Virologia Applicata E.A. Influenza VIROLOGIA

Virologia Applicata E.A. Influenza The virus and its replication

Virologia Applicata E.A. Genus Orthomixovirus Species (* indicates type species) Serotypes or SubtypesHosts Influenza virus AInfluenza A virus (*)H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7 Human, pig, bird, horse Influenza virus BInfluenza B virus (*)Human, seal Influenza virus CInfluenza C virus (*)Human, pig Influenza virus (Orthomyxovirus)

Virologia Applicata E.A. Influenza A virus: HA subtypes SubtypeHumanSwineHorseBird H1... H2.. H3.... H4. H5. H6. H7.. H8. H9. H10. H11. H12. H13. H14. H15. H16.

Virologia Applicata E.A. Influenza virus nomeclature HxNy (where 1 < x <16 and 1 < y < 9)

Virologia Applicata E.A. Influenza virus (Orthomyxovirus)

Virologia Applicata E.A.

Influenza virus

Virologia Applicata E.A. Influenza A virus genome RNA segments and coding assignments

Virologia Applicata E.A. Influenza virus life cycle

Virologia Applicata E.A. Influenza A virus: attachment Binds to cell surface carbohydrate - sialic acid Ubiquitous receptor Can be present as part of glycoprotein or glycolipid Specific requirement for  2-3 and  2-6 linkages gives different tropism for avian vs. human cells (pigs have both)

Virologia Applicata E.A. Influenza A virus: attachment Specific preferences for receptors and/or linkages gives different tropism for influenza viruses

Virologia Applicata E.A. Influenza A virus: attachment

Virologia Applicata E.A. Influenza A virus: entry

Virologia Applicata E.A. Influenza A virus: uncoating

Virologia Applicata E.A. Influenza A virus transcription and replication

Virologia Applicata E.A. Influenza A virus transcription and replication

Virologia Applicata E.A. Influenza A virus: maturation and budding

Virologia Applicata E.A. Influenza Pathogenesis

Virologia Applicata E.A.

Influenza virus: the infection Influenza virus enters through the nose and settles in the respiratory tract

Virologia Applicata E.A. Influenza virus:pathogenesis

Virologia Applicata E.A. Incubation : 1- 4 days Prodromic phase: malaise, headache Disease’s symptoms: fever (3-8 days), mialgia, cough The infection typically resolves within 7-10 days through the action of the innate and acquired immune systems Complications: »Pneumonia (viral),Pneumonia (bacterial), Myosites, Encephalitises, Convulsions »Reye Syndrome (treatment with aspirin) Influenza virus: the disease features

Virologia Applicata E.A. Influenza virus: the immune response

Virologia Applicata E.A. Influenza Epidemiology

Virologia Applicata E.A. Antigenic variation of influenza virus envelope proteins Antigenic drift Is the appearance of a virus with a slightly altered surface protein (antigen) structure following passage in the natural host. This process occurs by accumulating substitution mutations that facilitate evasion of the host immune response. Antigenic shift Is a major change in the protein of a virus as completely new surface proteins are acquired by the virus. This process occurs when viruses with segmented genomes exchange segments after coinfection. The new reassortant viruses display dramatic changes in surface proteins that facilitate escape from immune surveillance.

Virologia Applicata E.A. Influenza virus: the antigenic drift

Virologia Applicata E.A. Influenza virus: the antigenic shift

Virologia Applicata E.A. A pandemic strain of influenza may occur by genetic reassortment between human and avian viruses, or by adaptation of an avian virus. This may involve avian viruses from aquatic birds or domestic poultry, and could potentially involve an additional species such domestic pig. Reassortment could involve simply the HA gene, both HA and NA genes, or combinantion of HA and other genes from the avian virus Generation of pandemic influenza virus strains

Virologia Applicata E.A. Models for the generation of pandemic influenza virus strains In the classical genetic reassortment model, avian and human viruses bind their respective receptors in the pig tracheal epithelium In the adaptation model, avian viruses acquire the ability to replicate efficiently in humans by adapting to the human receptor in pigs. The change is mediated by a mutation in the HA gene

Virologia Applicata E.A. Models for the generation of pandemic influenza virus strains An avian virus may infect a human and reassort with a human virus An avian virus may infect a human and acquire the ability to recognize the receptor on human epithelial cells, leading to efficient replication in humans and the ability to spread from human to human

Virologia Applicata E.A. The 1918 flu was H1N1 The 1957 “Asian flu” was H2N2 The 1968 “Hong Kong flu” was H3N2 The 1977 “Russian flu” was H1N1 Eras of human Influenza A virus

Virologia Applicata E.A. Postulated evolution of human influenza virus A from 1889 to 1977 Antigenic shift, not drift, was the driving force for the five pandemics of human influenza during the past century

Virologia Applicata E.A. Origins of the major human pandemic influenza virus strains

Virologia Applicata E.A. Influenza Prevention and control

Every year, an estimated 3 million to 5 million people worldwide become seriously ill from influenza, and as many as 500,000 - primarily children and the elderly – die from the ensuing complications.

