Picornaviridae

Image:www.lasvacunas.org/enfermedades/poliomielitis.asp

Image: www.qub.ac.uk/afs/vs/vsd6e.html

Image:www.hms.harvard.edu/news/releases/0100hogle.html

Created by Emily Flynn ~ Created February 4, 2004, Last Modified March 14, 2004 ~ contact: eflynn@stanford.edu

This viral webpage was created for a Stanford University course: Humans and Viruses, MI 115A Program in Human Biology Instructor Dr. Robert Siegel Winter 2004 Follow the “Student Web Pages” link to view webpages from: · 1998 · 1999 · 2000 · 2002 For more general information: Centers for Disease Control & Prevention World Health Organization National Institutes of Health Contents of this webpage: Introduction to Picornaviridae Polio Virus Profile Epidemiology Incubation & Pathogenesis Clinical Presentation Treatment & Prevention Hepatitis A Virus Profile Epidemiology Incubation & Pathogenesis Clinical Presentation Treatment & Prevention Research Updates Drug Profile: Pleconaril Pathogen Cards

Introduction Though picornaviruses are named for their small (“pico” + “RNA” = picorna) size, they include a large and diverse array of viruses – over 200 serotypes. These viruses can be traced all the way back to Ancient Egyptian records of polio epidemics, but are still around and cause a menagerie of diseases today, from polio to hepatitis A to the “common cold.” Ø Picornaviruses contain positive sense, single-stranded RNA that is approximately 7-8 kilobases long. Ø The genome is monopartite and polyadenylated at the 3’ end, but has a VPg protein at the 5’ end in place of a cap. Ø The viral RNA is infectious and replication takes place in the cytoplasm. Ø The virus has an IRES (Internal Ribosomal Entry Site) which distinguishes it from many other RNA viruses. Ø The virus is naked with an icosahedral capsid. Ø The triangulation number is 3, while the capsid has four unique proteins: VP1, 2, 3, and 4. Ø The capsid is one of the smallest of all viruses with a diameter of only 27-30nm. Ø Translation and cleavage of viral polypeptides produces eleven distinct proteins.

There are four picornavirus genera that cause human disease:

Ø Enteroviruses

Ø Rhinoviruses

Ø Hepatovirus

Ø Parechoviruses

Ø Enteroviruses (more than 60 known serotypes):

· Poliovirus 1-3

· Coxsackie A1-24

· Coxsackie B1-5

· ECHOvirus 1-7, 9, 11-21, 24-27, 29-33

· Enterovirus 68-71

· Viluisk human encephalomyelitis virus

v Enteroviruses are transmitted through the fecal-oral route and are highly communicable. Generally, viral shedding persists long after symptoms cease so that transmission occurs frequently, particularly in schools, childcare centers, and with close contact. Enteroviruses cause a wide variety of syndromes that range in severity from mild and non-neurologic to neurologic, paralytic, and fatal:

· Assorted enteroviral exanthems (rashes)

· Acute hemorrhagic conjunctivitis (AHC)

· Hand, foot, and mouth disease

· Poliomyelitis

· Encephalitis

· Summer colds

· Herpangina

· Myocarditis

· Pericarditis

· Meningitis

· Pleurodynia

· Myalgia

For more information on poliomyelitis, see the Polio Viral Profile below.

Ø Rhinoviruses (more than 100 known serotypes):

v Rhinoviruses are transmitted through the respiratory route and replicate in the nose (“rhino”). The many serotypes are divided into “major” and “minor” groups and all cause a similar syndrome – the “common cold.” The large number of serotypes allows many rhinovirus infections to occur in one person over time, since immunity only develops for one serotype and each newly acquired rhinovirus causes a new “cold.” About half of all colds can be attributed to rhinoviruses, particularly those that occur in the winter.

Ø Hepatovirus (one serotype):

v Hepatovirus is the lone virus in its own genus. The virus is transmitted through the fecal-oral route, which is manifested most often by ingestion of contaminated food or water. The resulting disease is hepatitis A. For more information, see the Hepatitis A Viral Profile below.

Ø Parechovirus (two serotypes):

v Parechoviruses are limited to two serotypes of human parechovirus, formerly known as echovirus 22 and 23. These viruses are closely related to the ECHOvirus group, a name that refers to Enteric Cytopathic Human Orphan virus. Neither the ECHOviruses nor the Parechoviruses are now considered orphan viruses, but the name remains unchanged.

