Chapter 8: Empire of Viruses

The Empire of Viruses

Clinical Significance (CST)

• Viruses, viroids, and prions are non-living pathogens that lack cellular components for reproduction, making them obligate parasitic invaders of living cells.

• Immunocompromised patients are especially vulnerable.

• Healthcare workers with viral infections must avoid exposing others to infections like COVID-19 or influenza.

Basic Virology

• In the late 1890s, studies on tobacco plants and hoof-and-mouth disease identified ultra-small particles smaller than bacteria as the cause.

• The term "virus" was first used when studying tobacco mosaic virus (TMV).

• Viruses were visualized with the electron microscope in the 1930s.

• Initially grouped with bacteria, viruses gained equal standing under the Two Empires system (Cellular organisms being the other).

• Baltimore Classification System is used for taxonomy and nomenclature.

• Common human viruses include those causing the common cold, influenza, HIV, rotavirus, rabies, herpes, polio, and COVID-19.

• In 2021, 28 new viruses were discovered from glacial ice using advanced techniques.

• Characteristics of viruses:

  • Tiny particles of nucleic acids (RNA or DNA). Never both.

  • Lack cellular components needed for energy production or reproduction (binary fission, mitosis).

  • Viral genetic material can be single- or double-stranded, linear or circular.

  • Obligate parasites that invade living cells to replicate.

  • Possibly derived from organelles of ancient prokaryotes, developing receptor sites for cell attachment and genetic injection.

  • Size ranges from 25 nm to 400 nm, with varying numbers of capsomeres.

  • A protein coat protects the genetic component and enables host cell attachment.

  • The nucleocapsid is the nucleic acid and capsid unit.

  • Structural configurations include icosahedral, helical, or complex shapes.

  • Some virions have a nucleocapsid surrounded by an outer membrane (lipid bilayer), called an envelope, derived from the host cell membrane.

• Viral infection occurs through various routes:

  • Inhalation of respiratory droplets.

  • Exchange of body fluids, such as blood (HIV, HBV).

  • Ingestion of contaminated food or water.

  • Arthropod vectors.

• Viruses attach to host cells via capsomere receptors and enter through:

  • Direct penetration of the cytoplasmic membrane.

  • Receptor-mediated endocytosis.

  • Viral nucleic acid is then released, and replication begins.

• Lysogenic and lytic cycles:

  • Lysogenic cycle: Viral nucleic acids integrate with host cell genetic material, and viral instructions are copied into daughter cells in a latent state until rapid replication is triggered.

  • Lytic cycle: Viral genetic material takes over the host cell's machinery, producing virions, synthesizing protein capsids, assembling new viral particles, lysing the host cell, and releasing viral particles to infect other cells.

• Some virions acquire envelopes via budding through the host cell's cytoplasmic membrane.

• In some infections, like hepatitis B, host cells remain alive and slowly release viral particles, leading to chronic infection that becomes active when the host is immunocompromised.

• Viruses can disrupt the host cell's metabolic machinery and transform it into a malignant cell, leading to uncontrolled growth, invasiveness, angiogenesis, and tumor development. Hepatitis C virus can cause hepatic carcinoma.

• Bacteriophages (phages) are viruses that infect bacteria.

  • Phages bond with the host cell and bind to receptor sites on the bacterial cell wall, fimbriae, or flagella.

  • Complex phages have additional structures attached and are classified as virulent or temperate.

    • Virulent bacteriophages reproduce rapidly upon entry, causing the bacterium to lyse and release new phages (lytic stage).

    • Temperate phages combine with the host's chromosomes or become plasmids, replicating along with the host cell. They lyse the cell when the host is near death (lysogenic cycle).

• Scientists are developing enzymes produced by phages to lyse host bacterial cells for therapeutic use, such as nasal sprays for pathogenic bacteria and synthetic biology approaches to target bacterial biofilms.

• Latent viral infections remain in the host for a lifetime, emerging when conditions are favorable.

  • Human herpes virus can reactivate, causing death in some situations.

  • Heat, UV rays, or stress can reactivate the virus.

Key Terms

• Chickenpox virus (varicella) can migrate from blood to nerve cells after initial infection. Changes in immune response can reactivate the virus, causing herpes zoster (shingles).

