Influenza Virus Research

Influenza (flu) is a respiratory infection in mammals and birds. It is caused by an RNA virus in the family Orthomyxoviridae. Influenza virus is divided into four main types (Influenza A, Influenza B, Influenza C, Influenza D), which are distinguished by differences in two major internal proteins (hemagglutinin (HA) and neuraminidase (NA)). Three of the four types of influenza viruses affect humans: Type A, Type B, and Type C. Type D has not been known to infect humans, but is believed to have the potential to do so. Influenza virus type A is found in a wide variety of bird and mammal species and can undergo major shifts in immunological properties. Influenza virus type B is largely confined to humans and is an important cause of morbidity. Little is known about Influenza virus type C, which is not an important source of morbidity. Influenza D was identified in 2016.

Influenza A virus is further divided into subtypes based on differences in the membrane proteins hemagglutinin (HA) and neuraminidase (NA), which are the most important targets for the immune system. The notation HhNn is used to refer to the subtype comprising the hth discovered Hemagglutinin (HA) protein and the nth discovered neuraminidase (NA) protein. The influenza viral Hemagglutinin (HA) protein is a homo trimer with a receptor binding pocket on the globular head of each monomer, and the influenza viral neuraminidase (NA) protein is a tetramer with an enzyme active site on the head of each monomer. Subtypes are further divided into strains; each genetically distinct virus isolate is usually considered to be a separate strain.


Influenza Virus Genome

The genome of influenza virus consists of segmented negative-sense single-strand RNA segments. Influenza viruses are members of the family Orthomyxoviridae. There are four genera of this family: types A, B, C and Thogotovirus, of which, however, only genera A and B are clinically relevant for humans. The eight genome segments of influenza A and B viruses are loosely encapsidated by the nucleoprotein (NP). The influenza genome contains eight genes encoding 11 proteins.The polymerase complexes consisting of the three polymerase proteins PB1, PB2, and PA are located at the ends of the nucleocapsids. These helical capsids are encircled by the M1 matrix protein and by a host-derived lipid bilayer envelope in which the virus surface glycoproteins haemagglutinin (HA) and neuraminidase (NA) as well as the M2 matrix protein are embedded. The HA is synthesized as precursor protein and cleaved by cellular serine proteases into the functional proteins HA1 and HA2.The proteins NS1 (nonstructural protein 1) and NS2/nuclear export protein (NEP), whose roles are still being investigated.

Influenza virus genome illustration

Influenza Virus Types / Classification

In virus classification, influenza viruses are RNA viruses that make up four of the seven genera of the family Orthomyxoviridae. Influenza virus can identified as Influenza A, Influenza B, Influenza C and Influenza D. Influenza A viruses infect humans and a variety of other wildlife, including pigs and birds, which perpetuate the virus in nature throughout the world. Human influenza A viruses are thought to have originated from strains that infected wild aquatic birds. Influenza B viruses infect humans (and seals, interestingly) and primarily affect children. Infection with influenza C generally results in mild or subclinical infections. Influenza A and B cause seasonal epidemics, but only influenza A has caused worldwide pandemics. Generally, influenza A infections account for about 2/3 of human infections each year.

Classification / types of Influenza virus

  Influenza A Influenza B Influenza C
Hosts Humans, waterfowl, poultry, pigs, horses, sea mammals, bats Humans, seals Humans, pigs, dogs
Gene segments 8 8 7
Proteins 11 11 9
HA/NA antigenic subtypes 18 HA, 11 NA None None
Clinical features Moderate to severe illness Milder disease than Influenza A Largely subclinical
Epidemiological features Causes pandemics Less severe epidemics than Influenza A; no pandemics Does not cause epidemics or pandemics

Influenza Virus Structure

Influenza viruses possess segmented genomes: Influenza A viruses (IAVs) and type B viruses (IBVs) contain 8, negative-sense, single-stranded viral RNA (vRNA) gene segments, which encode transcripts for 10 essential viral proteins, as well as several strain-dependent accessory proteins. In comparison, influenza type C and D viruses only possess seven vRNA gene segments, as the hemagglutinin–esterase fusion protein vRNA replaces the hemagglutinin (HA or H) and the neuraminidase (NA or N) vRNAsInfluenza A, the predominant pathogen in seasonal influenza and the cause of pandemic influenza, provides the main focus for the remainder of this section. The influenza A genome encodes 11 viral proteins:

• Hemagglutinin (HA), which is divided into two subunits (HA1 and HA2);
• Neuraminidase (NA);
• two matrix proteins (M1 and M2);
• Heterotrimeric RNA-dependent RNA polymerase, composed of one polymerase acidic (PA) and two polymerase basic (PB1 and PB2) subunits and the alternatively transcribed proapoptotic peptide, PB1-F2;
• Nucleoprotein (NP);
• Two nonstructural proteins (NS1 and NS2; NS2 is also known as NEP, or nuclear export protein).
The virus particle (virion) has an irregular spherical shape with a lipid envelope, approximately 80–120 nm in diameter.

Influenza virus a-d structure

Influenza Virus Replication

Influenza virus replicates within the nucleus of the host cell. Here is the influenza virus replication cycle.


Cell Binding and Fusion

HA bind with SA residue

Genome Trafficking to the Host Cell Nucleus

vRNP trafficking to the nucleus,the viral proteins that make up the vRNP are NP, PA, PB1, and PB2.

Transcription and replication of the viral genome

The replication of the influenza genome involves two steps: transcription of complimentary RNA (cRNA), followed by transcription of new vRNA copies using the cRNAs as templates

Assembly and Trafficking of vRNPs


Export of vRNPs from the nucleus

vRNPs appear to be exported out of the nucleus via the CRM1 dependent pathway through the nuclear pores

Assembly and budding at the host cell's plasma membrane

Virus particles bud from the apical side of polarized cells

Influenza Virus Symptoms

A clinical characteristic of human influenza virus symptoms is a sudden rise in body temperature to >38.5 °C 1–3 days following infection. Other symptoms include headache, limb ache, tiredness, general faintness and dry cough. Infectivity can start already shortly (<24 h) before the onset of the clinical symptoms and usually persists 3–5 days. Small children can excrete the viruses earlier and over a longer period of time than adults. The most serious outcomes are peracute death within only few hours and primary influenza pneumonia. Encephalitis or myocarditis can also occur.

Symptoms of influenza virus:
• Fever
• Headache
• Limb ache
• Tirednedd
• General faintness
• Dry cough
• Encephalitis
• Myocarfitis
• Complications: chronic heart or lung disease, metabolic disorders


Influenza Virus Treatment

Some antiviral products for the treatment of influenza virus infections are authorised. The two classes of antiviral drugs used against influenza are neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir and peramivir) and M2 protein inhibitors (adamantane derivatives).
• Due to adverse reactions, the M2 ion channel blocker amantadine is hardly used. Rimantadine has fewer side-effects.
• Neuraminidase inhibitors oseltamivir and zanamivir can help shorten the phase of the disease and reduce the symptoms if administered in time.
• In different country, there are different policy on those drugs.


Influenza Virus Research Reference

Arbeitskreis Blut.Influenza Virus.Transfus Med Hemother. 2009 Feb; 36(1): 32–39.
• Dan Dou.Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement.Front Immunol. 2018; 9: 1581.
• Tasleem Samji.Influenza A: Understanding the Viral Life Cycle.Yale J Biol Med. 2009 Dec; 82(4): 153–159.
• Scott H. James, Richard J. Whitley, in Infectious Diseases (Fourth Edition), 2017