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Review
. 2017 Aug 12;9(8):223.
doi: 10.3390/v9080223.

Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis

Jung Min Shim  1 , Jinhee Kim  2 , Tanel Tenson  3 , Ji-Young Min  4 , Denis E Kainov  5   6   7
Affiliations
Review

Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis

Jung Min Shim et al. Viruses. .

Abstract

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here, we describe how IAV infection triggers cellular apoptosis and how this process can be exploited towards the development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

Keywords: antiviral agent; apoptosis; host response; influenza virus; innate immunity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Influenza A virus (IAV) replication cycle, interferon (IFN) response, viral counter-response, and apoptosis. (A) IAV replication cycle consists of entry through endocytosis into the host cell and uncoating of viral ribonucleoproteins (vRNPs), import of vRNPs into the nucleus, transcription and replication of the viral genome, translation of viral proteins in the cytoplasm, assembly of vRNPs in the nucleus, export of the vRNPs from the nucleus, and assembly and budding of virions at the host cell plasma membrane. (B) When IAV enters the cell, pathogen recognition receptors (PRRs) sense viral RNA (vRNA) and initiate the transcription of interferon (IFN) genes. Once transcribed, IFNs mediate the expression of IFN-stimulated genes (ISGs) in self or, when secreted, in neighboring non-infected cells. ISGs encode different antiviral proteins including RNases, which degrade vRNA in infected cells. ISGs also encode interleukins (ILs), C-X-C and C-C motif chemokines (CXCLs and CCLs) and other cytokines to recruit immune cells to the site of infection. (C) IAV nonstructural protein 1 (NS1) hinders the cellular IFN-ISG response by binding with cellular DNA, vRNA, or other cellular factors. The viral replication cycle continues. (D) Apoptosis is initiated in response to a large amount of vRNA or its replication intermediates. PRRs recognize vRNA and transduce signals to anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins. Bcl-2 proteins release pro-apoptotic proteins to initiate mitochondrial outer membrane permiabilization (MoMP), ATP degradation and caspase 3 activation. This results in cell death.
Figure 2
Figure 2
Bcl-2 inhibitors (Bcl2i) facilitate Bcl-2-dependent apoptosis in cells containing viral RNA. (A,B) Structures of ABT-263, ABT-737, ABT-199, WEHI-539, A-1331852, and A-1155463 revealed that these molecules fall into two distinct classes. Core structures are highlighted. (C) Table showing Bcl2i antiviral activities and affinities for three Bcl-2 proteins. “+” indicates inhibitory effect. Increased inhibition is marked by a higher “+” designation. (D) Schematic diagram showing how chemical inhibitors of Bcl-2 proteins induce premature death of cells containing viral nucleic acids. Bcl: B-cell lymphoma; CC50: half-maximum cytotoxic concentration; EC50: half-maximum efficacy concentration; SI: selectivity index; FC: fold-change; PRRs: pattern recognition receptors.
Figure 3
Figure 3
Two strategies of antiviral drug development. (A) One strategy is focused on discovery of antivirals to inhibit viral infection without affecting the viability of infected cells, whereas another exploits small molecules to inhibit viral replication by specifically killing only the virus-infected cells. (B) Examples of existing and emerging anti-IAV drugs. Existing and emerging drugs that target certain stages of virus replication cycle are shown. Bcl2 inhibitors (Bcl2i) are shown in a red box.
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