Influenza

See CDC.  Influenza Antiviral Medicines (CDC)   FDA (drugs approved for influenza)

See also Types A-C and Respiratory viruses

Videos: Antigenic shift

Introduction:

The flu is a contageous respiratory illness caused by influenza viruses. It causes mild to severe illness and at times can lead to death. Annually in the US, influenza is contracted by 5-20% of the population, hospitalizing about 200k and causing deaths of about 36K (WO2007/134327).

Occasionally, a new human influenza virus strain arises from an animal origin and spread rapidly among human populations that have no pre-existing immunity, causing excessive mortality and morbidity globally, known as a pandemic. There have been four influenza pandemics in modern times, the 1918–19 “Spanish” flu, the 1957 “Asia” flu, the 1968 “Hong Kong” flu, and the 2009 “Swine flu.” The 1918–19 “Spanish” flu was the most severe pandemic in recent history, which was estimated to have caused ~ 500 million infections and 50–100 million deaths worldwide.

Influenza viruses, including four major types (A, B, C, and D), can cause mild-to-severe and lethal diseases in humans and animals. Influenza viruses belong to the Orthomyxoviridae family and include four major types A, B, C, and D. Influenza A virus (IAV) can infect a wide range of avian and mammalian species, including humans, birds, ducks, chickens, turkeys, pigs, horses, and dogs [5]. Influenza B virus (IBV) infects humans and seals, whereas influenza C virus (ICV) infects humans and pigs. See Liang

Influenza viruses evolve rapidly through antigenic drift (mutation) and shift (reassortment of the segmented viral genome). New variants, strains, and subtypes have emerged frequently, causing epidemic, zoonotic, and pandemic infections, despite currently available vaccines and antiviral drugs.

Humans can also be sporadically infected by animal influenza viruses (zoonotic), most often avian and swine flu; however, they have yet to establish sustained infection in humans. In particular, avian H5 and H7 influenza A viruses have caused hundreds to thousands of infections in humans, with a high case fatality rate (30–50%). The likelihood of these avian influenza viruses gaining efficient human-to-human transmissions to cause the next pandemic poses a significant public health risk. See Liang

Structure:

Influenza viruses belong to the Orthomyxoviridae family and are enveloped single-stranded RNA viruses, that occur in 3 distinct antigenic types (A,B and C). Types A and B are responsible for epidemics, while type C causes mild respiratory illness. The lipid bilayer coating the influenza virus contains specific hemagglutinin (H) and neuraminidase (N) protein spikes that define distinct viral subtypes. Hemagglutinin (H) contribues to infectivity by binding to host cell receptors of the respiratory mucosa. Neuraminidase (N) breaks down the protective mucous coating of the respiratory tract, assists in viral budding and release, keeps viruses form sticking together and participates in host cell fusion.

The genomes of all influenza viruses are composed of eight single-stranded RNA segments. These RNAs are negative-sense molecules, meaning that they must be copied into positive-sense molecules in order to direct the production of proteins. Scitable by Nature

Unlike most RNA viruses that infect vertebrates, influenza virus transcribes and replicates its genome in the host cell nucleus. The advantages of nuclear over cytoplasmic replication include access to the nucleus facilitates cap snatching, the process by which the viral RdRp obtains 5′ cap structures from cellular RNA species to act as primers for transcription of the viral mRNA.

The ssRNA genomes of the influenza virus is known for its extreme variability. It is subject to constant genetic changes that alter the structure of its envelope glycoproteins. This constant mutation of the glycoporteins is called antigenic drift; the antigens gradually change their amino acid composition, resulting in decreased ability of host memory cells to recognize them. Antigenic drift is the reason that a new vaccine is required each year.