Sources:

1. D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman and S. E. Straus, Eds . Fields Virology, Fourth Edition, Volumes 1 and 2. Lippincott Williams and Wilkins, Philadelphia (2001)

2. Ryan, Kenneth, and Ray, C. George, Sherris Medical Microbiology, 4^th Edition, McGraw-Hill, 2004, pp 541.

Top

Polio Virus Profile

Poliomyelitis (commonly known as “polio”) is an infectious disease caused by polioviruses 1, 2, and 3 in the enterovirus genus of the picornaviridae viral family. From a public health standpoint, it is the most important of the enteroviruses. Like all enteroviruses, poliovirus is transmitted through the fecal-oral route, either directly from person-to-person or indirectly through contaminated water sources. It is characterized by permanent paralysis due to spinal nerve damage and muscular wasting, particularly in young children who are most commonly affected.

Polio EPIDEMIOLOGY

Poliovirus has been a primary subject of medical research and public health intervention for most of the 20^th century, as it continues to devastate communities worldwide. Though the summer epidemics of the 1940s and 1950s caused panic and widespread paralysis in the United States and Western Europe, polio has since become more of a concern in less developed countries. Since it can be transmitted both indirectly though contaminated food and water and directly from person-to-person, polio prevalence is highest in countries with poor sanitation and among children who generally have poor hygiene practices. Indeed, two thirds of cases occur in children under age 9 and nearly all cases occur in less developed countries. As development improves sanitary conditions in these countries, polio incidence drops significantly. As children are not exposed to the virus during childhood, adults may become infected when exposed at an older age. These adult cases carry a much higher risk of paralytic poliomyelitis, which is a serious concern that accompanies the positive trends in polio reduction.

Currently, there are only a handful countries in which polio is endemic (countries which have not successfully eliminated the virus). India, Pakistan, and Nigeria have 98 percent of polio cases in the world, with particular regions most affected: Uttar Pradesh and Bihar in India, North West Frontier Province in Pakistan, and Kano in Nigeria. Egypt, Niger, and Afganistan are also endemic. At the time of the World Health Assembly in 1988, there were more than 125 countries with significant poliovirus prevalence which paralyzed more than 1000 children every day. At the end of 2003, reports indicated that there were only 677 cases during the whole year – a reduction of 99 percent from 1988. This reduction is due to improvements in sanitary conditions in combination with widespread vaccination efforts. By 1993, wild poliovirus was eliminated from the Western Hemisphere and many parts of the world:

Images: WHO Polio Eradication: http://www.polioeradication.org/vaccines/polioeradication/all/global/default.asp

Polio INCUBATION & PATHOGENESIS

Poliovirus enters the body orally and makes its way to the upper gastrointestinal tract where it replicates in the epithelial and lymphoid tissues. The incubation period between infection and clinical presentation may last anywhere from 4-35 days, though it usually lasts 7-14 days. Once the virus reaches the gastrointestinal tract, it can spread to other locations in the body, including the central nervous system. Poliovirus’ unique ability to cross the blood-brain barrier allows it to travel to the peripheral spinal nerves – the axons and perineural sheaths. Anterior motor neurons are particularly vulnerable to infection. Viral infection induces an inflammatory response that can cause extensive neural destruction. This destruction is irreparable and often leads to paralysis and muscular wasting. After clinical symptoms cease, the virus may persist in the body for up to four weeks.

Polio CLINICAL PRESENTATION

Though polio infection can be devastating in its paralytic form, 9 out of 10 infections are actually asymptomatic or have symptoms that are too mild to be noticed. There are three types of disease caused by poliovirus:

· Abortive poliomyelitis: a non-specific febrile illness that lasts for 2-3 days without central nervous system involvement; has complete recovery.

· Aseptic meningitis: a non-paralytic poliomyelitis that includes irritation of the meninges (back pain, neck stiffness), in addition to signs of abortive poliomyelitis, has complete recovery.

· Paralytic poliomyelitis: a rare disease that occurs in less than 2% of infections; it often begins with minor illness that appears to improve but then results in asymmetric flacid paralysis. In the most severe cases, all four limbs may be paralyzed or the brainstem may be damaged with cranial nerve paralysis and respiratory muscle damage. Recovery may begin within a few days and can last six months, at which point the remaining paralysis is permanent.

The disease of greatest concern is paralytic poliomyelitis, since it can be permanently debilitating. Generally, acute flaccid (floppy) paralysis of the legs is more common than the arms. In some cases, more extensive paralysis results and can reach muscles of the trunk and result in quadriplegia. Bulbar polio is the most severe form of paralysis that reaches the brainstem and can impair breathing, speaking, and swallowing capacity. Death by asphyxiation is possible in such severe cases.

Post-polio syndrome (PPS) is a condition that occurs in 25-40 percent of polio survivors from 30-40 years after initial polio disease. Muscles that were damaged in the initial infection may become weaker and symptoms such as fatigue, joint pain and in some cases forms of scoliosis may occur. Some patients may even develop symptoms that resemble Lou Gehrig’s disease (amyotropic lateral sclerosis – ALS). Post-polio syndrome is not usually life-threatening and does not involve infectious virus.

