Host range adaptation of Influenza, Part I

Introduction

Influenza is a major problem worldwide. Even without a pandemic year (the 1918 "Spanish" flu killed between 20-50million people), influenza kills 36,000 people a year in the US and results in 200,000 hospitalizations. Why, when people get vaccinated every year, is influenza such a problem?

One reason is that the virus is not the same from year to year. This virus can evade host immunity in two main ways. One mechanism, called antigenic drift, is when the virus gradually changes its proteins such that it is no longer recognized as effectively by the immune system. Although this results in some viral escape, there is usually enough cross-reactivity in the population so that there are no large-scale pandemics. Think of it as panting a car. It's now harder to find in a parking lot, but it still has the basic shape and look of the original enough so that you can tell the difference.

Antigenic drift can cause many problems for the host, but antigenic shift is much scarier. Instead of a gradual change in the virus, a completely new one is created. But to explain what antigenic shift is, it's necessary to delve a little deeper into the biology of the actual virus


Influenza virus biology.

Influenza is an enveloped, single-stranded negative sense RNA virus that mainly infects epithelial cells of the respiratory tract. This virus has ~11 proteins (new ones continue to be discovered) contained in 8 separate genomic pieces. What are those proteins, and what are they doing? What role do they play in host adaptation?


Hemagglutinin (HA)


The hemagglutinin (HA) glycoprotein on the virus surface binds sialic acid, ubiquitous on many cell types besides epithelial cells. (Though for the most part, influenza does not go systemic and remains a respiratory virus)

Hemagglutinin's ability to bind sialic acid is a major factor of host range. For example, the H5N1 avian virus binds alpha 2'3 linked sialic acid. Although it has been known to infect humans, one of the major reasons it hasn't been spread by human-to-human contact (except in rare, close contact familial cases) is that our lungs mostly contain alpha 2'6 linked sialic acid in the upper respiratory tract. Thus, most human-adapted influenza viruses are 2'6 linked while those of avian origin are 2'3 linked and these viruses rarely cross species barriers.

Worry about a pandemic H5N1 outbreak is centered on the virus mutating its binding preference to alpha 2'6 so that it can readily infect humans. Although this switch is the major concern, binding preference is not the only determinant of host range. In fact, much of the genome is involved.

Detour, so what actually is antigenic drift?

What happens if a virus that is human-adapted except for its HA protein suddenly acquires this H5? This isn't just science fiction. The nature of influenza's segmented genome means that these separate pieces can be mixed and matched and in the Darwinian struggle for evolution, those that have the advantage will survive (This mixing and matching between different viruses is what's known as antigenic shift). So, even though the H5 is still avian-adapted, are the remaining proteins enough to let the virus infect humans? Will this spur the adaptation of a human (alpha 2'6 sialic acid binding) H5 subtype HA?


This is the concern that keeps scientists up at night, and why it's important to continue to study influenza as much as possible. Of course, it's unlikely that a fully human adapted virus will acquire the H5 HA, or that an avian H5 that becomes human adapted will be as pathogenic as the original. Why? Well this goes back to the role the other viral proteins play in infection. So what are those proteins?

Next topic: Getting back to the rest of influenza's proteins