The main natural reservoir of IAV is wild aquatic birds, which carry the virus with few, if any, symptoms. In non-reservoir avian species such as poultry, the disease is mostly intestinal and is spread via the faecal–oral route. IAV subtype names refer to which type of haemagglutinin (HA) and neuraminidase (NA), two of the three viral surface proteins, are present in the viral genome. So far, 18 HA and 11 NA subtypes have been described: H1-16 and N1-9 naturally reside in aquatic birds; H17N10 and H18N11 naturally reside in bats;

An even more serious problem is called antigenic shift. Antigenic shift is the swapping out of one of the 10 genes of the virus, which are coded on 8 separate RNA strands, with a gene or strand from a different influenza virus. For example, where ducks and swine and humans live close together, the swine can serve as a melting pot for creating hybrid influenza viruses that are not recognized by the human immune system. Experts have traced the flu pandemics of 1918, 1957, 1968, 1977 and 2009 to strains of a virus that came from pigs (swing flu). In 2009, a swine flu called H1N1 caused a limited pandmeic. It reappeared in 2014. Currently, only H1N1 and H3N2 are endemic in humans, but a genetic reassortment might yield a novel subtype, which is both highly pathogenic and capable of direct human-to-human transmission. Such an event has happened five times in the past century, including the 1918 influenza pandemic, which caused an estimated 20 million deaths. See Iqbal

Since the 1918 Spanish pandemic flu, the IAV subtype H1N1 persisted in humans until it was replaced in 1957 by an H2N2 subtype (Asian pandemic). H2N2 circulated in humans until 1968 when it was replaced by a H3N2 subtype (Hong Kong pandemic). The H1N1 virus reappeared in 1977 and was replaced by a new H1N1 strain in 2009 (swine pandemic). Currently, two IAV subtypes, H1N1 and H3N2, together with two lineages of IBVs (B/Yamagata and B/Victoria), o-circulate in humans. Therefore, annual flu vaccines are quadrivalent and contain two IAV subtypes and two IBV lineages.

Human influenza viruses are transmitted through the respiratory route, whereas avian influenza viruses are spread between birds primarily through direct contact via faecal-oral, faecal-faecal, and faecal-respiratory routes. Viruses replicate mainly in the epithelial cells lining the respiratory or intestinal tract.

Mild influenza infections generally involve the upper respiratory tract and trachea, whereas the most severe and fatal human infections are associated with viral infections in the lower respiratory tract. Influenza virus causes the death of epithelial cells through various mechanisms. In addition, infected epithelial cells release cytokines and chemokines to attract infiltrating inflammatory cells such as neutrophils and macrophages and activate adjacent endothelial cells. These activated immune and non-immune cells produce even more inflammatory cytokines, such as IL − 6, IL − 1β, TNFα, and CCL − 2, to stimulate further infiltration, damage the epithelial-endothelial barrier, and cause more epithelial cell death.

Cell Entry/Infection:

To initiate an infection, the influenza virus first binds to the cell surface receptor, sialic acid residues of glycoproteins or glycolipids, through the receptor-binding site (RBS) in the HA protein. Viruses are internalized into early endosomes and trafficked to late endosomes, where the low pH environment causes conformational changes in HA to expose a fusion peptide that leads to the fusion of viral and endosomal membranes. The M2 proton channels on the viral membrane mediate H⁺ influx into the viral interior, which lowers the pH to facilitate the release of vRNPs from M1 into the cell cytoplasm in a process called uncoating.

The released vRNPs are then imported into the nucleus for viral RNA replication and transcription. Viral RNA synthesis is mediated by the heterotrimeric polymerase complex PB1/PB2/PA.

Transcription & Replicaiton:

Transcription: refers to the synthesis of viral mRNA from vRNA:

Replication of the negative-sense vRNA genome involves the generation of a positive-sense cRNA intermediate, which is then replicated into a progeny vRNAAfter import of the viral ribonucleoproteins (vRNPs) into the nucleus (The vRNP bundle is imported into the nucleus via the classical importin pathway), the heterotrimeric viral polymerase on the vRNP snatches the first 10–13 nt from capped host mRNA and uses it and a vRNA template to transcribe viral mRNA, which is then exported and translated. Cytosolic viral proteins (PB2, PB1, PA, NP, M1, and NEP) are imported into the nucleus. Transmembrane viral proteins (HA, NA, M2) are translated into the ER.

