VIEWPOINT
COVID-19 and emerging viral infections: The case for
interferon lambda
Ludmila Prokunina-Olsson1*, No´emie Alphonse2,3*, Ruth E. Dickenson2*, Joan E. Durbin4,5*, Jeffrey S. Glenn6*, Rune Hartmann7*,
Sergei V. Kotenko5,8,9*, Helen M. Lazear10*, Thomas R. O’Brien11*, Charlotte Odendall2*, Olusegun O. Onabajo1*, Helen Piontkivska12*,
Deanna M. Santer13*, Nancy C. Reich14*, Andreas Wack3*, and Ivan Zanoni15*
Infection with SARS-CoV-2 has emerged as
a major global threat. First reported in China
at the end of 2019, this outbreak rapidly
spread throughout the globe and was declared a pandemic by the World Health
Organization on March 11, 2020. In the
absence of approved therapies or vaccines
to prevent or treat this infection, its rapid
dissemination has overwhelmed public
healthcare systems worldwide, causing severe economic and social distress. The previous high mortality outbreaks caused by
SARS-CoV-1 in 2003 and Middle East respiratory syndrome (MERS)–CoV in 2012 illustrate that the emergence of novel viruses
is not an isolated occurrence. However, the
former outbreaks differed substantively
from COVID-19, which can be transmitted
by asymptomatic individuals. Currently, the
primary tool to mitigate SARS-CoV-2 is social distancing, and an effective antiviral
pharmacologic agent would be an important
clinical and public health tool.
IFNs as natural broad-spectrum
antivirals
A wide spectrum of viruses can directly
cause human disease, ranging in severity
from asymptomatic to life threatening. Host
survival is dependent upon key factors including cellular mechanisms of innate antiviral immune response, intended to counter
virus replication until virus-specific lymphocytes can eliminate the infection.
Therefore, the development of therapeutic
intervention strategies that augment these
intrinsic, early broad-spectrum antiviral
mechanisms is desirable. Although the biology, life cycle, and pathogenesis of different viruses are widely divergent, IFNs
activate protective mechanisms aimed at
both virus control and elimination. Administration of IFNs can be used for prophylaxis
as well as early therapy, predicated on the
principle of supplementing to compensate
for insufficient IFN production or activity
that might be actively blocked by the virus.
IFN-λ as an antiviral drug
For decades, type I IFNs (IFN-α/β) have
been explored as mediators of rapid, innate
antiviral protection. In 2003, a novel group
of three cytokines, now known as type III
IFNs (IFN-λs), was discovered that act independently of type I IFNs to establish antiviral resistance in cells (Kotenko et al.,
2003; Sheppard et al., 2003). An additional
member of this family (IFN-λ4) was discovered in 2013 (Prokunina-Olsson et al.,
2013). Most of the information on the
function of IFN-λs has been generated using
mouse models and thus has to be critically
evaluated in relation to human disease (Ye
et al., 2019). The distinctive actions of type I
and type III IFNs are achieved through the
engagement of separate nonoverlapping
heteromeric receptor complexes: IFNAR
complex (with IFNAR1/IFNAR2 subunits)
for all type I IFNs and IFNL complex (with
IFNLR1/IL10R2 subunits) for all type III IFNs
(Fig. 1). Signaling pathways and sets of
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1
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; 2Department of Infectious Diseases, School
of Immunology and Microbial Sciences, King’s College London, London, UK; 3Immunoregulation Laboratory, Francis Crick Institute, London, UK; 4Department of
Pathology, Laboratory Medicine and Immunology, Newark, NJ; 5Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Rutgers Biomedical and Health
Sciences, Newark, NJ; 6Departments of Medicine and Microbiology & Immunology, Stanford University School of Medicine, and Palo Alto Veterans Administration, Palo
Alto, CA; 7Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; 8Department of Microbiology, Biochemistry and Molecular Genetics,
Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ; 9Center for Cell Signaling, Rutgers New Jersey Medical School, Rutgers
Biomedical and Health Sciences, Newark, NJ; 10Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; 11Infections
and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; 12Department of Biological Sciences, School of
Biomedical Sciences, Kent State University, Kent, PA; 13Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta,
Edmonton, Canada; 14Department of Microbiology & Immunology, Stony Brook University, Stony Brook, NY; 15Division of Immunology, Division of Gastroenterology,
Harvard Medical School, Boston Children’s Hospital, Boston, MA.
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With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this
class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our
opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.
