RNA Viruses

rna viruses
important points about rna viruses
• medically important rna viruses comprise fourteen families.
• most rna viruses contain ssrna genomes (except reoviruses have dsrna genome).
• rna viruses have genome exist either single molecule (non-segmented) or multiple molecules (segmented genome as in rotavirus, influenza virus).
• all viruses contain a single copy of genome (haploid) except retroviruses have two copies of rna(diploid).
• they replicate in the cytoplasm of the infected cell (except retroviruses and orthomyxoviruses are replicates in the nucleus).
• ssrna viruses have polarity strand, either positive strand or negative strand.
• rna viruses have nucleocapsid symmetry either icosahedral(mostly in positive strand viruses) or helical (mostly in negative strand viruses).

positive-sense rna "plus-strand"
positive-sense (5 to 3 ) viral rna signifies that a particular viral rna sequence may be directly translated into the desired viral proteins. therefore, in positive-sense rna viruses, the viral rna genome can be considered viral mrna, and can be immediately translated by the host cell. unlike negative-sense rna, positive-sense rna is of the same sense as mrna. some viruses (e.g., coronaviridae) have positive-sense genomes that can act as mrna and be used directly to synthesize proteins without the help of a complementary rna intermediate. because of this, these viruses do not need to have an rna polymerase packaged into the virion.
medical positive ssrna viruses encompass 6 families involve: picornaviridae, caliciviridae, astroviridae,togaviridae, flaviviridae and coronaviridae.

negative-sense rna " negative -strand"
negative-sense (3 to 5 ) viral rna is complementary to the viral mrna and thus from it a positive-sense rna must be produced by an (rna-dependent rna polymerase) prior to translation. negative-sense rna (like dna) has a nucleotide sequence complementary to the mrna that it encodes. like dna, this rna cannot be translated into protein directly. instead, it must first be transcribed into a positive-sense rna that acts as an mrna. some viruses (influenza, for example) have negative-sense genomes and so must carry an rna polymerase inside the virion.because of the above-stated property viruses in this group encode their own polymerase (rna-dependent rna polymerase [rdrp]) .
medical negative ssrna viruses divided into 6 families include : orthomyxoviridae, paramyxoviriae, rhabdoviridae, filoviridae, bunyaviridae and arenaviridae.
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rna viruses-related to respiratory tract infection
orthomyxoviruses
the family orthomyxoviridae contains virusee of single stranded segmented rna genome (6-8 segments) . out of all, influenza viruses are the most important members of this family which includes: influenza virus a, b, and c . the name orginates during 18th century from a disease that was thought to “influence” by stars . the pathogenic viruses are included in the genus influenzavirus a , whereas other two genera (b and c) circulate constantly in human subjects .
genus: influenza virus
important properties
• it is a member of family orthomyxoviridae.
• shape of the virus is spherical.
• symmetry of nucleocapsid is helical.
• viral genome is segmented, and (-) ssrna(7– 8 segments).
• enveloped (bi-layer membrane).
• spiked: 2 types antigens: h (hemagglutinin for attachment of the virus to target cell) and n( neuraminidase for a release of progeny virus from infected cells).
• standard nomenclature systems for influenza virus include type, host, geographic, strain number, year of isolation and serotype. for example: a/swine/iowa/15/30(h1n1).

classification
• influenza virus classified into three types according to group-specific antigens (nucleocapsid antigens): influenza virus type a, influenza virus type b and influenza virus type c.
• influenza virus types a and b contain 8 segments, while influenza virus type c has 7 segments of ssrna.
• the influenza virus type a (only) can be divided into subtypes(serotypes) according to type-specific antigen( h and n antigens). so far, 16 subtypes of h (h1-h16) and 9 subtypes of n(n1-n9) were identified.