Primary replication: refers to the synthesis of cRNA from vRNA.

The same vRNP then undergoes primary genomic replication, synthesising positive-sense complementary RNA (cRNA), which is swiftly captured by the nascently translated proteins to form a complementary RNP (cRNP)

Replication of the negative-sense vRNA genome involves the generation of a positive-sense cRNA intermediate, which is then replicated into a progeny vRNA. cRNA differs from viral mRNA in that it is an exact copy of vRNA, lacking an m7G cap and poly(A) tail, and is synthesised with different forms of initiation and termination. IAV polymerase switches between transcription- or replication-competent conformations through an intermediate state with a blocked cap-binding domain and contracted core region.

The vRNP-resident polymerase replicates a vRNA template into cRNA, which binds the nascently imported PB2, PB1, PA, and NP to form a cRNP. The cRNP is similarly but not identically replicated into progeny vRNPs. The progeny vRNPs are exported from the nucleus with the aid of M1 and NEP. The vRNPs form a fully assembled genome bundle en route to the plasma membrane.

Secondary replication: refers to the synthesis of vRNA from cRNA.

The cRNPs then undergo secondary replication to form progeny vRNPs.

People at Risk:

Epedemic influenza occurs annually and is a cause of significant morbidity and mortality worldwide. Children have the highest attack rate and are largely responsible for transmission of influenza virus in the human community. The elderly and persons with underlying health problems are at an increased risk for complications and hospitalization from influenza infection.  The flu and associated complications, including bacterial pneumonia, are the sixth leading cause of death in the world and the leading infectious cause of death.

Each year CDC estimates the burden of influenza in the U.S. CDC uses modeling to estimate the number of influenza illnesses, medical visits, flu-associated hospitalizations, and flu-associated deaths that occur in the U.S. in a given season. See CDC

Antigenic Drift: In the United States, seasonal influenza epidemics typically claim the lives of about 30,000 people each year and cause hospitalization of more than 100,000 (Reid & Tautenberger, 2003). Every two or three years, more virulent strains circulate, increasing death tolls by approximately 10,000 to 15,000 individuals. These seasonal epidemics are the result of antigenic drift, a phenomenon caused by mutations in two key viral genes due to an error-prone RNA polymerase. The high mutation rate leads to antigenic drift in the HA and NA genes. Antigenic drift refers to small changes in the HA and NA prtoeins such that previous vaccine induced immunity is no longer protective. Becasue antigenic drift is due to random mutations, it is impossible to predict precisely which viral strains will emerge each year. Immunologists and epidemiologists at the CDC use information on circualting strains to make the best possible predicitons which which strains to use for the upcoming sason.

Antigenic Shift: Less frequently, however, new and particularly virulent strains of influenza arise, which cause worldwide pandemics that are accompanied by greatly increased death tolls. These strains occur because of the phenomenon known as antigenic shift in which humans are infected with avian influenza viruses or viruses that contain a combination of genes from human and avian sources. In other words, antigenic shift occurs when an individual is infected with more than one virus, and the viral genomes are reassorted druing infection. Antigenic shift produces new HA-NA combinations. Since 1900, three of these pandemics have occurred. The first, which took place in 1918 and was referred to as “Spanish” influenza, was the deadliest, claiming an estimated 40 million lives worldwide in less than a year. Unlike weaker flu strains that are more of a threat to the elderly, this flu claimed the lives of many young people, including children and young adults. In fact, people under age 65 accounted for 99% of the deaths attributed to this strain, whereas subsequent pandemics claimed many fewer people from this age group. Later epidemics occurred in 1957, when the “Asian” flu killed 70,000 people in the United States, and in 1968, when the “Hong Kong” strain killed 30,000 Americans (Reid & Tautenberger, 2003).  Scitable by Nature