Source: The Pink Book, 8^th Edition, pp 90.

Polio TREATMENT AND PREVENTION

Image: http://www.unicef.org/immunization/index.html

Treatment for poliovirus infection is non-specific and targets alleviation of symptoms only, since no effective antiviral treatment is currently available. One anti-picornal drug, pleconaril, is currently being studied and has been delayed in clinical trials (see “Drug Profile” section for more information). In symptomatic cases, moist heat and physical therapy can help to stimulate and relax muscles to improve patient comfort. When paralysis occurs, it is almost always permanent, since motor nerve damage cannot be repaired. There are cases such as that of runner Wilma Rudolf in which wasted muscles might be strengthened with additional stimulation, but recovery is extremely rare. Most paralytic patients lose function of one or more limbs and often use crutches to assist with walking and daily tasks.

Prevention of poliovirus infection is possible with improvements in sanitary conditions and with immunization. Because poliovirus is often transmitted through water sources, efforts to improve sewage treatment and to ensure a clean water supply have had very positive effects in reducing polio prevalence in less developed countries, along with reductions in many other illnesses. However, more intervention is required since the virus can also be transmitted from person-to-person and can then spread rapidly where there is no immunity.

Prevention of polio through immunization has been proven to be tremendously successful in reducing polio incidence for the past 40 years. Development of the inactivated Salk vaccine in 1955 and the live attenuated Sabin vaccine in 1963 dramatically changed the face of the polio panic that engulfed the United States in the preceding decades. While both vaccines are effective in preventing most poliovirus infections, they differ in some characteristics:

· The Salk Vaccine

o Known as “IPV,” inactivated

o Contains all 3 viral serotypes

o Given in 3 subcutaneous injections

o Has no serious side effects

o Induces antibody response in 98 percent of recipients

o Standard childhood vaccine in the United States and most developed countries

· The Sabin Vaccine

o Known as “OPV,” live attenuated

o Contains all 3 viral serotypes

o Given in 3 oral doses

o Induces antibody response in 95 percent of recipients

o Boosters required to maintain antibody levels

o Small risk of vaccine-associated paralytic poliomyelitis (VAPP) in 1 out of every 2.4 million doses, higher risk with immunodeficiency

o Can lead to herd immunization

o No longer used in the United States since 1999

o Used frequently in less developed countries, easier to administer because it does not require injection by needle.

Vaccine-associated paralytic poliomyelitis (VAPP) is a concern with administration of the Sabin vaccine and has motivated many countries (including the United States) to use only the Salk vaccine. This paralytic disease occurs when the live attenuated virus in OPV reverts or mutates to a more neurotropic form and causes permanent neural damage. VAPP cases comprised the great majority of polio cases in the United States for many years:

Global polio eradication efforts have been largely successful in eliminating wild poliovirus from most countries and even continents. In 1988, the World Health Organization set a goal to eradicate polio from the world by 2000 in cooperation with The Global Polio Eradication Initiative (GPEI), Rotary International, the U.S. Centers for Disease Control, UNICEF, and over 200 national governments. It has been one of the world’s largest public health initiatives and has immunized over 2 billion children and has cost US$ 3 billion since it began.

Source: The Pink Book, 8^th Edition, pp 98.

Sources:

1. End of Polio Campaign: http://www.endofpolio.org/home.html

2. National Institute of Neurological Disorders and Stroke: Post-Polio Syndrome Fact Sheet. http://www.ninds.nih.gov/health_and_medical/pubs/post-polio.htm

3. Ryan, Kenneth, and Ray, C. George, Sherris Medical Microbiology, 4^th Edition, McGraw-Hill, 2004, pp 532.

4. The Pink Book, 8^th Edition. Poliomyelitis. Pp 88-100.

5. WHO: Polio Eradication, Background: The Disease and Virus. http://www.polioeradication.org/all/background/disease.asp

6. WHO: “Now more than ever: Stop Polio Forever,” Global Status and Progress. http://www.polioeradication.org/vaccines/polioeradication/all/news/20040115bpress.htm

top

Hepatitis A Viral Profile

The hepatitis A virus occupies its own Hepatovirus genus of the Picornaviridae viral family. It is one of two hepatitis viruses that is transmitted through the fecal-oral route and most often travels from person-to-person through contaminated water or food. Though its symptoms are usually mild and self-limited, this virus infects over 90 percent of the population in many less developed countries where clean water and sanitation are lacking, and is therefore a major public health concern.

Hepatitis A EPIDEMIOLOGY

Hepatitis A is a disease that affects both adults and children worldwide. It occurs most frequently in less developed countries or countries in transition where water and sanitation systems are often contaminated. In such countries, it affects communities of lower socio-economic status where people may live in more crowded conditions and without access to clean water sources. More than 90 percent of the population may show evidence of previous infection, and is therefore immune to further infection. In these countries, most hepatitis A infection occurs during childhood and is usually asymptomatic. International travelers are at increased risk, since they often are not immune, and vaccination is recommended.