transmission
• influenzavirus a has broad host range capable of infecting human, swine, horses, chicken and birds (aquatic birds). influenzavirus b and c host range are limited to human only.
• infected humans are the main reservoir of infection. the virus transmitted from person to person by air-borne respiratory dropinglets and by contact with contaminated materials of the patient.
• avian influenza virus (influenzavirus a) cause bird flu in domestic poultry birds. fortunately, avian virus was poorly transmissible to human.

antigenic variation
because viral genome is segmented, genetic reassortment can occur during viral replication. the reassortment could lead to an emergence of new human virus (new strain), the progeny of which will contain a mixture of genome segments from human and from an animal strain.
because pigs are susceptible to infection with both avian and mammalian viruses, including human strains, they can serve as a “mixing vessel” for the scrambling of genetic material from human and avian viruses, resulting in the emergence of a novel subtype.
therefore antigenic variation can occur due to a mutation in the sequence of amino acids in proteins of h and n. the mutation leads to change in antigenic nature of h or n or both resulting new strains that non-identified by immune system(escape from immune recognition). there are two types of antigenic variation are known:

1. antigenic shift (complete change in h or n or both). this can only occur with influenza type a because it has wide host range, when two different strains of viruses co-infect the same cell, during viral replication , the rna segments can be mis-packaged into another virus and release new strains. antigenic shift is responsible for influenza pandemics.
2. antigenic drift (partial changes). this occurs in type a and b. it involves minor changes affecting h or n, not both. it is responsible for influenza epidemics.

• antigenic variation of envelope proteins h and n is responsible for epidemic and pandemic diseases. influenzavirus a causes major epidemic disease (pandemic) with significant mortality. influenzavirus b causes sporadic and periodical epidemic disease, usually milder than influenza virus a. while the influenza virus c cause minor (mild), sub-clinical disease, because it stable antigenic and lack neuraminidase gene (the gene is located on the segment which the type c hasn’t it). shift variants appear every 10 years, whereas drift variants appear every year (approximately).

table (1.1): differences between influenza virus types
influenza virus type c
influenza virus type b influenza virus type a distinct characters
absent
absent present animal reservoir
sporadic
epidemic pandemic / epidemic spread
mild
moderate high severity
antigenic drift
antigenic drift antigenic shift / drift variations

pathogenesis
• virus is limited to ciliated epithelial cells of the respiratory tract.
• n antigen facilitates infection by reducing the viscosity of mucus lining by cleaves the substrate (neuramic acid) covering mucosal epithelial cells of respiratory tract and disrupts the mucin barrier, then exposing the cell receptor for h antigen (h responsible for absorption). then the virus enters by endocytosis into the host cell.

• within short time many cells in respiratory are infected and killed. the virus replicates within a nucleus of an infected cell and results in shut-off of host cell protein synthesis by 3 hrs. and new progeny viruses are produced within 8-10 hrs.
• the virus remains localized to respiratory, hence viremia does not occur.

• the virus leads to a death of epithelial cells . denudation of respiratory epithelial cells causes an acute inflammatory response and renders the individuals to bacterial super-infections.

clinical findings
the incubation period (1-4 days) dependent upon the size of the dose and immune status of human. fever, headache, nose secretion, anorexia, cough, chills and generalized myalgia (muscle pain) are most clinical features. if no complication, the disease resolves in 2-7days. complication of influenza individuals at greater risk for complication include elderly and immunocompromised people, the virus spreads to lrt, resulting in secondary infection such as bacterial pneumonia caused by strep.pneumoniae , staph.aureus or hemophilus influenza. when bacterial pneumonia secondary to influenza cause a significant number of deaths especially in older people. mortality rate may reach 40-60% in untreated cases.

epidemiology
influenza occurs primarily in winter months. in the southern hemisphere, eg in australia, and new zealand, influenza occurs in winter months of june through august. most cases caused by influenza type-a has been responsible for 3-5millions of infection worldwide. the epidemic infection caused by type a occurs in each 2-3 years, while epidemic caused by type b is longer 3-6 years. the pandemic disease occurs every 10 years or more.

