The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent

Abstract

Interferon alpha/beta (IFN-α/β) is a critical mediator of protection against most viruses, with host survival frequently impossible in its absence. Many studies have investigated the pathways involved in the induction of IFN-α/β after virus infection and the resultant upregulation of antiviral IFN-stimulated genes (ISGs) through IFN-α/β receptor complex signaling. However, other than examining the effects of genetic deletion of induction or effector pathway components, little is known regarding the functionality of these responses in intact hosts and whether host genetic or environmental factors might influence their potency. Here, we demonstrate that the IFN-α/β response against multiple arthropod-vectored viruses, which replicate over a wide temperature range, is extremely sensitive to fluctuations in temperature, exhibiting reduced antiviral efficacy at subnormal cellular temperatures and increased efficacy at supranormal temperatures. The effect involves both IFN-α/β and ISG upregulation pathways with a major aspect of altered potency reflecting highly temperature-dependent transcription of IFN response genes that leads to altered IFN-α/β and ISG protein levels. Discordantly, signaling steps prior to transcription that were examined showed the opposite effect from gene transcription, with potentiation at low temperature and inhibition at high temperature. Finally, we demonstrate that by lowering the temperature of mice, chikungunya arbovirus replication and disease are exacerbated in an IFN-α/β-dependent manner. This finding raises the potential for use of hyperthermia as a therapeutic modality for viral infections and in other contexts such as antitumor therapy. The increased IFN-α/β efficacy at high temperatures may also reflect an innate immune-relevant aspect of the febrile response.

Fever: Could A Cardinal Sign of COVID-19 Infection Reduce Mortality?

“…Studies in mammals have shown that elevated thermal support during an infectious challenge impairs viral replication to a variety of viral pathogens. 9 , 10 , 11 , 12 , 13 , 14 , 15 Following infection, pyrogens and other conserved molecules from these invading organisms trigger an innate immune response which recognizes these pathogen-associated molecular patterns (PAMPs) via the pattern recognition receptors, which in turn shape the immune response. 16 A fever then ensues following the release of endogenous pyrogenic cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon (IFN).…”

“…For viral infections, recent studies suggest that an effective temperature-dependent response may operate through the IFN-α/β receptor complex. 9 , 10 …”

“…For viral infections, recent studies suggest that an effective temperature-dependent response may operate through the IFN-α/β receptor complex. 9,10 But one may ask what about the elderly or an otherwise debilitated patient? Isn't a fever too much to bear for a patient in a weakened condition?…”

Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as A Therapeutic Strategy for Alphaviral Disease

“…A number of studies have outlined the sensitivity of the alphavirus-induced IFN response to fluctuations in temperature, with reduced antiviral efficacy at subnormal cellular temperatures and increased efficacy at supranormal temperatures [49,50]. Temperature-dependent transcription of IFN response genes leads to altered IFN-α/β and IFN stimulated gene (ISG) protein levels.…”

“…CHIKV replication and foot arthropathy were dramatically reduced in CHIKV-infected mice housed at 30 °C rather than 22 °C [50]. Conversely, a separate study demonstrated that lowering the temperature, at which mice were housed, exacerbated replication and disease in CHIKV-infected mice [49]. Both effects were dependent on type I IFN responses.…”