Evolution of Influenza

Influenza is a widespread respiratory disease caused by an RNA virus (Orthomyxoviridae). The influenza virus has been traditionally divided in three major types: A, B, and C. Influenza viruses of type A are known from many strains that infect both mammal and avian hosts, whereas the other two type are primarily known from humans. Influenza A is characterized by antigenic subtypes (see Sect. 2.3).

Influenza is interesting from both epidemiological and evolutionary points of view due to the interplay between genetic changes in the viral population and the immune system of hosts [EAR02]. There are two basic hypotheses on how influenza A viruses escape the immune response in host population to cause epidemics: (1) antigenic drift, meaning that random point mutations produces novel influenza strains that succeed and persist if they can infect and spread among hosts; (2) antigenic shift, meaning that genes derived from two or more influenza strains reassort thus creating a novel descendent genome with a constellation of genes that can infect and spread among hosts. In both scenarios zoonosis is often involved. In case of antigenic shift the ancestry of only a fraction of the influenza genes may be zoonotic.

Two major classes of influenza epidemics are recognized in humans: seasonal outbreaks and large-scale epidemics known as pandemics [WEB92]. Seasonal influenza is a significant public health concern causing 36,000 deaths and 200,000 hospitalizations in the United States in an average year [GER05]. Elderly and children account for many of these severe cases of seasonal influenza. Much of the population has partial immunity to seasonal influenza strains that are typically descendents of strains circulating in previous years. Pandemics are often caused by infection, replication, and transmission among the human population with influenza strains of zoonotic origin to which few people have prior immunity. Pandemics are rare but can affect the entire human population, irrespective of an individual's predisposition to respiratory diseases. In fact, the 1918 pandemic disproportionately affected young adults [TAU06], suggesting that older adults may have had some immunity.

There have been three major influenza A pandemics, 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2). The pandemic of 1918 is estimated to have killed tens to a hundred million people worldwide and 675,000 in the United States [TAU01]. The Asian flu pandemic of 1957 and the Hong Kong flu pandemic of 1968 were less severe, but caused tens of thousands of deaths in the United States [HHS04]

All of these pandemic strains are thought to have originated in wild birds [WEB92]. The 1957 and 1968 strains are believed to be the results of antigenic shift. However, recent studies suggest that the H1N1 influenza virus that caused the pandemic of 1918 was entirely of avian origin rather than a human-avian reassortant [TAU05]. Other researchers have countered that the 1918 H1N1 strains had a more commonly accepted route to infection of human populations by reassortment in mammals [GIB06; ANT06].

Pandemics can theoretically occur with any strain of influenza. Most influenza infections since 1968 have been attributed to influenza A H3N2 or H1N1 strains. However, there have been several recent reports of novel human infections from avian strains of influenza with subtypes thought to occur rarely in humans. Several cases of human infection of viruses of subtype H7 of avian origin have recently occurred in Canada [TWE04] and the Netherlands [KOO04]. Avian influenza of antigenic subtype H5 and H7 viruses can be found as low or high pathogenic forms depending on the severity of the illness they cause in poultry. Thus far, influenza H9 virus has only been identified as strains with low pathogenicity [LIN00].

Alarmingly, highly pathogenic strains of influenza A with an H5N1 subtype have spread rapidly among various species of birds in China, Southeast Asia, Russia, India, the Middle East, Africa, Eastern, and Western Europe [WHO07a]. These H5N1 influenza A strains share common ancestry with the outbreak of H5N1 that lead to a massive chicken cull and six human deaths in Hong Kong in 1997 [LI04]. Between 2003 and September 10, 2007, there have been 328 cases and 200 deaths among humans [WHO07b]. There are several instances of H5N1 infection of felids and swine in Asia. There is scant evidence of human-to-human transmission in Thailand [UNG05] and Indonesia [YAN 2007]. If lethality to human cases of H5N1 drops, the virus might spread rapidly and without being detected.

Many predict an upcoming avian influenza pandemic of devastating human and economic costs. In the United States alone, it is projected that 15-35% of the population will be affected and the costs could range from 71.6 to 166.5 billion United States (US) dollars [GER05]. Although vaccine production can in theory be modified to include H5N1 strains [DUT05], the genomes of interest are moving targets. It remains unknown whether the descendents of the contemporary H5N1 virus will achieve efficient human-to-human transmission and if this will occur via incremental mutations or a more punctuated reas-sortment mediated change. Thus phylogenetics is a key technology to track the evolution of H5N1 and compare those changes to genomic and zoonotic events that underlie pandemics.

Subtypes of Influenza Type A

The viruses of influenza type A are classified as various subtypes that represent differences in the antigenic reaction of two key glycoproteins: hemagglutinin (HA) and neuraminidase (NA). These proteins reside on the surface of the virion. These proteins play key roles in recognition and infection of susceptible hosts (HA) and viral replication (NA). These surface proteins are primary antigens recognized by the host immune system [WEB92].

The subtypes of influenza A are labeled according to the reaction of standard monoclonal antibodies to these HA and NA proteins provided by the US Centers for Disease Control to laboratories participating in the World Health Organization's (WHO) surveillance program [HHSb].

Although this number will soon expand, there are currently 16 different antigenic subtypes recognized for HA (labeled from H1 to H16) and 9 different antigenic subtypes of NA (from N1 to N9). Thus, a subtype of influenza virus type A is labeled with the number associated with HA and NA proteins (e.g., the most common subtype found in humans H3N2).

Since 1948, influenza viruses have been the focus of a coordinated surveillance program organized by the WHO [WHO05]. The hemagglutinin gene (HA) is the major target of the influenza surveillance. This program helps track predominant strains to inform the development of new vaccines. Influenza viruses are sampled worldwide through the National Influenza Centers located in 54 countries [WHO05]. Many of the viral isolates sampled by these programs are sequenced for the hemagglutinin gene, although there has been an increasing interest in sampling complete influenza genomes [GHE05, OBE06].

An extensive record of hemagglutinin sequences of the influenza viruses type A isolated since 1902 are publicly available. These data provide a unique set of challenges and opportunities for phylogenetics. The geographically wide and temporally long sampling of viral isolates provides an unprecedented opportunity to study evolutionary patterns underlying the spread and host range of an infectious disease. However, as described earlier, large datasets present an enormous search space of possible evolutionary scenarios to be evaluated.

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