Antigenic shift producing new HA-NA combinations was responsible for the three major flu pandemics of the 20th centure: The “Spanish flue” of 1918, A(H1N1) killed 50-100 million people worldwidse, the Asian flue of 1957, A(H2N2) killsed over 100k Americans and the Hong Kong flue of 1968 A(H3N2) infected 50 million people in the US with 70k deaths. In the 1990s, 3 indfluenza virsues infected pigs: a classical swine flue virus, a North American avian influenza virus and a human H3N2 virus. When all 3 viruses infect the same cell, the 8 genomic segments form each virus are all replicated. When new viruses are assembled, the 8 genomic segments are selected randomly, which can shuffle the genomes form different viruses to produce new combinations of genome segments. Because the HA and NA genes are on different genome segments, this can produce viruses with new combinations of HA and NA proteins. Such a recombined virus circulated in swine herds in North America, but could not be transmitted to human. Sometimes later, pigs harboring teh new virus were infected by an avian like influenza virus. This allowed a second round of reassortment in the pigs, to create a new virus called H1N1/09 (“swine flue”) which could now infect humans and cause disease. This reassortment created a virus with an HA protein much better suited to binding to human respiratory epithelia.

How Influenza spreads (transmission): 

Influenza speads from person to person via airborne droplets or coughs. Influenza viruses generally enter the body through mucous membranes like the eyes, nose and mouth. It is highly contagious and affects people of all ages.

Transmission is greatly facilitated by crowding and poor ventilation in classrooms, barracks, nursing homes, dormitories and military installations in the late fall and winter. The dry air of winter facilitates the spread of the virus as the the moist particles expcelled by sneezes and coughs become dry very quickly, helping the virus remain airborn for longer periods of time. In addition, the dry cold air makes respiratory tract mucous membranes more brittle, with microscopic cracks that facilitate invasion by viruses.

Symptoms: 

Although the flu is conisdered to be an infection of the respiratory tract, people suffering the flu usually become acutely ill with high fever (usually 100-103F in an adult and possibly hihger in children) , chills, headache, weakness, loss of appetite and aching joints. The suddenness with which these symptoms develop usually aid in distinguishing between influenza and other viral respiratory infectious such as the common cold, which are generally characterized by a slower onset of symptoms. The typical lenght of time form when a perosn is exposed to influenza virus to when symptoms first occur ranges between 1 and 3 days, with an average of 2 days. Adults can be infectious (i.e., shedding virus) starting the day before the onset of symptoms begin until about 3 days after the onset of illness. Children can be infectious for longer periods of time.

Infection initiation/Entry:

Human influenza viruses are transmitted through the respiratory route, whereas avian influenza viruses are spread between birds primarily through direct contact via faecal-oral, faecal-faecal, and faecal-respiratory routes. Viruses replicate mainly in the epithelial cells lining the respiratory or intestinal tract. Mild influenza infections generally involve the upper respiratory tract and trachea, whereas the most severe and fatal human infections are associated with viral infections in the lower respiratory tract.

The role of hemagglutinin in the lipid bilyer is to initiate infection of a host cell by binding to sialic acid residues present on cell surface molecules of a respiratory epithelial cell. The host cell then encloses the virus in an endosome, and the viral and cell membranes subsequently fuse. At a later stage of infection the neuraminidase functions to cleave the bonds between the nascent (newly replicated) viral particles which emerge form the infected host cell coated with a lipid bilayer aquired form the host cell plasma membrane. Neuraminidase is thus an essential enzyme for the replication of influenza virus and it has been described as a “molecular scissors” which cut the nascent viruses free. More specifically, neuraminidase cleaves terminal nueraminic (sialic) acid residues from carbohydrate moieties on host epithelial cell membrane proteins, and on viral enveope glycoprotein spikes of newly synthesized virions.

