Bioinformatics Analysis to Assess the Homology Among Influenza a Viruses and Other Pathogens

Abstract

The mechanisms by which influenza viruses cross species barriers to infect humans or other mammals, either causing dead-end infections or leading to subsequent human-to-human transmission, are unknown. Moreover, the properties of influenza viruses that have the greatest medical and public health relevance, such as human infectivity, transmissibility, and pathogenicity, appear to be complex and polygenic and are poorly understood (Morens et al., 2009). Influenza viruses are members of the Orthomyxoviridae family of RNA viruses and are grouped into types A, B, and C on the basis of their nucleoprotein (NP) and matrix protein characteristics. Type A influenza viruses are classified into subtypes based on two proteins on the surface of the virus, hemagglutinin (HA) and neuraminidase (NA) (Oliveira et al., 2003; Marjuki et al., 2007).
Every influenza A virus has a gene coding for 1 of 16 possible hemagglutinin (HA) surface proteins and another gene coding for 1 of 9 possible neuraminidase (NA) surface proteins. These two proteins (facilitating viral attachment and release) are critical for the infection of susceptible cells of a host (Portela and Digard, 2002).
Of the 144 total combinatorial possibilities, only three HAs and two NAs, in only 3 combinations (H1N1, H2N2, and H3N2), have ever been found in truly human-adapted viruses (Morens et al., 2009). Influenza A viruses infect a large variety of mammals and birds, occasionally producing devastating pandemics in humans (Alexander and Brown, 2000). Epidemics frequently occur between pandemics as a result of gradual antigenic change in the prevalent virus; this phenomenon is termed antigenic drift (Laver et al., 1990). Three notable (years: 1918, 1958 and 1968) severe pandemics have occurred during the 20th century: An H1N1 caused the 1918's "Spanish flu" pandemic, while an H3N2 was responsible for the 1968 "Hong Kong flu" pandemic (Taubenberger and Morens, 2006 a and b).
All avian influenza viruses are classified as type A. Only four avian influenza A viruses including H5N1, H7N3, H7N7 and H9N2 viruses have jumped host species to infect humans (Bao et al., 2008). The H5N1 subtype, in particular, has been reported in 410 human cases and has caused 256 human deaths in 15 countries. In Egypt it has been reported in 57 human cases and has caused 23 human deaths, as reported in World Health Organization website in the year 2009 (http://www. who.int/csr/disease/avian_ influenza/country/cases_table_2009_03_
10/en/index.html).
The species barrier reflects, at least in part, the different receptor preferences of mammalian and avian viruses. Researchers have suggested that human tracheal epithelial cells lack receptors for the attachment of avian influenza viruses and that avian tracheal epithelial cells lack the appropriate receptors for human viruses (Rogers et al., 1983). Pigs, however, possess receptors for both avian and mammalian viruses and are postulated to be the host in which influenza viruses of different origins can genetically reassort (Castrucci et al., 1994; Kida et al., 1994).
The genome of type A influenza is single-stranded, negative-sense RNA, that is their genomes cannot be translated into protein directly upon entering the host cell. It contains eight genome segments that encode 10 proteins (Huang et al., 1990; Portela and Digard, 2002). The eight influenza A viral RNA segments encode 10 recognized gene products. These are PB1, PB2, and PA polymerases, HA, NP, NA, Ml and M2 proteins, and NS1 and NS2 proteins. PB2 polymerase is encoded by RNA segment 1, PB1 polymerase is encoded by RNA segment 2, PA polymerase is encoded by RNA segment 3, HA is encoded by RNA segment 4, NP is encoded by RNA segment 5, NA is encoded by RNA segment 6, M1 is encoded by RNA segment 7, the mRNA for M2 is also transcribed from RNA segment 7 and RNA segment 8 encodes the two non-structural proteins NS1 and NS2 (Webster et al., 1992).
Influenza virus is very changeable. Mutations, including substitutions, deletions, and insertions, are one of the most important mechanisms for producing variation in influenza viruses. The lack of proofreading among RNA polymerases contributes to replication errors (Robert et al., 2008). RNA recombination would be another mechanism leading to genetic variation. Recombination in RNA viruses occurs by two different methods; reassortment and template switching or copychoice replication (Posada et al., 2002). Recombination by the process of reas-sortment is limited to viruses with segmented genomes such as influenza and rotaviruses (Lai, 1992). Reassortment occurs when two or more strains infect the same cell and exchange genomic segments during viral replication. This mechanism has been well studied for influenza A and is postulated to account for the emergence of antigenically and genetically novel viruses that enable microbes to evade the immune response and persist in the host’s body (Worobey and Holmes, 1999; Posada et al., 2002). The second method, copy-choice replication, can be utilized by either segmented or unsegmented viruses. Copy-choice is a process whereby the viral RNA-dependent RNA polymerase jumps from one RNA template to the other during replication creating a chimeric recombinant that is an amalgamation of both parental strands (Worobey and Holmes, 1999).