Question

One of the many immune system functions is to protect individuals from pathogens such as the influenza virus. Explain how innate immunity (non-specific defense) and adaptive immunity each respond differently to exposure to influenza virus?

Answer 1

Innate immune responses are non-specific defense mechanisms that respond to an antigen immediately or within few hours. They hold the antigen/infection in check until the adaptive immune responses are initiated. Innate immunity acts as physical and chemical barrier against the pathogen and activates the adaptive immune response through antigen presenting cells. Influenza virus is an infectious agent belonging to the Orthomyxo-viridae family that causes respiratory tract infections. Out of the three main species, influenza A causes the most virulent infections in humans.

Innate Immune response to the virus:

Influenza virus is an enveloped virus that contains a genome composed of 8 segments of negative-sense ssRNA tightly surrounded by nucleoprotein (NP). Haemagglutinin (HA) and neuraminidase (NA) are the major viral glycoproteins detected by the antibodies. This virus enters the host (humans) through oral/nasal cavity and is first encountered by the mucus lining of the respiratory epithelium. If the virus gets through this layer, it infects the immune and non-immune cells in the respiratory tract. The viral RNA is recognized as foreign by the pathogen associated molecular patterns (PAMPs) on the pathogen by pattern recognition receptors (PRRs) which leads to the secretion of type I interferons (IFNs), pro-inflammatory cytokines, eicosanoids and chemokines. PRRs that recognize Influenza are Toll-like receptors (TLRs) 3, TLR7, TLR8, retinoic acid inducible gene (RIG)-I (detects the 5'- triphosphate of the ssRNA after the viral replication) and NOD-LRR-pyrin domain containing 3 (NLRP3). RIG-I and NLRP3 detect the virus present inside the cytosol of infected cells where as TLR 3, TLR7 and TLR8 detect the viral RNA taken up by the endosomes of sentinel cells. TLR7 elicits antibody production through B cells. TLR8 stimulates the production of IL-12. RIG-I binds to ATP that enable the caspase-recruitment domains to bind to the signalling adaptor mitochondiral antiviral signalling protein (MAVS). MAVS signalling results in the production of pro-inflammatory cytokines downstream of NF-κB activation. NLRP3, activated by the trans-Golgi due to proton flux through the viral M2 (influenza virus-encoded matrix 2) channel, change in mitochondiral membrane potential and mitofusin 2, forms inflammasome complex. Primary human type II alveolar cells produce type III IFNs in response to human seasonal influenza virus, whereas differentiated human bronchial epithelial cells upregulate the expression of type I IFNs upon infection with human influenza virus.

Type I INFs (produced by the activation of NF-κB by TLR7 signalling) stimulate the expression of IFN-stimulated genes that induce an antiviral state in the neighbouring cells. Pro-inflammatory cytokines (produced by the induction of TLR3) and eicosanoids cause local and systemic inflammation and induce fever. Chemokines recruit various other immune cells such as natural killer (NK) cells, monocytes and neutrophils. NK cells mediate the viral clearance. Monocytes and neutrophils clear the infected dead cells in the respiratory tract along with the alveolar macrophages. Adaptive immune response is initiated and activated when the virus manages to survive after these innate immune responses.

Adaptive immune respose to the virus:

Though the innate immune response provides early control and induces slow replication of the virus, adaptive immune response ultimately clears the virus and allows recovery. It consists of humoral and cellular immunity mediated by virus specific antibodies and T cells respectively.

The HA specific antibodies bind to the trimeric globular head of HA and inhibit virus attachment and entry in the host cells therby neutralizing the virus. They facilitate the phagocytosis of the virus particles by Fc receptor expressing cells. Binding to HA mediates antibody-dependent cell-mediate cytotoxicity (ADCC). Antibodies binding to NA inhibit the enzymatic activity and limit virus spread. Antibodies binding to nucleoprotein (NP), a target for the T cells, induce complement mediated cell lysis of the infected cells. Main antibody isotypes in the influenza-specific immune response are IgA, IgM and IgG.

Upon infection, CD4+, CD8+ and regulatory T cells are induced. CD4+ cells are activated by the MHC class II associated peptides on the antigen presenting cells (APCs). The T helper (Th) 2 cells produce IL-4 and IL-13 and promotes B cell responses. Th1 cells produce IL-2 and IFN-γ involved in the cellular immune response. The main function of virus-specific CD8+ T cells is cytotoxic T lymphocytes (CTL).These cells are activated in the lymphoid tissues and recruited to the site of infection where they recognize and eliminate influenza virusinfected cells and thus prevent production of progeny virus. Their lytic activity is mediated by the release of perforin and granzymes (e.g. GrA and GrB). Perforin permeabilizes the membrane of the infectedcells andsubsequently granzymes enter the cell and induce apoptosis. CTL also induce apoptosis through Fas/FasL interactions. They produce cytokines that improve the antigen presentation by stimulating MHC expression and display antiviral activity.