Section 4: COVID-19 treatment by IFN-lambda: Pros and cons (from DOI: 10.1084/jem.20200653)
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From publication: "COVID-19 and emerging viral infections: The case for interferon lambda" published as J. Exp. Med.; 2020 05 04 ; 217 (5)
https://doi.org/10.1080/22221751.2020.1735265
Section 4: COVID-19 treatment by IFN-lambda: Pros and consCOVID-19 treatment by IFN-lambda: Pros and cons
With no time to spare for new pharmaceutical developments, the race is on for the repurposing of existing drugs. A compelling case can be made for IFN-lambda-based therapeutics. Pegylated IFN-lambda1 (peg-IFN-lambda1) is the only IFN-lambda currently available as a therapeutic agent. In vitro, treatment with IFN-lambda showed potency against a variety of viruses, including SARS-CoV1 and MERS-CoV. The main function of IFN-lambda is to prevent viral infection by establishing an antiviral state and, if infected, to slow viral replication and dissemination. In contrast to IFNAR, the IFNLR is largely absent on resting immune cells in humans and mice (with the notable exception of neutrophils and human B cells), allowing to avoid or minimize systemic inflammation caused by treatment with type I IFNs (; Fig. 1). Severe lung inflammation and tissue damage are hallmarks of COVID-19, significantly contributing to mortality from this infection; thus, enhancement of inflammation and cytokine storm must be avoided. However, it remains to be elucidated whether IFNLR can be up-regulated upon stimulation or in a highly inflamed environment, increasing the risk of possible adverse effects of IFN-lambda on human cells. The absence of pro-inflammatory effects in the lungs is one of the most important arguments for the specific advantage of IFN-lambda over type I IFNs as a treatment option for COVID-19. However, it is very important to establish if immune cells are responsive to IFN-lambda in COVID-19, as their activation exacerbates inflammation. It also remains to be seen whether IFN-lambda shares the known antiproliferative effect of type I IFNs and whether this could impede repair processes during recovery or sensitize epithelial cells to virus-induced cell death.
In addition, bacterial superinfections can be associated with severe cases of COVID-19 ( Preprint), although this varies between clinical studies. Type I IFNs are known to be detrimental in select bacterial infection models. For example, Ifnlr-/- mice show improved bacterial control in virus-bacteria superinfection models, and ectopic induction of IFN-lambda production proved to be detrimental in mice previously infected with influenza. While type I IFNs often suppress antibacterial action of immune cells, IFN-lambda may employ other routes to facilitate bacterial superinfection, such as reduction in neutrophil recruitment and/or neutrophil bactericidal activities. Although mouse models do not fully recapitulate human diseases with respect to IFN-lambda activities, animal studies give a mandate to carefully evaluate the use of IFN-lambda as a therapeutic agent against COVID-19.
Although the restricted expression pattern of IFNLR1 may be advantageous in potentially deleterious pro-inflammatory effects of IFN-lambda, it may come at the cost of efficacy. Indeed, IFN-lambda will only induce an antiviral program in cells expressing IFNLR1. For SARS-CoV-2, it is still debated whether alveolar macrophages or endothelial cells are productively infected and could serve as a virus reservoir not accessible to IFN-lambda antiviral action for lack of IFNLR1. While IFN-lambda may be better suited than type I IFNs as host-directed anti-SARS-CoV-2 therapy, studies are needed immediately to assess possible detrimental effects that should be factored into further use of IFN-lambda.
Although not yet used in active COVID-19 disease, no increased risk of lung infections has emerged from the 19 clinical studies of in over 3,000 patients who were treated for up to 48 wk with peg-IFN-lambda1. Potential adverse effects might also be minimized by the shorter duration of treatment. For example, the proposed Phase III clinical trial for chronic hepatitis D virus will be dosed once weekly for 48 wk, as it was in the preceding Phase II study (ClinicalTrials.gov identifier: NCT02765802). However, in the case of acute COVID-19, one or two doses of peg-IFN-lambda1 are deemed sufficient in the currently designed randomized clinical trials. This approach could provide immediate protection to healthcare workers and other persons at high risk of being infected or during early stages of infection, while patients show no sign of an inflammatory reaction, especially in the lungs.
There are many outstanding questions in relation to COVID-19 and IFN-lambdas. We need to understand whether the virus induces the endogenous expression of IFN-lambda and/or blocks IFN-lambda responses. Is there an age difference in the expression of IFN-lambda or its receptors that can explain the more severe disease in older patients? What are the effects of IFN-lambda on inflammatory responses and mechanisms of tissue damage and repair and how these activities should be measured in the clinical trials with peg-IFN-lambda1 in development for COVID-19? We also advocate for open access for the scientific community to the results of clinical trials to ensure their expert interpretation that can inform further measures. The COVID-19 pandemic illustrates the unmet need for prophylactic and rapid-response measures to boost the antiviral host response. IFNs, and IFN-lambda specifically, might address this need for broad-spectrum antiviral biologicals that could help not just this pandemic outbreak, but also future viral threats.
