IMMUNE RESPONSE TO VIRUS:

INFLUENZA A VIRUS (IAV) AS

CASE STUDY

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OUTLINE
• Immune response to virus: overview
• Immune response to Influenza A virus (IAV)
• Innate immune response to IAV
• Activation of innate immune response
• Antiviral molecules involved in innate immunity
• Cells involved in innate immunity
• Adaptive immune response
• Respiratory mucosal immunity.
• conclusion

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 Immune response to virus: Overview

2. Through agglutination by
1. Through cytotoxic cells antibodies

3. Through antibody-mediated phagocytosis

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https://www.immunology.org/public-information/bitesized-immunology/pat%C3%B3genos-y-en
Immune response to IAV
• IAV belong to the Orthomyxoviridae family, which is
characterized by a segmented, negative sense, and ssRNA
genome. (Nturibi et al, 2017)
• IAV gemone encode several protein that are associated
with the virus pathogenesis; mainly hemagglutinin (HA)
and neuraminidase (NA) protein.
• Respiratory epithelial cells also express mucin
glycoproteins at their surface that include MUC5AC,
MUC5B, and MUC1. These glycoproteins play an
important role in restricting IAV infection
• Mucin glycoproteins are rich in sialic acid (SA), which act
as viral receptor decoys and prevent the viral binding to
the target cells 4
 • HA is the most abundant
surface glycoprotein of the
IAV. It has the ability to
attach the host cell,
causing cellular fusion and
viral entry.

• NA is the second most

Schematic diagram of IAV showing
surface hemaglutinin and
neuramidiase.
abundant glycoprotein. It
cleaves sialic acid (SA)
moieties, promotes the
release of nascent virions,
and facilitates IAV
dispersion 5

Wang and Peter, 2009

 Innate immune response to IAV
 IAV primarily targets and infects airway and alveolar
epithelial cells, thus causing alveolar epithelial injury and
eventually failure of gas exchange.
 Physical barrier is made up of the mucus and collectins
produced by the mucosal glands of the upper respiratory
tract.
 IAV binds to specific receptors on the human epithelial cells
of the upper and lower respiratory tracts.
 The two major receptors are SA α-2,3 galactose and SA α-
2,6 galactose.
 Viral attachment to host cells induces endocytosis; the virus
uncoats and release viral ribonucleoproteins which initiate
the activation of innate immune system. 6

(Chen et al, 2016).

Activation of innate immune system
• Pathogen associated molecular patterns (PAMPs) are recognized
by host Pattern recognition receptors (PRRs).
• PRRs have the ability to distinguish self from non-self molecules
within the infected cells.
• PRRs like TLRs and RIG-I lead to activation of the innate
signaling, thus inducing the production of cytokines and other
antiviral molecules.
• TLRs senses the pathogens outside of the cell membrane and
internally at the endosomes and lysosomes.
• TLRs involved are TLR 3, 7 and 8 are involved in sensing IAV
components
• RIG-I is the main receptor to recognize the 7intracellular ssRNA
and transcriptional intermediates of IAVs in the infected host cells
(Chen et al, 2016).
Schematic diagram for innate response against IAV infection.

(Hiscott et al., 2006)

Antiviral molecules involved
innate immunity
• Activation of specific transcription factors including,
NF-κB, IRF3, and IRF7 during IAV infection results
in translocation of these factors into the nucleus where
they initiate the transcription of genes encoding IFNs
and pro-inflammatory cytokines (TNF, IL6, IL1β, etc.)
• Type I IFNs also known as interferon lambdas play
important roles in antiviral response in both virus-
infected and uninfected cells

(Chen et al, 2016).

