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The Immune Response to Influenza Infection

Effector mechanisms of the adaptive response

Antibodies to HA neutralize the virus

Influenza strain-specific antibodies, produced during the adaptive immune response, represent the principal mechanism by which infection of cells is prevented. The main virus-neutralizing antibodies are directed against the viral surface glycoprotein HA (see Figure 7 in Chapter 2). IgA and IgG are the main immunoglobulin subtypes that neutralize influenza virus on the mucosal surface of the respiratory tract. IgA is specifically designed for secretion onto the mucosal surface where these secretory antibodies provide the first line of defence, while IgG subtype antibodies circulate in the blood and transudate to the airways and lungs. Binding of anti-HA antibodies blocks the receptor-binding site on the HA, as shown in Figure 18 . This prevents attachment and cell entry of the virus particles, thus effectively neutralizing the virus. Furthermore, NK cells bind to antibody–virus complexes on the surface of infected cells and kill by antibody-dependent cell-mediated cytotoxicity (ADCC) as part of the adaptive immune response.

Figure 18 Mechanism of influenza virus neutralization by an antibody directed against the viral HA. The figure shows an HA monomer (in blue), with (in yellow) an attached Fab (antigen-binding) fragment of an antibody specific for epitope D of HA (see Figure 7). This figure was produced as described in the caption to Figure 6, on the basis of the co-ordinate file from the Protein Data Bank, code 1EO8. source: Fleury D et al. Structural evidence for recognition of a single epitope by two distinct antibodies. Proteins Struct Funct Genet 2000; 40: 572.

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References in context

  • Binding of anti-HA antibodies blocks the receptor-binding site on the HA, as shown in Figure 18.
    Go to context

The peptide sequences of the antigenic epitopes of HA (and NA) change as a result of selective pressure by the immune system against the native virus, a phenomenon known as antigenic drift (see Chapter 3). Mutant viruses thus produced may escape antibody binding due to changes in the antigenic epitopes determining the B cell response (see Figure 7). Influenza vaccines are updated annually to ensure that immunity to the relevant predicted strains of the H3N2 and H1N1 subtypes of influenza A and influenza B is stimulated (see Chapters 3 and 8). Thus, antibodies resulting from exposure to a different strain of influenza that circulated in previous years or was contained in a vaccine, may not provide adequate protection against the circulating strains. In this case, antibodies may not control influenza virus infection and illness may result from the successful replication of the virus in the respiratory tract. Infected respiratory epithelial cells need to be cleared from the system in order to prevent the formation of new virus particles and allow recovery from illness. This is achieved by the activation of the T cell-mediated adaptive immune response.

CTLs are critical for clearance of influenza virus and recovery from illness

The importance of CTLs in clearing virus from infected lung tissue has been clearly demonstrated. Human studies showed that CTL activity is important for recovery from influenza infection even in the presence of protective antibodies to the infecting virus strain. 13 x AJ McMichael, FM Gotch, GR Noble, PA Beare. Cytotoxic T-cell immunity to influenza. New Engl J Med 309 (1983) (13 - 17) Crossref. CTLs combat influenza viral infections by recognizing and destroying virus-infected host cells that otherwise become the factories for viral replication. Infected cells expressing on their surfaces the MHC I–viral peptide complex are recognized by virus-specific CTLs. The mechanisms by which CTLs induce lysis of virus-infected cells include perforin- or granule-mediated killing. 4 x PC Doherty, DJ Topham, RA Tripp, et al.. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev 159 (1997) (105 - 117) Crossref. Granule-mediated killing appears to be the critical effector function of CTLs against influenza-infected cells.

Virus-specific, granule-mediated killing results from the production of granules within CTLs that contain pore-forming proteins (perforins) and granzymes ( Figure 19 ). Granules are transported to the surface of activated CTLs at the point of contact with an appropriate target cell. Through a process facilitated by perforin, granzymes are transported across the cell membrane into the target cell Through a process facilitated by perforin, granzymes are transported across the cell membrane into the target cell and subsequently trigger an enzymatic cascade that eventually results in DNA fragmentation and cell death (apoptosis). The combined activity of Grz B and perforin is important for target-cell lysis. Thus, the activation of CTLs and associated increase in Grz B that leads to apoptotic cell death is a critical component of antiviral immunity.

Figure 19 Mechanism of CTL-mediated killing. Granules in the CTL migrate to the cell surface upon CTL activation and cross into the virus-infected cell to induce apoptotic cell death through DNA fragmentation and disruption of mitochondrial metabolism. source: Reproduced from Abbas AK, Lichtman AH. Basic Immunology, 2nd edn. WB Saunders, 2004 with permission from Elsevier.

f04-19-9780723434337

References in context

  • Virus-specific, granule-mediated killing results from the production of granules within CTLs that contain pore-forming proteins (perforins) and granzymes (Figure 19).
    Go to context

T cell responses offer more cross-protection between different strains of influenza