• Cytomegalovirus (CMV) is common, present in 60-70% of humans by age 40. It remains dormant until reactivation due to compromised immunity from age, HIV/AIDS, or immunosuppression after organ transplantation.

Anti-viral vaccinations

• Immunizations cause the body to produce antibodies specific to an infecting virus.

• Due to rapid viral replication, mutations can alter the protein coat, reducing vaccine effectiveness in subsequent years.

• Previously, lifetime immunity was assumed after childhood immunization or infection recovery, but adults should have serum titers checked or receive booster vaccinations to restore protection.

• Reasons for getting/maintaining vaccine protection:

  • Protecting babies and young children from adult-carried infections.

  • Preventing shingles from dormant herpes zoster in adults over 50.

  • Travel immunizations for endemic disease areas.

  • Annual influenza protection due to frequent viral strain changes.

  • Preventing serious COVID-19 infection even with viral variants.

  • Initial or booster doses for adults who may not have had recent vaccinations.

  • HPV vaccines for young males and females before sexual activity.

  • Bacterial meningitis prevention in students living in dorms; viral meningitis caused by enteroviruses is less aggressive but without vaccine.

  • Healthcare workers protecting themselves from infectious materials and patients.

  • Sexually active individuals protecting themselves against blood-borne STD infections.

Interferons (INFs)

• Two types and three groups of glycoproteins that interrupt replication of RNA and DNA viruses.

  • Type I: Produced by leukocytes (INF-α) and fibroblasts (INF-β).

  • Type II: (INF-γ) Produced by lymphocytes during immune response.

• Interferon released from infected cells binds to neighboring cells, signaling the cell's nucleus to activate a gene coding for antiviral protein to inhibit translation of messenger RNA into proteins

• Natural killer cells are energized by INFs.

  • Macrophages, T- and B-lymphocytes are also influenced by interferons.

Herpes Viruses

• 100 identified strains affecting animals, family Herpesviridae, named after "Herpein" (Greek for "to creep"), signifying chronic, recurring conditions.

  • Eight strains affect humans: alpha, beta, and gamma

    • Herpes simplex I: cold sores in oral or nasal mucosa

    • Herpes simplex II: sexually transmitted genital or anal vesicles

    • Epstein-Barr: infectious mononucleosis flu-like symptoms and swollen lymph nodes

    • Cytomegalovirus: minor flu-like symptoms to organ failure

    • Varicella zoster: chickenpox and shingles blister-like lesions

Varicella Zoster (VZV)

• Chickenpox, childhood infection without vaccine protection.

  • Multiplies at inoculation sites (respiratory tract, conjunctiva), enters blood, reticuloendothelial system, manifests on skin/mucosa as fluid-filled vesicles.

  • VZV retreats to sensory ganglia, reactivating from stress or immunosuppression.

  • Like HSV, travels axon length to reinfect skin supplied by sensory nerve (thoracic dermatomes, trigeminal nerve).

  • Vesicles are painful, neuralgia can occur (shingles).

Cytomegalovirus (CMV)

• Usually asymptomatic, rarely causing disease in healthy individuals.

  • Can invade every human cell type, causing liver failure, retinal inflammation, colitis.

  • Females can pass to fetus during pregnancy, causing vision/hearing loss, seizures, cerebral palsy.

  • Adult infection often resembles infectious mononucleosis.

Epstein-Barr Virus (EBV)

• Estimated that 90% of the world’s population has been infected.

  • Causes infectious mononucleosis (glandular fever, "kissing disease") transmitted through saliva, causes fever, malaise, lymphadenopathy, hepatosplenomegaly (swelling of liver and spleen).

  • Clinically identified with Paul-Bunnell test and symptoms treated with steroids.

Human Herpes Virus 6 (HHV-6)

• Isolated in 1986 in peripheral blood mononuclear cells of patients with lymphoreticular disorders, cause of roseola infantum.

Human Herpes Virus 7 (HHV-7)

• Closely related to HHV-6 but not known to cause human diseases but could be a common co-factor for HHV-6.

Gastrointestinal Viruses

• Two classifications: enteropathogenic and non-enteropathogenic.

  • Enteropathogenic viruses include Caliciviridae family members, single-stranded, non-enveloped, spherical or hexagonal shaped, and chemically icosahedral.