Cells Involved In Innate Immune against IAV
Infection
 All cell types of the respiratory tract interact with
virus-infected cells to limit viral replication, and also
prime adaptive immune cells for antigen-specific
immunity and memory.
Airway epithelial cells are the first target of IAVs
These cells produce antiviral and chemotactic
molecules that initiate immune responses by rapid
recruitment of innate effector cells
TNF-α and IL-1 induces the epithelial adhesion
molecule which triggers the migration of
Macrophages, Dendritic cells (DC), Natural killer
(NK) cells, monocytes, and neutrophils to the 10
site of
infection.
(Mendelson et al, 2010).
NK cells eliminate IAV infection by lysing IAV-infected cells.
Alveolar macrophages limits viral spread. When activated,
they phagocytose IAV-infected cells and thus limit viral
spread.
DCs are specialized antigen-presenting cells, helps to bridge
up the innate and adaptive immune responses during the IAV
infection.
DCs degrade the viral protein into immune peptides which are
exported to the endoplasmatic reticulum, where they bind with
MHC class I for recognition by virus-specific CD8+ cytotoxic
T cells (CTL)
Viral proteins degraded in endosomes/lysosomes are
associated with MHC class II molecule for recognition by
CD4+ T helper (Th) cells.
This process may lead to B cell proliferation and maturation
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to antibody producing plasma cells.
(Chen et al, 2016).
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
• Cytokines from innate stimulates CD8+ cell differentiation to
cytotoxic T cells (CTLs).
• CTLs also have the ability to induce apoptosis by expressing
cytokines, such as TNF which recruit death receptors in IAV-infected
cells.
• CTLs produce cytotoxic granules that contain molecules like perforin
and granzymes (e.g., GrA and GrB). Perforin binds target cells to
form pores on the cell membrane that promote passive diffusion of
granzymes to induce apoptosis. Also, GrA can restrict virus
replication via cleavage of viral and host cell proteins that are
involved in protein synthesis.

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(Andrade, 2010).
• CD4+ T cells can also target IAV-infected epithelial cells
through MHC class II expression.
• When stimulated CD4+ T cell differentiate into Th1 cell
which expresse antiviral cytokines and activates
macrophages.
• Cytokines expressed by Th1 cell helps to regulate CD8+ T
T cell differentiation into CTLs, and hence clear the viral
infection.

• B cells are stimulated by multiple co-stimulatory

receptors on CD4+ T cell.
• When activated, B cells produce antibodies which
facilitate viral elimination. 13

Seibert et al., 2013

Respiratory Mucosal Immunity
• Nasal secretions are known to have IgA which
neutralize the HA and NA of IAVs.
• After opsonization of pathogens with antibodies
in nasal secretion, the macrophages in the NALT
interact with T&B cells.
• Since the T&B cells have been primed, they move
to the lungs, differentiate and produce more
antiviral antibodies

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(Chen et al, 2016).

CONCLUSION
• Influenza A viruses (IAVs) are contagious pathogens
responsible for severe respiratory infection in humans
and animals worldwide.
• Upon detection of IAV infection, host immune system
aims to defend against and clear the viral infection.
• 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.
• The adaptive immunity is mediated by B cells and T
cells, characterized with antigen-specific memory
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cells, capturing and neutralizing the pathogen
REFERENCE
• Nturibi E, Bhagwat AR, Coburn S, Myerburg MM, Lakdawala SS.
Intracellular Colocalization of Influenza Viral RNA and Rab11A Is
Dependent upon Microtubule Filaments. J Virol. 2017 Oct 1; 91(19):
• Wang T. and Peter P. Universal epitopes of influenza virus hemagluttinins.
Nature structural and molecular biology 16: 233-234 (2009)
• Cao X. Review Self-regulation and cross-regulation of pattern-recognition
receptor signalling in health and disease. Nat Rev Immunol. 2016 Jan;
16(1):35-50.
• Chen X, Liu S, Goraya M, Maarouf M, Huang S and Chen J. Host
immune response to influenza A virus infection. Front immunol. 2018; 9:
320
• Seibert CW, Rahmat S, Krause JC, Eggink D, Albrecht RA, Goff PH, et
al. Recombinant IgA is sufficient to prevent influenza virus transmission
in guinea pigs. J Virol (2013) 87(14):7793–804.10.1128/JVI.00979-13
• Andrade F. Non-cytotoxic antiviral activities of granzymes in the context
of the immune antiviral state. Immunol Rev (2010) 235(1):128–
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46.10.1111/j.0105-2896.2010.00909.x 
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