Flu: the H and the N

The organism that causes flu is the influenza virus. It belongs to the family Orthomyxoviridae and they are included in Group V of the Baltimore classification, consisting in negative sense, single-stranded RNA viruses. Within this family there are three genres that are responsible for the flu: Influenza A virus, Influenza B virus and Influenza C virus. Besides these, there are two other genera such as Isavirus (which infects fish) and Thogovirus (that infect humans using ticks as vector).

Figure 1. Negative stained transmission electron micrograph (TEM) of influenza virus recreated 1918 influenza virions. | Credit: Wikimedia Commons
Figure 1. Negative stained transmission electron micrograph (TEM) of influenza virus recreated 1918 influenza virions. | Credit: Wikimedia Commons

But let’s focus on those that interest us. They are the Influenza virus types A, B and C; as they are those which cause what is called seasonal flu.

Differentiation of influenza virus in these three types refers to differences in the antigenic characteristics of the nucleoprotein and matrix protein.

Influenza is transmitted from infected individuals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Moreover, influenza can also be transmitted by other kind of samples such as saliva, nasal secretions, faeces and blood.

All of three types of Influenza virus have a very similar structure. Viral particles have a diameter between 80-120 nanometres with a spherical shape, surrounded by a lipid bilayer. Its genome has the particularity of being fragmented: 7 (type C) or 8 segments (A and B types). Its structure is composed by several proteins: Ribonucleoproteins, RNA-Dependent RNA Polymerase, NS2 protein, matrix proteins and membrane glycoproteins: hemagglutinin (H) and neuraminidase (N).

Figure 2. Structure of the influenza virion. | Credit: Wikimedia Commons
Figure 2. Structure of the influenza virion. | Credit: Wikimedia Commons

The incidence of influenza C virus, which infects humans and pigs, is much less common and, therefore, the seasonal flu vaccine includes only virus types A and B.

The influenza B virus, which infects humans and seals, is less common, less aggressive and genetically less diverse than type A.

Given that the type A is the most important, from an anthropocentric point of view, it will be the type which we will focus on.

Influenza A virus has the ability to infect humans and birds as well as different kinds of mammals, such as equines, swine, mink, seals, whales, etc. Its natural reservoir is wild waterfowl and it is the most aggressive of the three genres.

As mentioned above, parts of the virion are the H and N glycoproteins. Such proteins will be critical in the pathogenesis and infectivity as well as in the generation of different subtypes (also known strains), being relevant factors in the generation of global pandemics.

Hemagglutinin protein is the protein involved in the first step of infection together with sialic acid (the latter responsible for membrane anchoring of epithelial cells). This protein is composed of three polypeptides which has located both signal sequences, glycosylation domain and a hydrophobic region, which is a fusogenic peptide responsible for the fusion of the viral membrane with the cell to allow entrance to the cell, in a process called binding.

Figure 3. Virus replication cycle. | Credit: Wikimedia Commons
Figure 3. Virus replication cycle. | Credit: Wikimedia Commons
(Figure 4. Structure of Influenza Hemagglutinin Protein. | Courtesy of Sino Biological Inc.
(Figure 4. Structure of Influenza Hemagglutinin Protein. | Courtesy of Sino Biological Inc.

Neuraminidase protein is a tetramer composed by small polypeptides with a membrane anchor region and a functional globular region. Exposed areas have a recognition function with the molecules of the host. These external areas also serve as antigenic determinants.

Figure 5. Crystal structure of the neuraminidase tetramer of the 1918 influenza virus. The tetramer is shown in green, with 1 of the 4 subunits colored from blue to red along the chain from the N terminus to the C terminus. | Courtesy of The Skaggs Institute of Chemical Biology

Importantly, this virus has the ability to recombine and exchange genome fragments with other influenza virus whose major guests are not humans. This gives to the flu virus a capacity to produce interspecies transmission and to evade the host immune response, producing enormous public health problems.