Influenza virions attach to a specific surface carbohydrate on respiratory epithelia cells, using a viral envelope protein called hemagglutin (HA). The virus is then endocytosed into the host cell’s cytoplasm. The eight seignts of the viral genome are released for the capsid and transproted into the nucleus. The viral genome is replicated and used to make mRNA from which viral proteins are translated. Viral capsids containing the genomic segments are assembled at the cell membrane and a virion buds form the cell surface. The viral envelope is created from the host cell membrane. Release of the virus from the cell surface depends on a viral protein embedded in the host cell membrane called neurominidase (NA).

How Influenza Causes Disease:

Disease is partly due to tissue damage caused by the virus itself and mainly due to the inflammatory response of the host. HA adn NA is the iral envelope are the two viral proteins most commonly recognized by the immune system. As inflammatory cells of the immune system respond to the virus, infected cells are killed and this contributes to tissue damage. Most cases resolve without intervention. However, in immunocompromised persons, disease can be severe, leading to respiratory failure and death. Ironically, a very strong immunoglogical response can be as dangerous as a weak one. For example, the strenght of the immune response triggered by the 1918 infleunza A virus may explain its high mortality rate.

Treatment:

Even an uncomplicated case of acute influenza is likely to require days of bed rest.

Patients who present with suspected influenzy might benefit from treatment with antiviral agents. Antiviral drug against influenza was first discovered and available in 1960s when the amantadine (an amino derivative of adamantine) was approved for treatment and prophylaxis of influenza A viruses with an efficacy of around 90%. n the 1990s, another drug, rimantadine (an analog), was approved and showed fewer side effects than amantadine. Extensive mechanistic studies on the action of adamantines led to the discovery of a new influenza viral protein (M2) and studies on the mutants resistant to rimantadine demonstrated that all mutant strains had a mutation in the second splicing readout of the gene 7, encoding protein M2. In late 1990s, the second generation of anti-influenza drugs called the neuraminidase inhibitors (NAI), were approved, and found to act against influenza A viruses. The 2 major NAIs used for treatments were the oseltamivir (widely used) and zanamivir (lower patient acceptance rate). Oseltamivir gained more popularity and became the choice of anti-influenza drug throughout the world. The drug inhibits the activity of viral neuraminidase thus preventing the viral budding and thereby restricting infection in respiratory tract. Of the 5 currently used, major anti-influenza drugs, only 3 NAIs (oseltamivir, zanamivir and peramivir) are approved for use by the U.S. Food and Drug Administration (US-FDA). See Kumar 

NA inhibitors (NAI): that prevent the release of viral particles from the cell surface and stop the viral spread. Zanamivir and oseltamivir are NA inhibitors (NAI) that prevent the release of viral particles from the cell surface and stop the viral spread.

NAI-resistant mutations such as H275Y, E119G, I223R, R292K, and Q136K, as well as PAIresistant mutations such as I38M or I38T, have been identified from influenza isolates.

–Zanamivir and oseltamivir are available for the treatment of both influenza A and B disease. In adults, therapy with these agents may reduce the severity and duration of illness if given with the first 48 h of onset of illsness.

–Oseltamivir (Tamiflu): is approved for treatment of uncomplicated influenza in adults over 18 who have been symptomatic for no more than 2 days. Oseltamivir is a long acting oral agent with a systemic bioavailability of 80% and a half life of 6 to 10 hours. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase and prevention of viral budding from infected cells (US 2004/0248825).

Tamiflu is available in capsules or as a powdered mix to be made into a drink. It can also be used for prevention of influenza A and B.

Baloxavir marboxil (BXM) is an inhibitor of PA endonuclease activity (PAI) and suppresses viral transcription.

Anamivir is approved for treatment of uncomplicated acute influenza in people over 12 who have been symptomatic for no more than 2 days. it is most effective if administered within 30-36 hrs of symptoms onset.

–Relenza (zanamivir) is an inhalation powder approved for treatment of uncomplicated illness due to influenza A and B virus. It is indicative for preventitive (prophylaxis)in adults and pediatrics (5 years and older). Zanamivir is poorly absorbed in the gastroinestinal tract and formulated as a dry powder for inhalation. Most of the drug is deposited in the throat and about 20% of the inhaled drug reaches the lungs. It has a half-life of 2.5 to 5 hrs.

