Switch from protective to adverse inflammation during influenza: viral determinants and hemostasis are caught as culprits

Abstract

Influenza viruses cause acute respiratory infections, which are highly contagious and occur as seasonal epidemic and sporadic pandemic outbreaks. Innate immune response is activated shortly after infection with influenza A viruses (IAV), affording effective protection of the host. However, this response should be tightly regulated, as insufficient inflammation may result in virus escape from immunosurveillance. In contrast, excessive inflammation may result in bystander lung tissue damage, loss of respiratory capacity, and deterioration of the clinical outcome of IAV infections. In this review, we give a comprehensive overview of the innate immune response to IAV infection and summarize the most important findings on how the host can inappropriately respond to influenza.

Fig. 1

Structure of the IAV particle. The virion consists of 8 vRNP (ssRNA, NP, PB1, PB2, PA) surrounded by M1 proteins and an enveloped derived from the plasma membrane of the host cell. The viral HA, NA, and M2 as well as host proteins such as annexins (not shown) are incorporated into the enveloped

Fig. 2

Schematic representation of the replication cycle of IAV. The viral HA binds to sialylated glycoprotein receptors (1) and upon binding the virus becomes endocytosed (2). From the endosome, the virus genome is released following a low PH-dependent fusion event mediated by HA (3). The RNPs are transported to the nucleus (4) where the transcription (5) and replication (6) occur. The newly synthesized viral RNAs are produced through a complementary positive-stranded intermediate RNA (cRNA). The mRNA are transported to the cytoplasm and translated into protein (7). HA, NA, and M2 are transported to the plasma membrane through the reticulum/Golgi route (8) while PB1, PB2, PA, NP, NEP, and M1 re-enter the nucleus (9). Association of M1 and NEP with the vRNA complex (vRNA, NP, PA, PB1, PB2) allows the translocation of the vRNPs (10). Budding of the vRNP/M1/NEP from the plasma membrane expressing host proteins and HA, NA, and M2 form the new virions (11)

Fig. 3

Model of unbalanced inflammation following influenza infection. When the response to influenza infection is low or excessive, immunopathology of influenza develops. Strong interplay may exist between insufficient versus excessive inflammation. Immune escape from immunosurveillance (low response) may increase viral replication, which in turn induces strong release of secretory molecules (intensity of infection). When excessive inflammation is sustained by an uncontrolled host response, collateral lung damage increases IAV pathogeneses

Fig. 4

Pattern-recognition receptors (PRRs) sensing influenza viruses. Three groups of PRRs (TLR, RLR, and NLR) are able to sense influenza viruses. TLR7/8 and TLR3, endosome-expressed receptors, are activated by nucleic acids upon IAV infection. RIG-I, expressed in the cytoplasm recognizes the 5′triphosphate genome of influenza. NLRP3 is activated upon modification of ionic concentration mediated by the viral M2 protein of influenza. Activation of PRRs allows the release of both pro-inflammatory cytokines and IFN

Fig. 5

Signals required for IL1 and IL18 release in IAV-infected macrophages TLR7/8 senses influenza and initiates pro-IL-1β (and pro-IL18) synthesis (Signal 1). NLRP3 senses modification of ionic concentration mediated by the viral M2 protein upon IAV infection leading to the assembly of the complex NLRP3/ASC and caspase-1, which is then activated. Caspase1 activation cleaves the immature cytokines into mature IL1 and IL18

Fig. 6

Model of protective and destructive inflammation during influenza. Upon IAV infection (non-severe infection), epithelial cells are infected and release secretory molecules promoting activation of the host immune response. Initial immune system activation is protective and aims at the elimination of the invading pathogen. PAR1, expressed at the surface of epithelial cells, cooperates with PRRs for effective activation of innate immunity against influenza. However, if the infection is not controlled (severe infection), endothelial cells are injured (1). Hemostasis is activated (2) and deregulation of fibrinolysis through hyperactivation of plasminogen/plasmin promotes excessive and deleterious inflammation (3). PAR1, which is also expressed at the surface of the endothelium, cooperates with plasminogen and further exacerbates inflammation and injury