  • Result in 2.2 million deaths annually worldwide from complications of gastrointestinal viral infections.

  • Enteropathogenic viruses include rotavirus, astrovirus, norovirus, and adenovirus.

Rotavirus

• Non-enveloped, icosahedral, triple-layered particles with double-stranded RNA segments that form the complex circular shape (from the Latin word rota, meaning wheel).

  • Responsible for severe gastrointestinal infections of very young children with complications including dehydration as a result of severe watery diarrhea, vomiting, and fever.

  • Rotavirus vaccination protocols for infants in standard vaccine regimens prevent 40,000 to 50,000 hospitalizations of infants and young children.

Norovirus

• Non-enveloped, single-stranded RNA viruses responsible for acute gastroenteritis infections; in 1929 was given the name “the winter vomiting disease” and subsequently called “Norwalk-like” virus after an outbreak in 1968 at a school in Norwalk, Ohio.

  • Described as the “stomach flu,” it is unrelated to the respiratory influenza virus.

  • Most common cause of acute gastroenteritis and foodborne-disease outbreaks.

  • Causes 19 to 21 million cases of vomiting and diarrhea illnesses with 109,000 hospitalizations, mainly of young children or older adults.

Astroviruses

• Named for their characteristic star shapes.

  • Responsible for less severe gastroenteritis infections in younger populations.

  • Chief cause of acute diarrhea in immunocompromised patients.

Enteroviruses

• Enteroviruses are very small viruses and part of the family Picornaviridae and genus Enterovirus made up of ribonucleic acid (RNA) with a protein covering.

  • The group includes rhinoviruses, polioviruses, coxsackieviruses, echoviruses, and 61 strains of pathogenic non-polio enteroviruses.

  • Rhinovirus

    • The most common communicable infections in humans called the “common cold” in types A, B, and C, and found primarily in the upper respiratory tracts (mouth and nose).

    • Rhinoviruses are some of the smallest viruses, measuring on average only 30 nm.

    • Easily spread by aerosol spray and by contact with inoculated surfaces.

    • No vaccines or cure, so use of preventative tactics including strict hand washing and avoidance of infected individuals is key.

Poliovirus

• Small viruses that multiply in the mucosa of the GI tract with mainly fecal-oral route transmission.

  • Inside the aerodigestive tract, virus grows in cells of the oropharynx and lymph nodes.

  • The virus can be released in respiratory secretions during initial phase of infection then moves into gut mucosa, shedding large numbers of viral particles in the feces.

  • Viremia can spread to the CNS and permanently damage motor neurons, resulting in paralysis requiring mechanical respiratory assistance.

  • Three types of wild poliovirus serotypes (WP1, WP2, and WP3) cause disease world-wide.

  • The Global Polio Eradication Initiative has achieved a 99% decrease in global incidences of polio infections.

Coxsackie Virus

• Coxsackie virus – Responsible for hand, foot, and mouth disease, which causes ulcers on the inside of the mouth and the palms of the hands, fingers, and soles of the feet.

  • Young children in daycare or nursery schools are commonly infected through the fecal-oral route but it can be spread by respiratory aerosols.

Echovirus

• Small viruses composed of a protein capsid enclosing a single-stranded RNA, first isolated from feces of asymptomatic children in the 1950s.

  • Causes a wide range of symptoms including being the most common cause of aseptic meningitis in infants with high mortality rates, especially in first 2 weeks after birth.

  • Can cause viral encephalitis, acute motor weakness, and paralysis resembling poliomyelitis.

Non-polio virus

• Nearly as common as rhinovirus; fecal-oral transmission or respiratory aerosols leading to flu-like symptoms, or even viral meningitis.

  • Suspected to play a role in juvenile-onset diabetes, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and chronic fatigue syndrome.

Respiratory viruses

• 200 viruses infect the respiratory system, but only members of the family Paramyxoviridae adenovirus, influenza A, parainfluenza 1, 2, and 3, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and coronavirus pose significant threats to the very young, older adults, and the immunocompromised.

  • Paramyxoviridae – Includes two subfamily viral species: Paramyxovirinae and Pneumovirinae.

