Interferons modulate the inflammatory response to infections

November 23, 2016

Interferons are a class of cytokines, small signalling molecules secreted by immune cells that direct the behaviour of surrounding cells to orchestrate the appropriate immune response to a particular type of infection. Interferons are classically associated with immunity against viruses in that they instruct cells to turn on defence mechanisms, which impede viral replication. As interferons are universally protective in the context of viral infections, they are commonly administered to treat viral infections such as hepatitis. More recently, a number of immunomodulatory bioactivities have been attributed to interferons opening the way for their use in the treatment of autoimmune disorders such as multiple sclerosis. Although it has been well established that interferons are also induced in response to bacterial infections, their function in these contexts remain ill defined. In fact, depending on the bacterial pathogen at hand, interferon signalling has been linked to both beneficial and detrimental outcomes of infection.

Our work with interferons in the context of bacterial infections began with the observation that mice deficient in interferon signalling became more susceptible to necrotizing fasciitis when infected with the common human pathogen Streptococcus pyogenes. This unexpected observation initially lead us on a quest to identify the mechanism through which a bacterial pathogen can induce the production of cytokines, which are typically triggered in response to viruses. I related our findings on this aspect in a previous INBIONET outreach report entitled “Of mice and men – Evolutionary divergence in pathogen-recognizing immune receptors.” However, from the start in this area of investigation in our group, one important question remained to be addressed: what are the protective mechanisms engaged by interferon signalling in the context of infection with S. pyogenes?

Typically, bacterial infections result in death when insufficient inflammatory responses are triggered to control bacterial growth. This results in increased bacterial burdens and dissemination to distal sites from the origin of the infection, which eventually overwhelms our immune defenses. To our surprise, inadequate immune responses were not the cause of lethality in interferon signalling-deficient mice because these animals did not carry higher bacterial burdens or show increased dissemination when compared to wild types. In light of these observations, we wondered whether in the case of loss of interferon signalling the opposite was true, i.e. whether loss of interferon signalling resulted in exacerbated rather than insufficient inflammation. Lo and behold, when we examined infected interferon signalling-deficient mice, we noted that these animals show increased inflammation in the lesions at the site of infection. In addition, distant organs such as the liver and kidneys were sustaining massive inflammatory tissue injury and were beginning to fail in these animals despite bacterial burdens comparable to those of wild types.

Having established that loss of interferon signalling resulted in lethal hyperinflammation in response to infection with S. pyogenes, we sought to identify the causative proinflammatory mediator. In doing so, we noted that animals deficient in interferon signalling produced higher systemic levels of the very proinflammatory cytokine interleukin 1 (IL-1) in response to infection. IL-1 was in fact a very plausible causative agent of the inflammation driven tissue injury we observed in interferon deficient mice. Because its receptor is broadly expressed across cell types and organs, IL-1 signalling stimulates immune cell activation in addition of promoting many inflammatory processes such as fever, vasodilation, endothelial activation, leukocyte migration and hematopoiesis. Given its broad biological activities in mediating inflammation, IL-1 is also a significant drivers of the pathogenic mechanisms associated with many infectious, autoimmune, autoinflammatory and degenerative conditions.

At this point we had to provide a mechanistic link between the hyperinflammatory phenotype in interferon signalling-deficient mice and exacerbated production of IL-1. To this end, we treated interferon signalling-deficient mice with various pharmacological inhibitors of IL-1 signalling pathways. These inhibitors had the effect of decreasing the susceptibility of interferon signalling-deficient mice to S. pyogenes infection. Moreover, we showed in vitro that interferon signalling inhibited the expression of the IL-1 gene in S. pyogenes-infected cells.

It is important to note that loss of IL-1 cytokines results in inadequate inflammatory responses and is ubiquitously lethal in the context of bacterial infections. Therefore, our study serves to demonstrate that while IL-1 is absolutely indispensable to combat infections, its production must be carefully balanced to avoid a deadly overreaction of our immune system. Regulation of IL-1 responses by interferons are foreseeably but one of the many yet to be discovered mechanism involved in modulating our inflammatory responses.


Read more about our latest published finding on the role of interferons in modulating immune responses to infection:

Castiglia, V., et al., Type I Interferon Signaling Prevents IL-1beta-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue. Cell Host Microbe, 2016. 19(3): p. 375-87.

Man, S.M. and T.D. Kanneganti, Type I Interferon Keeps IL-1beta in Check. Cell Host Microbe, 2016. 19(3): p. 272-4.