea, vomiting, cramps

43. Poliomyelitis/Polio (cont.) • Virus may pass via blood into the NS, localizing in: • Meninges, causing meningitis • Anterior horn, causing muscle weakness, paralysis • Brain stem (bulbar), affecting the medulla (worst) • Difficulty swallowing, paralysis of diaphragm, affects breathing (iron lung), paralysis of tongue, facial & neck ms. • Vaccine • Salk-killed virus (some viruses could still be fxn) • Sabin-attenuated (grown in monkey kidney) • Sequelae • Post polio syndrome (20-30 yrs.) after initial infection • Muscle weakness

44. Viral Gastroenteritis • General name for a common illness occuring in both epidemic & endemic forms • 2nd in freq to common cold in U.S. • Usually explosive onset with varying: • Diarrhea, nausea, vomiting, low grade fever, cramps, headache, malaise • Can be severe in infants, the elderly, persons compromised by other illnesses • Associated with: • Reoviruses, rotoviruses, enteroviruses

45. Reoviruses • Double stranded DNA (link) • Antigenically 3 human types- orthoreovirus • REO = respiratory enteric orphan * • Enters oropharnx & replicates in respiratory tract & intestines • Ab against it present in 10 days • By age 16: • 50-80% of population have Ab to all 3 types * an orphan is a virus without a famous disease

46. Rotaviruses • Most common cause of severe diarrhea among children • In U.S – 55,000 hospitalizations/yr • Worldwide – 600,000 deaths/yr • Incubation period – 2 days • Vomiting and watery diarrhea for 3-8 days • Fever & abdominal pain occur frequently • Immunity after infection is incomplete, but repeat attacks are less severe

47. Rotovirus (cont.) • Primary mode of transmission • Fecal-oral • Virus is stable in environment • Transmission via ingestion of contaminated food/water, or contact with contaminated surfaces • Highest incidence in infants/young children • Most children in U.S. infected by 2 yrs. • Disease in adults tend to be mild

48. Enteroviruses • RNA viruses (picornaviridae) • Noroviruses- named after “Norwalk virus” • Four groups divided into at least 20 genetic clusters • Fecal-oral • Highly contagious • Incubation 24- 48 hours • Acute onset • Vomiting, watery diarrhea, abdominal cramps, nausea, with occasional low grade fever • Dehydration is most common complication • Symptoms last 24-60 hours • Recovery usually complete with no sequelae

49. Enteroviruses (cont.) • Coxsackie virus • Two groups • A (link)- Associated with diseases with vesicular lesions • B (body) (link)- Most frequently associated with myocarditis and pleurodynia • 29 different variants causing a variety of divers & distinct disease entities • Conditions • Herpangina- Sores inside the mouth, sore throat & fever • Pleurodynia- Severe pleuritic pain, fever, headache • Aseptic Meningitis – associated with mild paresis (transient) • Myocardiopathy – arrhythmias, tachycardia, can cause permanent heart damage • Common cold • Diabetes Mellitus • Hand, Foot, Mouth Disease- rash (vesicles to ulcers)

50. Enteroviruses (cont.) • Echovirus (link) • Enteric Cytopathogenic Human Orphan • Occur in many strains • Symptoms • Gastroenteritis • Aseptic meningitis (not associated with bacterial infection) • Rash • Common cold • Fairly viable in sewage/water • 31 different virus in this group • Upper respiratory tract is portal of entry