Virus and Pathogenesis

Last updated December 16, 2010. At the current time, this content is considered historical and will not be updated until further notice.

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Influenza A Viruses
Origins of the Pandemic H1N1 2009 Influenza Virus
Pathogenesis

General Information About Influenza A Viruses

Descriptive information

• Influenza A viruses are negative-sense single-stranded RNA viruses and belong to the family Orthomyxoviridae and the genus Influenzavirus A. 
• Enveloped virions are 80 to 120 nm in diameter, are 200 to 300 nm long, and may be filamentous. They consist of spike-shaped surface proteins, a partially host-derived lipid-rich envelope, and matrix (M) proteins surrounding a helical segmented nucleocapsid (6 to 8 segments).
• The virus envelope glycoproteins (hemagglutinin [HA] and neuraminidase [NA]) are distributed evenly over the virion surface, forming characteristic spike-shaped structures; antigenic variations in these proteins form the basis of the classification system for influenza A virus subtypes.

Influenza A virus subtypes

• There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A.
• Human disease historically has been caused by three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2). More recently, human disease has been recognized to be caused by additional HA subtypes, including H5, H7, and H9 (all from avian origin).
• All of these subtypes have been found in birds, and birds are the primordial reservoir for influenza A viruses.
• Several subtypes have been found in pigs (see section below for more information).

Origins of the Pandemic H1N1 2009 Influenza Virus

• The pandemic H1N1 2009 influenza A virus (pH1N1 2009 virus) is antigenically unrelated to human seasonal influenza viruses but genetically related to viruses that have been circulating in swine for a number of years—North American H3N2 triple reassortment, classical swine H1N1 lineage, and the Eurasian avian-like swine H1N1 virus (Garten 2009).
• The NA and M gene segments are in the Eurasian swine genetic lineage; they were originally derived from a wholly avian influenza virus and likely entered the Eurasian swine population in 1979. Until emergence of the current novel H1N1 strain, these gene segments had not been identified outside Eurasia.
• The HA, NP, and NS gene segments are in the classical swine lineage which is common in North America; they likely entered the swine population around 1918 and can be traced to the 1918 H1N1 pandemic virus, which caused the "Spanish flu." The HA gene, which codes for the surface protein most important for immune response, is related most closely to the HA found in contemporary influenza viruses circulating among swine.
• The PB1, PB2, and PA gene segments are from the North American H3N2 triple reassortment lineage, which was first isolated from swine around 1998. Viruses that seeded this lineage were originally of avian origin.

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Pathogenesis

Virulence Factors

Several unusual features of the pH1N1 2009 virus include the following (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza):

• The virus shows increased ex vivo replication in human bronchial epithelium at 33°C compared with seasonal influenza strains.
• The virus shows increased replication in ex vivo human lung tissue.
• The virus targets type I and type II pneumocytes (which line the alveoli of the lungs).

Pathologic Features

Early changes include vascular congestion; alveolar hemorrhage also can occur.

A report of autopsy tissue samples from 100 fatal cases of pH1N1 2009 virus infection showed the following major findings (Shieh 2010):

• The most prominent histopathological feature observed was viral pneumonia associated with diffuse alveolar damage.
• Alveolar lining cells, including type I and type II pneumocytes, were the primary infected cells.
• Bacterial co-infections were identified in >25% of the patients.

Another study of autopsy findings from 21 Brazilian patients with confirmed pH1N1 2009 infection showed (Mauad 2010):

• Diffuse alveolar damage was present in 20 patients.
• Diffuse alveolar damage was associated with necrotizing bronchiolitis in six patients and extensive hemorrhage in five patients.
• A cytopathic effect was noted in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways.

Investigators in Norway found that a specific mutation in the viral HA (D222G) of pH1N1 2009 was associated with increased frequency in severe fatal cases; this mutation was not found in clinically mild cases (Kilander 2010).

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