Introduction:
There are three basic types of influenza viruses: A, B, and C. Influenza B and C viruses only infect humans, so novel antigens are not introduced from other species. Only influenza A viruses infect nonhuman hosts, and a reassortment of genes can occur between those subtypes that typically infect animals and those that infect humans, resulting in antigenic shift and potential pandemics. Epidemics of seasonal influenza occur due to influenza A or B viruses. Because many different subtypes of the influenza A hemagglutinin and neuraminidase proteins exist, the human immune system is frequently challenged with new antigens. For example, point mutations in the HA and NA genes can lead to changes in antigenicity that allow a virus to infect people who were either infected or vaccinated with a previously circulating virus. This phenomenon is referred to as antigenic drift. In addition to humans, other animals can be infected with or serve as a reservoir for influenza, and outbreaks have been seen in poultry, pigs, horses, seals, and camels. When a strain is named, the host (if not human), the location where the virus originated, the strain number, the year of isolation, and the HA/NA subtype are all included in the name. Scitable by Nature
Influenza A virus:
In 1918 – 1919, an outbreak of severe respiratory infection, the so-called “Spanish flu”, occurred which rapidly spread through the human population and resulted in an estimated 20 – 50 million deaths worldwide. The agent causing this catastrophe was subsequently revealed to be a type A influenza (IAV) virus strain. Unique features of IAV structure, replication, transmissibility among certain species and the existence of zoonotic reservoirs make this viral pathogen ideally suited to escape immune recognition and to produce both epidemic (seasonal) disease outbreaks, as well as sporadic pandemic infections. Since the identification of the cause of influenza as a “filterable virus” increasing emphasis has been placed on the analysis of the host response to this virus, not only to improve vaccination strategies, but also to understand the role of the innate and adaptive immune system in controlling/clearing infection and in the development of lung inflammation and injury. See Braciale
Classification: Influenza A viruses are described by a nomenclature which includes the sub-type or type, geographic origin, strain number and year of isolation (e.g., A/Beijing/353/89. The influenza A virus is further classified into various subtypes depending on the different hemagglutinin (HA) and nueraminidase (NA) viral proteins displayed on their surface. Hemagglutinin mediates cell entry, first by recognizing host proteins bearing sialic acid on their surface, and second by triggering the fusion of viral and host membranes following endocytosis, allowing viral RNA to enter the cytoplasm. Neuraminidase, cleaves sialic acid from host and viral proteins, facilitating cell exit. There are at least 16 known HA subytypes (e.g., H1-H16) and nine sub-types of NA (N1-N9). All sub-types are found in birds, but only H1-H3 and N1-N2 are found in humans, swine and horses.
influenza pandemic occurs when a new influenza A virus emerges for which there is little or no immunity in the human population, begins to cause serious illness and then spreads easily person to person worldwide. During the 20th centruy there have been 3 such influenza pandemics. In 1918, the “Sapnish Flu” influenza pandemic caused at least 500k deaths in the US and up to 40 million deaths worldwide. This pandemic was caused by influenza A H1N1 subtype. In 1957, the “Asian Flu” pandemic, caused by the influenza A H2N2 subtype, resulted in at least 70k deaths in the US and 1-2 million deaths worldwide. In 1968 , the “Hong Kong Flu” pandemic caused by the influenza A H3N2 subtype, resulted in about 34k US deaths and 700k deaths worldwide. In 1997, the first influenza A H5N1 cases were reported in ong Kong. This was the first time that this avian type virus directly infected humans, but a pandemic did not result because human to human transmission was not observed. Of the 15 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes circulating in aquatic birds, only the , H2N2 and H3N2 subtypes are known to have caused pandemics in humans.
–H5N1: The H5N1 virus has become a pandemic among animals, raging through bird populations world-wide.The H5 group has been circulating in birds for about 25 years.
In 2024, it has become a pandemic among US cattle. There have been several known human transmission in the US who were dairy farmers exposed to infected cows. The first two cases only involved eye symptoms but the third involved the lungs.
Structure: Influenza A virus is member of the family Orthomyxoviridae and is a negative sense RNA virus with a segmented genome. It consists of 8 segments of single-stranded, negative sense RNA. Its genetic composition allows this virus to evolve by reassortment of gene segments from different strains. Unlike positive strand viruses (i.e., poliovirus), the negative sense viral RNA (vRNAs) of influenza A viruses are not infectious. Only vRNA molecules encapsidated with the four viral polymerase complex proteins (PB1, PB2, PA, nucleoprotein) are able to initiate a viral replication and transcription cycle. After the ribonucleoporteins (RNPs) penetrate the cell nucleus, the associated proteins begin to transcribe the (-)vRNAs into mRNA dn the (+)cRNAs. These cRNAs sever as template for the synthesis of vRNAs.