M2 inhibitors (M2I) – amantadine and rimantadine – block M2 ion channel activity.

Resistance to M2Is develops rapidly and requires a single or a limited number of mutations in M2 such as L26F, V27A, and S31N, which are prevalent in circulating influenza viral strains. Thus, the M2Is amantadine and rimantadine are no longer recommended to treat influenza infections

—Amantadine and rimandtadine are available for both the prevention and treatment of influenza A disease only. The M2 protein that also acts as an ion channel, is responsible for the internal acidification of the virus which is essential at the early stage of viral trafficking in endosomes and releasing its genetic material. The amantadine and rimantadine increases the pH inside the endosomes by inhibiting the transport of protons. This event hampers the separation of viral ribonucleoprotein (RNP) from M1 protein and subsequently on the onset of viral genome transcription. Both drugs were active against influenza A viruses and blocked their replication in both cell lines and animal models, however, viral resistance soon developed against them and they produced marked side effects.

Vaccination for Influenza & associated Disease:

Current antibody mediated influenaza vaccines are strain specific due to targeting of the highly variable hemagglutin (HA) and neuraminidase (NA) glycoproteins. Indeed, given the continual sequence evolution of HA and NA through antigenic drift and ability of the segmented virus to recombine two or more different strains through antigenic shift, seasonal influenza vacdine effectiveness ranges from 30-60% depending on matching of the vaccine sequence to influenza viruses subsequently circulating that year. Although influenza vaccines are available, because an antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza, it is necessary to incorporate one or more new strains in each year’s influenza vaccine.

Influenza vaccines are usually trivalent vaccines. They generally contain antigens derived from two influenza A virus strains and one influenza B strain. The efficacy of such vaccines in preventing respiratory disease and influenza complications ranges from 75% in healthy adults to less than 50% in the elderly. Persons between the ages of 25-64 with health conditions associated with higher risk of medical complications from influenza, including HIV infection, should be vaccinated. Additional groups include ages 6 months-24 years, Healthcare personnel, pregnant woman household contacts and caregivers for children younger then 6 months.

Influenza predisposes people to developing community-acquired pneumonia. (pneumococcus) is the most common. S. pneumoniae is a illness and such vaccines can be useful in preventing secondary pneumococcal infections and reducing death among those infected with influenza viruses. CDC recommends a single dose of the pneumococcal polysaccharide vaccine (PPSV) for all people over 65 and for persons 2-64 with high risk conditions.

Immune Response:

Innate Immune Response: Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. See Chen

The innate immune system provides immediate protection against infection by recognizing and responding to pathogens in a non-specific manner. The innate responses to influenza A virus (IAV) are initiated by recognition of pathogen-associated molecular patterns (PAMPs) by host’s pattern recognition receptors (PRRs), such as retinoic acid-inducible protein I (RIG-I) and TLRs. A family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection.   See Metcalf

–Dendritic cells: 

Influenza virus enters the respiratory tract and replicates (undergoes “productive” infection) in the respiratory epithelial cells lining the airways and, in more severe infections, the alveolar lining type I and II pneumocytes. The viral antigens generated are sampled by distinct subsets of resident RDCs that are located within or at the margins of the epithelial mucosal lining (i.e., CD103+ RDCs) or within the pulmonary interstitium (i.e., CD11bhi RDCs). Antigen acquisition by RDCs, along with virus-induced local inflammatory stimuli, triggers upregulation of CC-chemokine receptor 7 on the responding RDCs, which enables the chemokine-dependent migration of the activated RDC from the infected lung through the afferent lymphatics to the lung-draining lymph nodes (DLN). See Kim

–Macrophages are essential components of innate immunity and are commonly involved in viral infections and antiviral states. In the case of IAV, animal studies showed that macrophage depletion results in increased viral replication, with higher lung inflammation responses and increased mortality. During pathogenic infection, macrophages demonstrated plasticity via activation into two polarized phenotypes, classically activated (M1) and alternatively activated (M2) macrophages.

