Innate immune sensing and response to influenza - PubMed (original) (raw)

Innate immune sensing and response to influenza

Bali Pulendran et al. Curr Top Microbiol Immunol. 2015.

Abstract

Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocompromised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza.

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Figures

Fig. 1

Fig. 1

Recognition of influenza virus infection by pattern-recognition receptors. Activation of TLRs upon detection of viral RNA (TLR3 and TLR7/8) or binding of death-associated molecular patterns (DAMPS; TLR4) recruits adaptor molecules (MyD88 and TRIF) triggering distinct signaling pathways that activates nuclear translocation of transcription factors (IRF3/7 and NF-kB) to induce production of type I interferons (I IFNs) and inflammatory cytokines (IL-6, TNF and pro-IL-1β and -IL-18). Recognition of 5’ppp-RNA by RIG-I activates recruitment of MAVS on mitochondrion, which in turn induces the production of cytokines through IRF3/IRF7. Of the NLRs, NOD2 detects ssRNA to activate translocation of MAPK and IRF3/IRF7 by recruiting adaptor molecules, RIPK2 and MAVS, respectively, to induce cytokine production. Activation of NLRP3 mediated by diverse stimuli, dependent on ionic channel M2 protein of influenza virus, recruits ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which in turn interact with pro-caspase-1 to form NLRP3 inflammasome. Autoactivation of caspase-1 cleaves pro-IL-1β/IL-18 to mature IL-1β/IL-18 for their secretion

Fig. 2

Fig. 2

Innate control of adaptive immunity to influenza. Innate immune cells, particularly dendritic cells (DCs) in the respiratory tissues acquire antigens either through direct infection or by uptake of influenza-infected dead cells and undergo maturation process triggered by TLR7 or RIG-I-signaling, under the influence of type I IFNs produced by macrophages and pDCs. Respiratory DC subsets (CD103+ cDCs, CD11b+ cDCs and pDCs) migrate to the draining lymph node (LN), where they can transfer influenza antigens (Ag) to LN-resident CD8α+ cDC. In the LN, respiratory CD103+ cDCs together with CD8α+ cDCs stimulate the naïve CD8+ T cells to proliferate and differentiate into cytotoxic effector CD8+ T cells, in a CD24-dependent manner. On the other hand, CD11b+ cDCs drive the activation of CD8+ T cells, mainly effector T cells at later stage of infection, to induce memory CD8+ T cells. Interaction of naïve CD4+ T cells with cDCs generates IFN-γ-producing Th1 cells, which in turn facilitates the differentiation of effector B cells in a TLR7-dependent manner. These effector cells migrate from LN to respiratory tissues, where they have second interaction with Ag-bearing innate immune cells to undergo further activation and differentiation to terminal effector cells that secrete effector molecules to control virus spread

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