    • Paramyxovirinae subfamily includes genus Paramyxovirus comprised of the human parainfluenza viruses 1 and 3.

    • Genus Rubulavirus includes human parainfluenza viruses 2, 4a, and 4b, as well as the mumps virus.

    • Genus Morbillivirus includes the measles virus.

    • Subfamily Pneumovirinae contains human respiratory syncytial virus (hRSV).

Paramyxoviridae

• The paramyxoviruses are important pathogens in children, causing serious respiratory diseases: laryngotracheobronchitis (called croup), bronchiolitis, and pneumonitis.

  • Measles is an acute disease seen primarily in children as the virus invades the lymphatic and respiratory systems via the oropharynx.

    • Clinically, the virus produces respiratory symptoms during the initial prodromal stage (fever, cough) and a subsequent rash during the eruptive stage (red spots on the head and body).

Key Terms

• Dermatomes

• Lymphadenopathy

• Neuralgia

• Prodromal stage

• Rhinovirus

• Shingles

• Steroids

Paramyxoviridae (cont.)

• Mumps is a common acute disease seen primarily in children.

  • The virus enters the body via the pharynx or conjunctiva and then spreads to the salivary glands or in some cases to the testes, ovaries, pancreas, and brain.

  • The mumps virus produces obvious and painful parotid salivary gland inflammation.

Human Parainfluenza Viruses (PIVs)

• Cause 30–40% of acute lower respiratory tract infections in infants and children; transmitted by respiratory droplets, they first replicate in ciliated epithelial tissues of the upper respiratory tract (nose and throat) then spread into the lungs.

  • PIV types 1 and 2 cause more severe lower respiratory tract infections, like acute laryngotracheobronchitis (croup).

  • Types 4a and 4b are rarely isolated and, when diagnosed, tend to be the least virulent.

Human Metapneumovirus (hMPV)

• First discovered in 2001.

  • A common pathogen responsible for upper and lower respiratory tract infections, primarily in infants and young children, and a known trigger for asthma.

Respiratory Syncytial Virus (RSV)

• The pathogenic agent in most infant respiratory infections and the major cause of viral pneumonia and bronchiolitis in adults and children.

  • The virus initiates as a local infection in the upper respiratory tract, invading the ciliated epithelia of the nose, eye, and mouth.

    • Moves to the lower respiratory tract to cause croup, pneumonia, or bronchiolitis most often seen in infants; premature infants are most at risk so antiviral mists are given.

Adenoviruses

• Double-stranded DNA viruses with icosahedral capsids, non-enveloped, spherical, and approximately 70 to 90 nm in size, causing pharyngitis, acute respiratory disease, pneumonia, fever, viral conjunctivitis (pink eye), genitourinary infections, and gastroenteritis.

  • Transmission is by fecal-oral route, direct contact (hand to eye), or respiratory aerosols.

Coronavirus

• Named for the crown-like spikes on the viral surface, they are grouped into alpha, beta, gamma, and delta subcategories, of which six types can infect humans.

  • The two best known in the previous two decades were SARS (severe acute respiratory syndrome) in 2002 and MERS (Middle East respiratory syndrome) in 2012.

  • The pathogen first described as a novel coronavirus in late 2019 was described as 2019-nCoV then later designated as SARS-CoV-2.

  • The virus spread rapidly in 2020 and was responsible for the COVID- 19 pandemic that continues at this time with hundreds of millions of infections worldwide and millions of deaths from the original virus as well as delta and omicron variants.

Influenza A

• Influenza viruses are divided into types A, B, and C.

  • Types A and B cause seasonal outbreaks in human populations and are constantly mutating.

  • Type C causes only mild upper respiratory symptoms; not believed to cause epidemic outbreaks.

  • Constant changes require a modified yearly vaccine.

  • Occasionally, a new influenza virus appears for which there is no immunity or vaccine and is referred to as an antigenic shift, often resulting in local epidemics or global pandemics.

    • The most devastating now known as influenza A virus (H1N1) occurred in 1918 (called the Spanish flu) and killed 25 to 50 million people worldwide (700,000 Americans died).

  • Influenza causes a wide range of symptoms, including fever, cough, muscle aches, and chills.

  • Most influenza infections are self-limiting and do not require hospitalization.

