Influenza virus is an ancient virus that has affected man for many centuries. Every year, influenza causes the deaths of thousands
of people. Throughout history, there have been pandemics that have lead to the deaths of millions. The natural reservoir of
influenza virus is birds, particularly waterfowl; however, various mammalian species, including man, are also susceptible
to infection. A hallmark characteristic of influenza viruses is their ability to mutate rapidly, and sometimes dramatically,
which has contributed to their importance as a human pathogen.
In most species, influenza virus is spread by aerosol and droplet transmission. It replicates primarily in the epithelia lining
the respiratory tract. The virus damages and ultimately kills the cells in which it replicates, leading to the typical symptoms
of influenza, including cough, fever, muscle ache, and fatigue. Pneumonia, either due directly to the virus or secondary bacterial
infection, may occur, in some cases leading to death.
To understand the threat from influenza, we first we need to understand the virus. Influenza virus is classified by its antigenicity,
or how it is seen by the immune system. The types of influenza (A, B, and C) are based on the antigenicity of internal viral
proteins. Subtype classification is based on the antigenicity of two important surface proteins, hemagglutinin (HA, or H)
and neuraminidase (NA, or N), which are given numeric designations (H1-16; N1-9). While nearly all combinations of these two
proteins may occur in birds, a limited number of combinations are seen in mammals. For example, the seasonal influenza of
humans is usually H3N2, or H1N1.
The virus itself is encased in a lipid membrane, making it easy to inactivate with any common detergent. The genetic material
of the virus is single-stranded RNA, and, uniquely, this genetic material is in separate segments, with each segment encoding
a different protein. This unique structure allows this virus to have a high mutation rate. Mutations may be small, within
a single virus, termed antigenic drift; or they may involve the exchange of entire genes between different influenza viruses,
termed antigenic shift.
Antigenic drift, while small, can lead to important changes in the virus. These include changes in antigenicity, allowing
it to escape the immune response, and changes in viral protein properties which can lead to increased virulence of the virus
or drug resistance. Antigenic shift occurs when two distinct viruses infect the same host, allowing mixing of the genomic
segments. This ability of influenza virus to mutate in small and large ways makes it a potential threat.
As stated above, waterfowl are the natural reservoir of influenza viruses. In these animals, the virus replicates in both
respiratory and gastrointestinal tracts, with shedding in respiratory droplets and feces. These hosts can potentially spread
the virus to a variety of hosts and geographic locales. In its natural host, avian influenza is often asymptomatic. In domestic
fowl, disease may vary from mild respiratory disease to severe systemic disease with high mortality. These latter strains
are referred to as highly pathogen, or HP strains, and are reportable in the USA.
The host susceptibility to the many different influenza viruses is determined by several viral proteins. The surface protein
HA, which is responsible for attachment of the virus to its target cell of infection, is a major determinant of host susceptibility.
This protein attaches to sugar residues on cellular surface proteins. It is these structures that determine in part host susceptibility.
These cell surface structures differ between birds and mammals, which in turn leads to differences in virus susceptibility.
Other virus proteins also play a role in host susceptibility, though the mechanism is not well understood.
Another property of the HA protein that affects the tissue tropism of the virus is its requirement for proteolytic cleavage:
If the HA protein is not cleaved into 2 subunits, virus entry into the cell for replication cannot occur. This cleavage is
done by cellular proteases; thus, the virus requires the presence of this cellular enzyme in order for viral replication to
occur. In mammals, this leads replication in the respiratory tract where the necessary enzyme is present. The easier the HA
protein is able to be cleaved, the more pathogenic, or lethal the virus is. Thus, many HP strains have a HA protein that is
easily cleaved, allowing them to spread systemically, beyond the respiratory tract.