Crosstalk Between IL-1β and Type I Interferon Responses Against Flaviviruses

Abstract

Viruses of the family Flaviviridae, genus Flavivirus, such as dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus, yellow fever virus, West Nile virus, and tick-borne encephalitis virus, pose continuous severe threats to public health due to their epidemic potential and the lack of effective therapeutics. The four DENV serotypes are capable of causing dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Millions of people are infected with DENV every year, with around ten thousand deaths and billions of people at risk. The incidence of dengue fever has increased over 30‑fold in recent decades and is growing at an alarming rate. ZIKV is another medically important flavivirus of global health concern. ZIKV is transmitted sexually and vertically, causing congenital syndrome and microcephaly in fetuses during pregnancy with the potential to give rise to explosive epidemics. There are no approved or widely used vaccines or treatments to tackle the health threats caused by flavivirus infections.

Multiple cytokines are produced by innate immune cells, protecting the host from viral infections. In particular, the antiviral immunity mediated by the type I interferons (IFNs) provides a robust first line of host defense against viral infections. Besides antiviral IFN signaling, inflammation is also one of the first responses of innate immunity that plays an essential role in controlling pathogens. Consequently, flaviviruses, such as DENV and ZIKV, evolved strategies to counteract the antiviral IFN system, the central mediator of the host's innate immune defense, to establish infections. Therefore, approaches to identifying molecules that compensate and potentiate host antiviral responses can be useful to hamper the immune-evasive mechanisms of flavivirus infections.

In this study, the activation of type I IFN signaling by IFNα in combination with the proinflammatory cytokine interleukin (IL)-1β, a central inflammatory mediator involved in initiating innate defenses, was investigated in depth. Specifically, efforts were made to examine the role of IL-1β in IFNα-mediated antiviral responses against DENV and ZIKV. Firstly, I determined that IL-1β together with IFNα leads to a more robust antiviral effect against DENV and ZIKV infections in human hepatoma-derived (Huh-7) cells that co-treat with IL-1β and IFNα restricted DENV and ZIKV in vitro infections. Secondly, to test whether IL-1β contributes to the activation of IFNα signaling, the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 was measured. The results showed that IL-1β could enhance IFNα-induced phosphorylation of both STAT1 and STAT2. Thirdly, to delineate the pathways induced by IL-1β that augment IFNα-mediated antiviral control against DENV and ZIKV, the effects of specific inhibitors targeting IL-1β-activated canonical nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, including extracellular-signal-regulated kinase (ERK), c-Jun Kinases (JNK), and p38, were evaluated. ERK mediated the crosstalk between IL-1β and IFNα in limiting DENV and ZIKV infections via stabilizing STAT2 and increasing STAT2 phosphorylation. Therefore, I hypothesized that ERK signaling plays a role in inhibiting DENV and ZIKV NS5-induced STAT2 degradation. The results indicated that the IL-1β treatment alone can inhibit DENV or ZIKV NS5-mediated STAT2 degradation to similar levels to that of IFNα treatment. Collectively, the results from this study lead to the mechanistic understanding of IL-1β function in restoring and enhancing antiviral type I IFN signaling in cells infected with flaviviruses. In conclusion, the findings from this study meet an urgent need and provide essential information towards developing IFNα-based therapeutics against immune-evasive flaviviruses, which may eventually help decrease the death rate and alleviate the economic and health burden caused by flaviviruses.

Date of Award	2 Dec 2024
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Akos KENEZ (Supervisor) & Luis M. SCHANG (External Co-Supervisor)