The influenza virus is classified into subtypes depending on the structure of the H and N.

The nomenclature of these subtypes refers to the type of encoding H and N proteins through the code H/N. In the case of, for example, influenza A subtype H1N2, this nomenclature is indicating that the virus has the hemagglutinin type 1 and neuraminidase type 2. There are 16 H and 9 N types and they may be combined among them to give all possible subtypes. Thus, we find a good group of subtypes that have been responsible for worldwide pandemics.

In all likelihood, the best known of these strains is the pandemic occurred in 1918 by the H1N1 subtype. It killed an estimated 20 to 50 million people worldwide. It was erroneously called “Spanish flu”. Although it has been shown that their origin was not in Spain, most people are still calling it that. This subtype is caused by influenza type A, a strain that has mutated into several subtypes including human influenza, swine flu, avian and bovine. Currently, this mutated wild-type subtype is circulating and it is responsible for thousands of cases of flu with several hundred deaths worldwide 1. The original subtype H1N1 responsible for pandemic occurred between 1918-1919 is not circulating as a wild-type strain but it was reconstructed in 2005 by molecular biology techniques by the group of Dr. García-Sastre 2.

One of the most famous cases of pandemic flu was produced by the viral subtype H2N2. This strain is a type of avian flu virus. It was responsible for the Asian flu occurred in 1957. This subtype has mutated into various strains including the Asian flu H3N2, which caused Hong Kong flu in 1968-1970, responsible for approximately 700,000 deaths 3.

Another very well-known and controversial pandemic flu was the one caused by the highly pathogenic H5N1 subtype of avian influenza occurred between 2004-2005. The first case of this flu in humans occurred in 1997 in Hong Kong. The main problem that occurred, for purposes of public health, and so this subtype became a potential hazard to humans, settled in the infection in humans coincided with an epidemic of avian flu, caused by the same strain. The fact that both subtypes circulate in the human population and poultry at the same time made it possible to recombine both of them and the resulting strain could have high transmission capacity between humans and the lethality of the avian strain that it showed by in infected chickens. Up to October 2005 there were only reported about 200 people infected with H5N1 subtype, but the mortality rate was very high (about 50%). Thirteen countries in Asia and Europe have been affected, and more than 120 million birds have died, have been slaughtered or have been quarantined. This subtype has been called HPAI A/H5N1 (Highly Pathogenic Avian Influenza), and became the greatest threat of global pandemic 4.

In recent days, there has been a warning by the H7N9 subtype of avian influenza 5, which has produced over a dozen deaths in China from the 60 infected. WHO rule out the possibility of a currently epidemic due to is not confirmed that the virus has the ability for spreading among humans.

However, scientists’ fear that the strain could mutate into a form transmissible from person to person is present. It is the constant fear of possible combinations of H and N: more than two simple letters.

References

  1. Evolution of a pandemic A (H1N1) (download pdf)
  2. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solórzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, García-Sastre A. Science. 2005 Oct 7;310(5745):77-80.
  3. Pandemic (avian) influenza. Rajagopal S, Treanor J. Semin Respir Crit Care Med. 2007 Apr;28(2):159-70.
  4. Epidemiology of H5N1 avian influenza. Yee KS, Carpenter TE, Cardona CJ. Comp Immunol Microbiol Infect Dis. 2009 Jul;32(4):325-40.
  5. Global Concerns Regarding Novel Influenza A (H7N9) Virus Infections. Uyeki TM, Cox NJ. N Engl J Med. 2013 Apr 11.

2 Comments

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Andrea

This article makes me remember the H7N9 virus in 2013 when most cases had illness onset during the month of April,and in May, new report said the human H7N9 infection in China became less frequent. From June to the end of September,WHO report three more H7N9 infections in China. Studies indicate that influenza virus like season influenza viruses which circulate in high level in cold weather while in low level in warm weather.
Creative Animodel is trying its best to research medicine,hoping to help to solve such problem.

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