Understanding viral zoonoses: H1N1 influenza
INFLUENZA BASICS: STRUCTURE AND VIRULENCE FACTORS
Influenza is an RNA virus with eight separate gene sequences, and it holds its genome together like eukaryotic cells with multiple chromosomes. This structure allows hybrids to form between different influenza strains. Furthermore, the virus has a high mutation rate because of inefficient RNA polymerase editing functions, and that allows additional viral variation.Three matrix forms of influenza exist—A, B, and C. Influenza A and B cause disease in people. Influenza's primary modus operandi is to create epidemic disease among susceptible people, and most of the mortality results from pulmonary complications. The two major antigenic constituents of influenza are hemagglutinin (H) and neuraminidase (N).
Influenza viruses have five basic virulence factors:
1. The F2 sequence of its polymerase targets the virus to the inner and outer mitochondrial membranes, which injures cells by dissipating energy production and inducing intrinsic apoptosis and cell death.
2. A nonstructural protein, NS1, has several characteristics, but the most important is that it inhibits alpha-interferon, which is critical in the host's initial control of influenza. NS1 essentially shuts down a host defense against influenza that results in extensive disease.
3. Hemagglutinin must initially undergo partial proteolysis by host-derived enzymes to allow it to bind to its receptor, so the degree of hemagglutinin's protease susceptibility is a viral virulence factor.
4. Hemagglutinin binds to neuraminic acid, which is the substrate for neuraminidase. The hemagglutinin-neuraminidase ratio has to be just in the right concentration to allow the virus to rapidly invade other cells and to escape from one infected cell to another, and that ratio is important.
5. The lack of immune recognition of the two major epitopes that the virus expresses is a key event, and the reason new H1N1 is so successful—its major antigenic constituents are not previously recognized by the human immune system. So virtually every person is susceptible to a greater or lesser degree to this new strain of influenza.
MAJOR INFLUENZA OUTBREAKS: 1918-2009
In the past century, the most famous influenza outbreak was the Spanish Flu—H1N1—of 1918. That was the only time in recorded history that the world population actually diminished for a short period of time. Then in the 1950s the first episode of the Asian flu, H2N2, occurred. In 1968, the Hong Kong flu, H3N2, occurred, and in 2009, we had swine flu, or new H1N1. The last major pandemic flu occurred more than 40 years ago, and nearly everyone expected that the next pandemic flu would be H5N1—avian flu.
H5N1 is a particularly virulent virus and is of great concern. When this virus leaps from avian species to people, it is a serious disease. More than 100 cases of avian influenza have occurred in people, and the fatality rate is between 40% and 70%—it is 70% in infected people who do not receive antiviral drugs. The Ebola virus has about the same level of lethality associated with it. The good news is that so far H5N1 is inefficiently transmitted from person to person. Only individuals who have had extensive interaction with avian species have contracted this disease.
So rather than avian flu, the next pandemic flu strain evolved right under our noses in Mexico—new H1N1.
Influenza cases were first recognized in March 2009 in Mexico, and by April, the first cases were identified in southern California. Within two months the World Health Organization (WHO) raised its worldwide pandemic alert level to phase 6, which correlates with an uncontrolled pandemic. New H1N1 caused an unprecedented springtime outbreak (in contrast to usual annual influenza-like illness outbreak patterns) and presaged a large epidemic in the usual winter season, which we are in now. As of November 2009, the pandemic alert level was still phase 6, and about 4,000 deaths had been attributed directly or indirectly to new H1N1 in the United States. The median age of infected people who have died is 36 years.
A large number of international travelers who passed through Mexico City in April and May 2009 when the virus was just starting to spread. By the time the WHO realized what was occurring, the virus had become widely distributed. Travelers had already returned to their countries of origin, and the virus had been distributed to several North American and European cities and other parts of the globe. There was no way to control it other than to attempt to deal with its consequences. Keep in mind that based on airline statistics, about 1,000,000 international travelers move from one country to another every week. So controlling influenza spread is difficult.