With the HA and NA genes, the influenza A genome contains eight genes encoding 11 proteins. These proteins include three RNA polymerases that function together as a complex required by the virus to replicate its RNA genome. Interestingly, these polymerases have been shown to have high error rates due to a lack of proofreading ability, which leads to high mutation rates. This high rate of mutation and evolution is one source of influenza virus genetic diversity. The influenza genome also encodes additional structural proteins necessary to form the capsid, the nucleoprotein (NP), and the proteins NS1 (nonstructural protein 1) and NS2/nuclear export protein (NEP), whose roles are still being investigated. Still other proteins encoded by the viral genome include membrane proteins M1 and M2 (which are needed for nuclear export and several other functions) and, of course, HA and NA (which play roles in viral attachment and release from host cells, respectively). Scitable by Nature
Due to the segmented nature of the influenza genome, in which coding sequences are located on individual RNA strands, genomes are readily shuffled in host cells that are infected with more than one flu virus. For example, when a cell is infected with influenza viruses from different species, reassortment can result in progeny viruses that contain genes from strains that normally infect birds and genes from strains that normally infect humans, leading to the creation of new strains that have never been seen in most hosts. Moreover, because at least 16 different hemagglutinin subtypes and nine different neuraminidase subtypes have been characterized, many different combinations of capsid proteins are possible. Of these subtypes, three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) have caused sustained epidemics in the human population. Birds are hosts for all influenza A subtypes and are the reservoir from which new HA subtypes are introduced into humans. Scitable by Nature
Replication & Transcription: Influenza A virus RNA is transcribed inside the nucleus of the host cell. This is an unusual characteristic for an RNA virus, as most others replicate solely within the cytoplasm. Influenza viral transcription and replication occurs in the nucleus; therefore, after being released into the cytoplasm, the vRNP must enter the nucleus. The viral proteins that make up the vRNP are NP, PA, PB1, and PB2. All of these proteins have known nuclear localization signals (NLSs) that can bind to the cellular nuclear import machinery and, thus, enter the nucleus.
After entering the host cell, the viral ribonucleoproteins (vRNPs), which contain the negative-sense RNA genome, are transported into the nucleus via the host cell’s nuclear import machinery.
Once in the nucleus, the viral RNA polymerase transcribes the negative-sense viral RNA (vRNA) into positive-sense messenger RNA (mRNA). This mRNA resembles the host cell’s own transcripts, and is ready for translation. The viral polymerase also uses a process called “cap-snatching,” where it steals the 5′ capped ends from the host’s newly transcribed pre-mRNAs to prime its own mRNA synthesis. This allows the viral mRNA to be efficiently translated by the host’s ribosomes. The newly created viral mRNAs are then exported from the nucleus to the cytoplasm to be translated into viral proteins by the host’s machinery. These proteins are then used to create new virus particles.
The enzyme that reproduces influenza RNA is known as an RNA-dependent RNA polymerase. This enzyme, which consists of the viral proteins PA, PB1, and PB2, is present in every virus particle. If this enzyme were absent from virions, they would never initiate infection, because the (-) strand viral RNAs cannot be translated into protein, and the cell has no enzymes which can copy such long RNA molecules. Of course, additional molecules of the viral RNA polymerase are made in infected cells, but the enzyme that is brought in with the virion is crucial for initiating the infectious cycle.
The mRNAs are not complete copies of the viral (-) strand RNAs – they are missing sequences from both the 5′- and 3′-ends. Therefore, to produce more viral (-) strand RNAs that are needed to assemble new virions, a full length (+) strand is produced, which in turn is copied to a full-length (-) strand RNA. The (-) strand RNAs are then used to assemble new virions.
Vaccination:
Efficient influenza A vaccines are available which induce antibodies predominantly against the two major components of the virus membrane, hemagglutinin (HA) and neuramidase (NA). Protection is mediated primarily by neutralizing antiobdies against HA. Since HA undergoes continous change due to mutations (antigenic drift), new antigenic variants of influenza A arise every year requiring constant update of the vaccines. Effective vacination is further complicated by the occasional reassortment of the segmented viral genome leading to the replacement of HA or NA from one subtype by another subtype, a process called antigenic shift.
How Composition of yearly Influenza Virus Vaccine is determined:
–2024-2025: The composition of the 2024–25 U.S. seasonal influenza vaccines includes an update to the influenza A(H3N2) component. For the 2024–25 season, U.S.-licensed influenza vaccines will contain hemagglutinin (HA) derived from 1) an influenza A/Victoria/4897/2022 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/67/2022 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines, 2) an influenza A/Thailand/8/2022 (H3N2)-like virus (for egg-based vaccines) or an influenza A/Massachusetts/18/2022 (H3N2)-like virus (for cell culture-based and recombinant vaccines), and 3) an influenza B/Austria/1359417/2021 (Victoria lineage)-like virus (for egg-based, cell culture-based, and recombinant vaccines). Recommendations for the composition of Northern Hemisphere influenza vaccines are made by the World Health Organization (WHO), which organizes a consultation, usually in February of each year. Surveillance data are reviewed, and candidate vaccine viruses are discussed. See CDC
When to Administered Influenza Virus Vaccine:
Decisions about timing need to consider the unpredictability of the influenza season, possible waning of vaccine-induced immunity over the course of a season, and practical considerations. For most persons who need only 1 dose of influenza vaccine for the season, vaccination should ideally be offered during September or October. However, vaccination should continue after October and throughout the influenza season as long as influenza viruses are circulating and unexpired vaccine is available.
Influenza C virus:
The C group causes the common cold.