Hepatitis Viruses

• Hepatitis is an inflammation of the liver caused by viral, bacterial, or fungal infection. Inflammation of the liver can also be caused by toxins, alcohol, and autoimmune disorders.

  • In 1969, the first hepatitis virus was isolated (hepatitis B). Hepatitis A was isolated in 1973, followed by C, D, and E.

Hepatitis A Virus (HAV)

• A linear strand of RNA and member of the enterovirus group of picornaviruses.

  • Transmitted primarily by the fecal-oral route; also found in semen and blood.

  • Illness usually begins with jaundice, fever, and weakness, preceded by flu-like symptoms and lymphadenopathy treated with gammaglobulin after initial exposure; is not chronic.

  • Vaccinations are effective and required for school children.

Hepatitis B virus (HBV)

• Contains a circular, partly double stranded DNA genome, acquired parenterally (blood transfusions, contaminated needles) or sexually.

  • As a bloodborne pathogen, HBV is of concern in healthcare settings where sharps injuries from hollow-bore (hypodermic) or solid-bore (suture) needle sticks, or puncture from sharp surgical instruments, or even inoculation into the eyes from blood splatter present particular risk for healthcare workers in those critical care areas.

  • The acute phase causes jaundice, weakness, fever, and nausea.

  • Chronic HBV infection can be benign with normal liver tests or may be an aggressive inflammatory process that can lead to cirrhosis (hardening of the liver). HBV is also known to cause cancer of the liver.

  • Two types of vaccine are available and highly recommended for healthcare workers.

Key Terms

• Cirrhosis

• Conjunctivitis

• Jaundice

• Pharyngitis

Hepatitis C Virus (HCV)

• A single-stranded, enveloped RNA viral bloodborne pathogen transmitted parenterally and sexually, though source is unknown in 20% of cases.

  • HVC belongs to the family Flaviviridae and genus Hepacivirus. Other genera include Flavivirus and Pestivirus.

    • Flavivirus diseases include yellow fever, Dengue fever, Japanese encephalitis and tick-borne encephalitis; Pestivirus diseases include bovine viral diarrhea and classic swine fever.

  • Acute HCV infection develops 6 to 10 weeks after exposure, but infection is often not detected until years after exposure.

  • Chronic HCV occurs in 50–60% of cases and most remain contagious for life but are asymptomatic.

  • Many develop aggressive hepatitis and eventual cirrhosis and liver failure, requiring transplantation.

  • The WHO estimated that approximately 3 percent of the human population is infected with HCV.

  • Direct-acting antiviral drug treatments of HCV have been approved.

Hepatitis D Virus (HDV)

• Known as the delta virus, this is an incomplete RNA virus that infects only those liver cells that are already infected with HBV and structurally is unlike any other hepatitis virus.

  • It takes advantage of the HBV enzymes for replication and the acquisition of a protein coat that allows it to survive outside of the liver.

  • Chronic HBV carriers who are infected with HDV may develop fatal superinfection.

Hepatitis E Virus (HEV)

• Is similar to HAV: Both are RNA viruses transmitted through the fecal-oral route and both cause acute, but not chronic, infection.

  • HEV is believed to be the primary cause for hepatitis in countries with poor or marginal sanitation and contaminated water supplies.

  • The illness is usually benign but can be fatal for pregnant women.

Human Immunodeficiency Virus (HIV)

• Virus that causes acquired immunodeficiency syndrome (AIDS); first recognized in 1983.

  • Part of a family of RNA viruses with viral reverse transcriptase that transcribes viral RNA into provirus DNA that is integrated into the host cell’s genome, targeting CD4 T-lymphocytes and macrophages.

    • These retroviruses are generally host-specific and are divided into two subfamilies: oncoretroviruses (with human T-cell lymphotropic virus, or HTLV) and lentiviruses (HIV).

  • Chief routes of HIV transmission: blood, sexual contact, and mother to child

  • Those infected are vulnerable to opportunistic infections and a profound decrease in their T-lymphocyte counts.

    • Infected homosexual males and IV drug users may develop a rare type of skin cancer called Kaposi’s sarcoma for which there is no cure. Can be managed and good health maintained by those infected if healthy lifestyles and drug regimens are followed closely.