Adaptive Immune Response: T cells and B cells play key roles in adaptive immunity against the IAV infection. T cells are mainly known as CD4+ T and CD8+ T cells. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), which produce cytokines and effector molecules to restrict viral replication and kill virus-infected cells. Therefore, T cells are crucial for the restriction of viral infection. Upon infection with IAV, naïve CD8+ T cells are activated by DCs migrated from lungs to T-cell zone of the draining lymph nodes, leading to T-cell proliferation and differentiation into CTLs. Moreover, type I IFNs, IFN-γ, IL-2, and IL-12 also help CD8+ T  cells to differentiate into CTLs. Mechanism by which CTLs function is well understood. Upon targeting the virus-infected cells, CTLs produce cytotoxic granules that contain molecules like perforin and granzymes (e.g., GrA and GrB). See Chen

–Secretory IgA (sIgA) does not preexist on mucosal cells; B cells must first be activated in mucosal-associated lymphoid tissues (MALT) to produce and secrete sIgA. Naive B cells encounter antigens in MALT, where they are activated by other immune cells like T-helper cells and various cytokines, particularly. After activation, B cells differentiate into plasma cells that are located near mucosal surfaces, and these cells then produce polymeric IgA that is transported across epithelial cells by a secretory component to be released as sIgA into secretions like tears, saliva, and gut fluid.

–T cells:

—-Transmigration into peripheral tissues: After initial infection, downregulation of CD62L and CCR7 allows activated T cells to exit the lymph nodes and traffic to the peripheral tissues. Both CD4 and CD8 T cells express the integrin LFA-1, which binds to Intracellular Adhesion Molecule-1 (ICAM-1) present on endothelial cells and allows their transmigration into inflamed tissues. Expression of LFA-1 has been shown to be important in the migration and retention of effector CD8 T cells to the lung during Influenza infection. The chemokine receptor CXCR3 has been shown to be important in the migration of CD4 T cells to the lung in primary Influenza infection. One of the ligands for CXCR3, IP-10, is notably upregulated during Influenza infection. The chemokine receptor, CCR5, which also binds RANTES and MIP-1α, was shown to facilitate the accelerated recruitment of memory CD8 T cells to the lung airways following secondary challenge. As with homing, tissue retention of T cells seems to be regulated by the expression of various chemokine receptors and integrins. Expression of LFA-1 and the α1β1 integrin Very Late Antigen-1 (VLA-1, a dimer of CD49a and CD29), which binds collagen, were shown to contribute to retention of memory CD8 T cells in the lung following Influenza infection See Farber

—-Memory CD4 T cells: Both CD4 and CD8 T cells play important roles in the adaptive immune response to Influenza. However, in contrast to CD8 T cells, which are limited to cytotoxic killing of virally-infected cells, CD4 T cells play much more diverse roles in responses to infection. Effector CD4 cells are capable of providing help necessary for both CD8 T cells and B cells to achieve their full functional potential, as well as mediating direct effector functions through cytolysis of Influenza-infected cells. Following Influenza infection, virus-specific CD4 T cells are maintained as long-lived memory populations with an enhanced capacity to protect against secondary infection, due to their ability to respond more rapidly and robustly upon antigen encounter. In addition, in contrast to naïve cells, which remain in lymphoid tissues, memory cells localize to peripheral sites, poised to respond to secondary challenge at the site of infection. In mouse models of Influenza infection, memory CD4 T cells have been shown to mediate protective responses independently of B and CD8 T cells. See Farber

How Influenza Viruses Evade the Immune System: 

Influenza viruses evade infection fighting antibodies by constantly changing the shape of their marjor surface protein. This shape-shifting is called antigenic drift. It is why invluenza vaccines which are designed to elicity antibodies much be reformulated annually to match each year’s circulating virus strains.