Study: Receptor Binding Changes with H1N1 D222G Mutation

[indigo girl]

Study: Receptor Binding Changes With H1N1 D222G Mutation

Warning! This is not for the faint of heart or anyone not really "into" micro or or virology. Mike Coston over at Avian Flu Diary does a great job of explaining but, many will fall by the wayside if this is not their topic. Sorry, about that but, if you read patiently with an open mind, this is clear enough.

This mutation had actually been detected months earlier, and in many other countries, but Norway was the first country to announce a possible link between that mutation and greater virulence.

This mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G).

The World Health Organization’s take on this mutation has been pretty consistent. It is worth following, and studying, but there is no evidence (as yet) that it poses a substantial public health hazard.

This view is not universally held, however. There are some who have maintained that that the WHO is underestimating the impact of this mutation.

In March of this year, researchers from the Norwegian Institute of Public Health in Oslo reported that they found the mutation in 11 of 61 severe illness cases that they analyzed, but that it was not found in any of the 205 mild cases they looked at (see CIDRAP Report On The H1N1 Mutation Debate).

...it should be noted that mild cases have been detected with this D222G mutation in other studies, and most of the severe and fatal cases of pandemic H1N1 that have been examined did not have this mutation.

http://jvi.asm.org/cgi/content/abstract/JVI.01136-10v1

From the abstract:

The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands.

Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding.

Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans.

Seasonal H1N1 viruses, when they invade the lungs, are more likely to attack type I pneumocytes which handle the gas exchange (02 and C02) between the lungs and the blood stream.

Type II pneumocytes are responsible for the production of surfactant with antimicrobial, immunomodulatory, and anti-inflammatory properties, and are the lung’s primary mechanism for repairing damaged cells.

Damaging them can significantly degrade the lung’s ability to recover from injury.

Which brings us to the last major finding, that D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids.

A virus’s ability to bind to specific cells is controlled by its RBD or Receptor Binding Domain; an area of its genetic code that allows it to attach to, and infect, specific types of host cells.

Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

Avian adapted influenza viruses bind preferentially to Alpha 2,3 receptor cells, which are commonly found in the digestive tract of birds.

Human adapted viruses have an affinity for the alpha 2,6 receptor cell, which populate the upper airway and lungs.

Humans have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs.

This has been suggested as the reason that when humans contract H5N1, it is usually a deep lung infection. It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.

This duel receptor affinity with the D222G mutation may help explain why some patients that contract it also develop more serious lung infections.