• global epidemic influenza infections:
1889 h2n2
1900 h3n2
1918 h1n1(spanish flu due to swine flu that causes a catastrophic pandemic, 20 million died with complicated bacterial pneumonia).
1957 h2n2(asian flu)
1968 h3n2(hong kong flu)
1977 h1n1(russian flu)
1997 h5n1
1999 h9n2 (bird flu)
2004 h5n1(bird flu)
2005 h5n1(bird flu)
2009 novel strain contains mixed genome (originated from bird well as swine and human). new h1n1(in 2009).


laboratory diagnosis
• virus is isolated from a clinical specimen (nasal washings, gargles, and throat swabs) in cell culture.
• detection of specific antibodies level over 2 weeks by serological tests: cft and elisa
• detection of viral nucleic acid by pcr.
• detection of viral proteins.

control methods
a. treatment
• amantadine and rimantadine are used to prevent uncoating of influenzavirus a. whereas sanamavir and oseltamivir are inhibitors for neuraminidase in influenza virus a and b.
• children given aspirin when they have influenza can develop a severe liver and brain disease called (reye?s syndrome, it is severe encephalitis). give acetaminophen for fever in children, no aspirin.

b. prevention
• killed influenzavirus a and b vaccine is given intramuscularly for elderly and immunocompromised patients. attenuated influenza a vaccine (given spraying into the nose ) is available for healthy adults and children. because the virus undergoes antigenic shift, the vaccine will not be effect in protecting against the new subtypes of virus. therefore, it becomes necessary to develop a new vaccine as quickly as possible. influenza vaccines give protection for 6 months.

• personal hygiene and avoid contact with patients.

• covering mouth and nose during coughing and sneezing with a mask.

• avian virus was controlled by destroying poultry.




paramyxoviruses
paramyxoviruses are included under the family paramyxoviridae.all the viruses in this group are enveloped and contain surface glycoproteins over it . the genome consists of ssrna of negative polarity and 13-19 kb in size. the paramyxoviruses are the leading cause of respiratory disease in children general illnesses include croup and inflammation of respiratory tract. replication of the virus takes place in the cytoplasm and are released by the budding process.
parainfluenza virus
genus: respirovirus (parainfluenza type-1 and 3).
genus : rubulavirus( parainfluenza type-2,4a and 4b).


important properties
• it belongs to paramyxoviruses.
• ss(-)rna, non-segmented.
• helical nucleocapsid.
• enveloped virus.
• spikes (glycoprotein include: f and nh).

transmission
parainfluenza virus transmitted from person to person by air-borne respiratory dropinglets or aerosol and by direct contact with contaminated materials of a patient . humans are considered as main sources of infection.

pathogenesis
• primary infection of upper respiratory tract, may involve nose, throat, resulting in common cold. the infection may move extensive and, especially with type-1,2 may involve larynx and upper trachea, resulting in croup (laryngotracheobronchitis). it is characterized by respiratory obstruction due to swelling of the larynx and related structures.

• the infection may spread deeper to lower trachea and bronchi, resulting pneumonia or bronchiolitis, especially with type-3 (type-4 does not cause serious disease).

clinical findings
• the incubation period appears to be 5-6 days. the infection result in rhinitis and pharyngitis and pneumonia characterized with fever, headache, and cough. the most common complication of infection is otitis media.


epidemiology
• parainfluenza viruses are widely distributed geographically.
• they are a major cause of lower respiratory tract infection in young children.
• type-3 is endemic, with some increase during spring, whereas type-1 and 2 tend to cause epidemics during fall or winter.

laboratory diagnosis
• isolation of virus in tissue culture.
• serological test: by haemagglutination inhibition test (hi), complement fixation test (cft), elisa and radioimmunoassay ria tests.
• nucleic acid detection by pcr.


control
• treatment with ribavirin.
• no vaccine is available.

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