Principles of Effective and Robust Innate Immune Response to Viral Infections: A Multiplex Network Analysis

Abstract

The human innate immune response, particularly the type-I interferon (IFN) response, is highly robust and effective first line of defense against virus invasion. IFN molecules are produced and secreted from infected cells upon virus infection and recognition. They then act as signaling/communication molecules to activate an antiviral response in neighboring cells so that those cells become refractory to infection. Previous experimental studies have identified the detailed molecular mechanisms for the IFN signaling and response. However, the principles underlying how host cells use IFN to communicate with each other to collectively and robustly halt an infection is not understood. Here we take a multiplex network modeling approach to provide a theoretical framework to identify key factors that determine the effectiveness of the IFN response against virus infection of a host. In this approach, we consider the virus spread among host cells and the interferon signaling to protect host cells as a competition process on a two-layer multiplex network. We focused on two types of network topology, i.e., the Erdős-Rényi (ER) network and the Geometric Random (GR) network, which represent the scenarios when infection of cells is mostly well mixed (e.g., in the blood) and when infection is spatially segregated (e.g., in tissues), respectively. We show that in general, the IFN response works effectively to stop viral infection when virus infection spreads spatially (a most likely scenario for initial virus infection of a host at the peripheral tissue). Importantly, we show that the effectiveness of the IFN response is robust against large variations in the distance of IFN diffusion as long as IFNs diffuse faster than viruses and they can effectively induce antiviral responses in susceptible host cells. This suggests that the effectiveness of the IFN response is insensitive to the specific arrangement of host cells in peripheral tissues. Thus, our work provides a quantitative explanation of why the IFN response can serve an effective and robust response in different tissue types to a wide range of viral infections of a host.

The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways

“…Simultaneously, innate and adaptive immune cells respond to the presence of the tumor micro-environment. This response across different cell types occurs via the recognition of viral nucleic acids, viral proteins or tissue-damage and results in the activation of different families of cellular receptors [32]. This section demonstrates that the same miRNA can be dysregulated in hepatocytes in HBV-HCC pathogenesis, as well as in immune cells for a range of related reasons, e.g., to modulate pro and anti-inflammatory response [56].…”

“…A few million years of 'warfare' between viruses and their hosts have led to the evolution of 'clever' viruses [31]. The first line of defense occurs in the innate immune system when interferon (IFN) molecules are produced and secreted from infected cells, in order to trigger anti-viral gene transcription and a broadly antiviral state [32]. HBV infection is characterized by a relatively delayed early innate immune response with weak induction of antiviral IFNs, as a result of poor detection of HBV and/or specific immunosuppression by viral proteins [33,34].…”

COVID-19: Loss of bridging between innate and adaptive immunity?

“…The IFN-α (alpha) and IFN-β (beta) act as signalling molecules and activate an antiviral response in surrounding cells, turning them refractory to infection. A few hours after a viral infection, both α and β IFNs are rapidly and efficiently produced by macrophages [11]. SARS coronavirus (SARS-CoV) which is similar SARS-CoV-2, is known to suppress the induction of antiviral type I interferons (IFN-α/β).…”

“…Elderly patients are unable to mount a stable immune response against all types of viral infections due to the decreased interferon production or its inhibition through viral non-structural protein 1 (NS1) which in turn increases the relentlessness of viral infection [7,8,11]. Furthermore, new-born babies have limited bacterial exposure, reduced antigen presentation by the dendritic cells, decreased lethal action by the NK cells and compromised adaptive lymphocyte response [11]. However, the paediatric clinical manifestations of COVID-19 are not typical, mild in severity and presents faster recovery [2].…”

Autocrine and paracrine interferon signaling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

“…Therefore, to investigate the 2 interaction between virus and the IFN response early in infection, a spatially explicit model is most appropriate. We previously modelled the spread of virus infection and the effectiveness and robustness of IFN signaling among host cells using a network approach [28,29]. however, the explicit roles of autocrine and paracrine signaling in suppressing virus spread are not clear.…”