Viroids

• In 1971, a plant pathologist isolated tiny particles one-eightieth (\frac{1}{80}) the size of typical viruses, determined to be the cause of potato spindle tuber disease (PSTD) first recognized in the 1920s.

• Viroids are naked loops or short strands of RNA without protein coats.

  • The genetic material is composed of fewer than 400 nucleotides as compared to the typical influenza virus, which has approximately 14,000 nucleotides.

  • Once inside the host cell, the viroid RNA invades the host cell’s RNA strands, tricking it into making new copies. The RNA segment then breaks off and loops itself into a circular shape.

• More than 30 other species of viroids cause diseases in food crops and the only recognized defense currently used against the spread of viroids to other plants is complete destruction of the entire crop.

• Key term: viroid

Prion Diseases

• Transmissible Spongiform Encephalopathy (TSE): A group of diseases in animals and humans caused by infectious prions, mainly in the central nervous system, especially the brain.

• Prions lack nucleic acids and cellular structure.

• Disease results from normal proteins (PrPc) developing abnormal folds, creating prions (PrPsc) on neural tissues, causing destruction, holes, and a sponge-like appearance.

• The function of proteins that become pathogenic prions is unknown.

• Familial transmission accounts for only 10% of cases; 90% are acquired from sources like infected cattle or iatrogenic transmission.

• Animal TSE infections: bovine spongiform encephalopathy (mad cow disease), ovine spongiform encephalopathy (scrapie), chronic wasting disease (CWD) in North American hooved animals.

• Human infections: Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru.

  • Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal neurodegenerative disorder.

  • Variant CJD is distinctly different from classic CJD, although both have long incubation periods before onset of observable symptoms.

  • Initial symptoms of CJD are neurologic disorders or dementia, and behavioral or psychiatric symptoms with generalized diffuse pains are initially seen in vCJD and delayed signs of dementia.

• Gerstmann-Straussler-Scheinker syndrome: Rare neurodegenerative disease found in a few families worldwide.

  • 85% of CJD cases are sporadic; 5–15% involve inherited mutations of the prion protein gene, resulting in Gerstmann-Straussler-Scheinker syndrome.

  • Inherited prion disease manifests ataxia and dementia between 35 and 55, progresses slowly over 2 to 10 years.

• Fatal familial insomnia (FFI): Rare, incurable, autosomal dominant inherited prion disease like G-S-S; presents with increasing insomnia progressing to death within 9 months.

• Kuru: Rare disease in New Guinea in the 1950s among the Fore tribe, whose funeral rites involved consuming bodies of the deceased.

  • Kuru was highly contagious and easily transmitted through cannibalism but strongly discouraged by the government and once discontinued and the infected had died of the disease, kuru was considered eradicated.

• Key terms: ataxia, dementia

• Viruses are considered non-living microbes, yet they are responsible for major disease outbreaks across various life forms.

• A patient with a history of living in the UK is scheduled for a craniotomy to biopsy possible variant Creutzfeldt-Jakob disease (vCJD).

• The patient is non-ambulatory due to coordination loss and pain, and their mental status is rapidly declining.

Definitions:

• Angiogenesis – Formation of new blood vessels.

• Arthropod vectors – Insects or ticks that spread disease.

• Ataxia – Lack of muscle coordination.

• Capsomere – Protein subunit of a virus’s outer shell.

• Cirrhosis – Scarring of the liver.

• Comatose – In a deep unconscious state.

• Conjunctivitis – Inflammation of the eye’s outer membrane ("pink eye").

• Dermatomes – Skin areas supplied by a single spinal nerve.

• Endocytosis – Cell process of taking in substances by engulfing them.

• Enteroviruses – Viruses that infect the intestines.

• Icosahedral – 20-sided geometric shape, common in virus structures.

• Interferons – Proteins that help fight viruses.

• Lymphadenopathy – Swollen lymph nodes.

• Lymphocytes – White blood cells that fight infection.

• Neuralgia – Nerve pain.

• Pharyngitis – Inflammation of the throat.

• Prodromal stage – Early signs before full disease symptoms appear.

• Rhinovirus – Virus that causes the common cold.

• Syncytial – Cells fused together into one with many nuclei.

• Viroid – Infectious RNA molecule without a protein coat.