Hepatitis A causes disease in more developed countries as well, particularly under crowded conditions, as in child-care centers, residential living centers, and residential hospitals. Outbreaks may occur, but are difficult to trace to specific sources. In the United States, as many as 35,000 people have been infected in outbreaks, sometimes linked to contaminated shellfish or vegetables exposed to contaminated water. Only about one third of the population has immunity due to previous infections. Transmission can also occur directly from person-to-person through close contact. Men who have sex with men, drug users, people with chronic liver disease, and people with clotting factor disorders are at increased risk. With improving sanitation and wide vaccination initiatives, hepatitis A incidence has been decreasing since the 1970s.

Hepatitis A Cases in the United States:

Source: http://www.cdc.gov/ncidod/diseases/hepatitis/a/vax/index.htm

Hepatitis A INCUBATION & PATHOGENESIS

Once the virus enters the body, it begins to replicate in the enteric mucosa, then in the intestine, and eventually in the liver during the viremic phase. Once in the liver, the virus infiltrates lymphoid cells and causes necrosis of parenchymal cells depending on the severity of infection. This liver infection is responsible for many of the symptoms of infection. Patients are most contagious one or two weeks before symptoms appear, during which time virus can also be detected in fecal samples.

Hepatitis A CLINICAL PRESENTATION

Hepatitis A infection causes clinical symptoms in about half of infected adults. It is more than five times more likely to be symptomatic in adults than children, so most children have asymptomatic infection. Presentation of clinical symptoms begins quickly after incubation with fever, nausea, diarrhea, loss of appetite, and abdominal pain. Some with acute infection present with jaundice within 2-3 days of clinical onset, due to elevated serum bilirubin and aminotransferase levels resulting from liver swelling and damage. Jaundice is a common sign of most hepatitides. This liver malfunction causes stools to be reddish and urine to be dark before jaundice becomes evident in the skin. Clinical disease may last days or sometimes weeks, but 99 percent of cases are self-limiting and leave no lasting damage. Fewer than one sixth of people have relapse of mild symptoms over a period of 6-9 months. In very rare cases (0.01%), severe liver necrosis may occur, which can lead to fulminant disease that can also cause death.

Hepatitis A TREATMENT AND PREVENTION

Treatment of acute hepatitis A is non-specific and targets alleviation of symptoms only. Nutritious foods and adequate rest are recommended until symptoms improve, which they almost always do without intervention.

Prevention of hepatitis A infection is possible with both behavioral interventions and with immunization. Avoiding exposure to water and food that may be contaminated whenever possible is the most direct approach to avoid infection. In less developed countries, improvements in sanitation and access to clean water sources have reduced hepatitis A infection rates significantly. Travelers to these countries are advised to avoid drinking tap water and foods (especially vegetables) that have been peeled or rinsed in unpurified water.

Effective vaccines against hepatitis A virus have been available for many years and are in widespread use in the United States. The inactivated, formalin-killed vaccine is almost 100 percent effective in inducing long-lasting immunity. Live attenuated vaccines are not nearly as effective. Hepatitis A vaccination is common, though not universal, and is highly recommended for international travelers to endemic areas. Passive immunization is also widely available and consists of immune serum globulin (ISG) collected from a large group of donors. It can be effective (80-90%) in preventing hepatitis A infection when administered to people with determined exposure before the appearance of clinical symptoms. This can also be given to travelers who need vaccination right before travel, with short-term notice. Overall, vaccine immunization is preferred over passive ISG immunization.

Though an effective hepatitis A vaccine is available, universal immunization may not be the most cost-effective method to reduce disease burden. Because hepatitis A causes a mild disease that is severe only in extremely rare cases, health programs in less developed countries may not find immunization campaigns necessary. With limited financial resources, their money may be better spent on prevention efforts for more severe diseases such as polio, tuberculosis, measles, and malaria, which cause much higher fatality and have a larger socio-economic impact.

Sources:

1. MMWR: Recommendations and Reports: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). February 8, 2002 / 51(RR02);1-36. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm

2. National Center for Infectious Diseases, CDC: Hepatitis A Fact Sheet. http://www.cdc.gov/ncidod/diseases/hepatitis/a/fact.htm

3. Ryan, Kenneth, and Ray, C. George, Sherris Medical Microbiology, 4^th Edition, McGraw-Hill, 2004, pp 541.

4. World Health Organization: Water-borne Diseases. http://www.who.int/water_sanitation_health/diseases/hepatitis/en/

top

Research Updates

On Recombinant Polioviru