In contrast to the antibody response to a specific strain of influenza virus, T cell responses tend to be cross-protective within the types and subtypes of influenza, as the viral peptides that stimulate the T cell response are relatively more conserved than antibody binding sites across the different strains of influenza. 14 x PG Thomas, R Keating, DJ Hulse-Post, PC Doherty. Cell-mediated protection in influenza infection. Emerg Infect Dis 12 (2006) (48 - 54) Crossref. Internal peptide sequences of HA and NA are similar within the subtypes of influenza (e.g. A/H3N2 vs A/H1N1) and the internal viral proteins – the matrix and nucleoproteins (NP) – are relatively conserved within the types of influenza (e.g. influenza A vs B). Although T cell responses are much more cross-reactive compared to antibody responses, recent data suggest that antigenic drift also affects CTL responses against NP as soon as immunological pressure is applied. 15 x GF Rimmelzwaan, AC Boon, JT Voeten, et al.. Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. Virus Res 103 (2004) (97 - 100) Crossref. Although B cell memory is largely strain-specific, it lasts a lifetime. In contrast, T cell memory is more cross-reactive but the duration is much more short-lived. 16 x FA Ennis, Q Yi-Hua, GC Schild. Antibody and cytotoxic T lymphocyte responses of humans to live and inactivated influenza vaccines. J Gen Virol 58 (1982) (273 - 281) Crossref.

 
x

Figure 18 Mechanism of influenza virus neutralization by an antibody directed against the viral HA. The figure shows an HA monomer (in blue), with (in yellow) an attached Fab (antigen-binding) fragment of an antibody specific for epitope D of HA (see Figure 7). This figure was produced as described in the caption to Figure 6, on the basis of the co-ordinate file from the Protein Data Bank, code 1EO8. source: Fleury D et al. Structural evidence for recognition of a single epitope by two distinct antibodies. Proteins Struct Funct Genet 2000; 40: 572.

f04-18-9780723434337

References in context

  • Binding of anti-HA antibodies blocks the receptor-binding site on the HA, as shown in Figure 18.
    Go to context

Figure 19 Mechanism of CTL-mediated killing. Granules in the CTL migrate to the cell surface upon CTL activation and cross into the virus-infected cell to induce apoptotic cell death through DNA fragmentation and disruption of mitochondrial metabolism. source: Reproduced from Abbas AK, Lichtman AH. Basic Immunology, 2nd edn. WB Saunders, 2004 with permission from Elsevier.

f04-19-9780723434337

References in context

  • Virus-specific, granule-mediated killing results from the production of granules within CTLs that contain pore-forming proteins (perforins) and granzymes (Figure 19).
    Go to context

References

Label Authors Title Source Year
4

References in context

  • Helper T cells, through the production of cytokines, contribute to B cell proliferation and differentiation to plasma cells, and to the activation and proliferation of virus-specific cytotoxic T lymphocytes (CTLs).4 Figure 16 details many of the interactions of the different cell populations involved.
    Go to context

  • The mechanisms by which CTLs induce lysis of virus-infected cells include perforin- or granule-mediated killing.4 Granule-mediated killing appears to be the critical effector function of CTLs against influenza-infected cells.
    Go to context

PC Doherty, DJ Topham, RA Tripp, et al.. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Crossref. Immunol Rev 159 (1997) (105 - 117) 1997
13

References in context

  • Human studies showed that CTL activity is important for recovery from influenza infection even in the presence of protective antibodies to the infecting virus strain.13 CTLs combat influenza viral infections by recognizing and destroying virus-infected host cells that otherwise become the factories for viral replication.
    Go to context

AJ McMichael, FM Gotch, GR Noble, PA Beare. Cytotoxic T-cell immunity to influenza. Crossref. New Engl J Med 309 (1983) (13 - 17) 1983
14

References in context

  • In contrast to the antibody response to a specific strain of influenza virus, T cell responses tend to be cross-protective within the types and subtypes of influenza, as the viral peptides that stimulate the T cell response are relatively more conserved than antibody binding sites across the different strains of influenza.14 Internal peptide sequences of HA and NA are similar within the subtypes of influenza (e.g.
    Go to context

PG Thomas, R Keating, DJ Hulse-Post, PC Doherty. Cell-mediated protection in influenza infection. Crossref. Emerg Infect Dis 12 (2006) (48 - 54) 2006
15

References in context

  • Although T cell responses are much more cross-reactive compared to antibody responses, recent data suggest that antigenic drift also affects CTL responses against NP as soon as immunological pressure is applied.15 Although B cell memory is largely strain-specific, it lasts a lifetime.
    Go to context

GF Rimmelzwaan, AC Boon, JT Voeten, et al.. Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. Crossref. Virus Res 103 (2004) (97 - 100) 2004
16

References in context

  • In contrast to the antibody response to a specific strain of influenza virus, T cell responses tend to be cross-protective within the types and subtypes of influenza, as the viral peptides that stimulate the T cell response are relatively more conserved than antibody binding sites across the different strains of influenza.14 Internal peptide sequences of HA and NA are similar within the subtypes of influenza (e.g.
    Go to context

FA Ennis, Q Yi-Hua, GC Schild. Antibody and cytotoxic T lymphocyte responses of humans to live and inactivated influenza vaccines. Crossref. J Gen Virol 58 (1982) (273 - 281) 1982

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