Virologia Applicata E.A. Influenza virus infection: prevention

Virologia Applicata E.A Northern Hemisphere winter season The composition of virus vaccines for use in the Northern Hemisphere influenza season recommended by the World Health Organization on February 18, 2010 was: * an A/California/7/2009 (H1N1)-like virus; * an A/Perth/16/2009 (H3N2)-like virus; * a B/Brisbane/60/2008-like virus. The H1N1 strain used in this composition is the same strain used in the 2009 flu pandemic vaccine

Virologia Applicata E.A. Influenza virus infection: therapy Antiviral Drugs for the Flu Season: Two flu antiviral drugs are recommended for use in the United States during the flu season: oseltamivir and zanamivir. Oseltamivir and zanamivir are effective against both influenza A and B viruses. Oseltamivir (Tamiflu) is approved to both treat and prevent flu in people one year of age and older. Zanamivir (Relenza)Zanamivir (Relenza) is approved to treat flu in people 7 years and older and to prevent flu in people 5 years and older. Oseltamivir (Tamiflu) Rimantadine (Flumadine)

Virologia Applicata E.A. Virus isolation in primary cell cultures Haemoadsorption on infected cells Haemogglutination Immunofluorescence ELISA RT-PCR Influenza virus infection: diagnosis

Virologia Applicata E.A. Influenza Avian flu

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Transmission electron micrograph of avian influenza H5N1 virus

Virologia Applicata E.A. Avian influenza virus pathogenicity All of the HPAI viruses belong to the H5 or H7 subtypes

Virologia Applicata E.A. Factors of probable relevance The prevalence of an avian influenza virus subtype in domestic poultry Documented human infection and human-to-human transmission of the virus Factors of unknown relevance High pathogenicity of the avian influenza virus The pathogenicity of the virus in mammals other than humans The ability of the viral haemagglutinin glycoprotein to bind to sialic-acid residues with an -2,3-linkage (avian) or with an -2,6- linkage (human) The stalk length of the viral neuraminidase glycoprotein The presence of a Lys627 instead of the Glu627 of the viral RNA polymerase protein PB2 (polymerase basic protein 2) (high virulence in mice) Factors contributing to the emergence of pandemic H5N1 influenza

Virologia Applicata E.A. A pandemic strain of influenza H5 may occur by genetic reassortment between human and avian viruses, or by adaptation of an avian virus. This may involve avian viruses from aquatic birds or domestic poultry, and could potentially involve an additional species such domestic pig. Reassortment could involve simply the HA gene, both HA and NA genes, or combinantion of HA and other genes from the avian virus Generation of pandemic influenza H5 virus strains

Virologia Applicata E.A.

Affected areas with confirmed cases of H5N1 avian influenza Overall mortality in reported H5N1 human cases is approximately 60%

Virologia Applicata E.A. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO

Virologia Applicata E.A. Phylogenetic relationships of H5N1 viruses Currently, there are ten different groups (clades) of H5N1 viruses circulating among poultry (clade 1 and clade 2 viruses). Clade 1 viruses have caused human infections. At least three subgroup or subclades of clade 2 H5N1 viruses have infected humans to date: subclades 2.1, 2.2 and 2.3 viruses

Virologia Applicata E.A. Prevention of pandemic H5N1 influenza

Virologia Applicata E.A.

Influenza Pandemic H1N1 (swine flu) 2009

The 2009 pandemic influenza H1N1 (swine flu) virus

Generation of pandemic 2009 H1N1 (swine flu)virus 2009 H1N1 influenza virus is a quadruple reassortment with gene products from pigs (Europe and Asia origin), avian influenza and human influenza. This virus is antigenically unrelated to H1N1 influenza viruses in circulation since 1957.

Host and lineage origins for the gene segments of the 2009 A (H1N1) virus PB2, polymerase basic 2;PB1, polymerase basic 1;PA, polymerase acidic;HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; M, matrix gene; NS, nonstructural gene

A maximum likelihood phylogenetic tree for nucleotide sequences of the HA gene of selected influenza viruses

Pandemic 2009 H1N1 swine flu: deaths by august 2010