*All authors contributed equally to this paper; Ludmila Prokunina-Olsson: prokuninal@mail.nih.gov.
© 2020 Prokunina-Olsson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months
after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike
4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Rockefeller University Press
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https://doi.org/10.1084/jem.20200653
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IFN-stimulated genes (ISGs) induced by
these IFNs are remarkably similar but not
redundant (Crotta et al., 2013; Galani et al.,
2017). IFNAR is expressed on all cells, while
IFNLR, limited by IFNLR1 expression, is restricted to epithelial cells and a subset of
immune cells, including neutrophils. Due to
these specific expression patterns, type I
IFNs provide a systemic response, and IFNλs guard epithelial surfaces (Broggi et al.,
2020; Fig. 1).
Type I IFNs have been used to treat
chronic hepatitis C virus and hepatitis B
virus infection and may have the potential
to protect patients during outbreaks of other
viruses. However, these treatments have
significant systemic side effects due to the
ubiquitous expression of IFNAR. In mice,
IFN-λ was found to be more effective than
IFN-α in preventing and treating influenza
virus infection, with no increase in inflammation and tissue damage as compared with
IFN-α (Davidson et al., 2016; Galani et al.,
2017). IFN-λ was also more potent than
IFN-α in restricting viral dissemination
from nasal epithelium to the upper
Prokunina-Olsson et al.
COVID-19 and IFN lambda
respiratory tract (Klinkhammer et al., 2018).
Clinical trials of IFN-λ for the treatment of
chronic hepatitis C virus infection documented fewer and milder side effects, but
equal efficacy, when compared with IFNα–based therapies (Muir et al., 2014).
These studies suggest specific advantages
for IFN-λs as antiviral therapeutics at epithelial surfaces.
COVID-19 treatment by IFN-λ: 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-λ–based therapeutics. Pegylated IFN-λ1 (peg-IFN-λ1) is the
only IFN-λ currently available as a therapeutic agent. In vitro, treatment with IFN-λ
showed potency against a variety of viruses,
including SARS-CoV1 and MERS-CoV. The
main function of IFN-λ 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 [Blazek et al., 2015;
Broggi et al., 2017; Espinosa et al., 2017] and
human B cells [Goel et al., 2020]), allowing
to avoid or minimize systemic inflammation caused by treatment with type I IFNs
(Broggi et al., 2020; Fig. 1). Severe lung
inflammation and tissue damage are hallmarks of COVID-19, significantly contributing to mortality from this infection
(Mehta et al., 2020); 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-λ on human cells
(Espinosa et al., 2017; Goel et al., 2020). The
absence of pro-inflammatory effects in the
lungs (Davidson et al., 2016; Forero et al.,
2019; Galani et al., 2017) is one of the most
important arguments for the specific advantage of IFN-λ 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-λ in COVID-19, as
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Figure 1. Potential benefits of using type III IFNs for prevention and treatment of COVID-19 Type I IFNs (IFN-α/β) signal through a heterodimeric
receptor complex, IFNAR, which is comprised of IFNAR1 and IFNAR2 subunits. IFNAR activation induces expression of ISGs and triggers pro-inflammatory
responses via the recruitment and activation of immune cells. This promotes an antiviral state in the host, but as IFNAR is expressed on all cells, the administration of type I IFN can have serious systemic side effects. In contrast, type III IFNs (IFN-λ1-4) signal through a distinct receptor complex, IFNLR, which
consists of IL10R2 and IFNLR1 subunits. IFNLR1 expression is restricted to epithelial cells and a subset of immune cells, including neutrophils. Therefore, type III
IFN administration as a prophylactic treatment or at an early stage of COVID-19 would result in ISG expression and antiviral response localized to epithelial
cells, reducing side effects and inflammation associated with the systemic action of type I IFNs.
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COVID-19 and IFN lambda
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-λ1 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-λs. We need to
understand whether the virus induces the
endogenous expression of IFN-λ and/or
blocks IFN-λ responses. Is there an age difference in the expression of IFN-λ or its
receptors that can explain the more severe
disease in older patients? What are the effects of IFN-λ on inflammatory responses
and mechanisms of tissue damage and repair and how these activities should be
measured in the clinical trials with peg-IFNλ1 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-λ specifically, might address this
need for broad-spectrum antiviral biologicals that could help not just this pandemic outbreak, but also future viral
threats.
Acknowledgments
We would like to acknowledge the input of
other members of the interferon lambda
community who participated in discussions
on this topic: Evangelos Andreakos, Francine Baker, Connor Bamford, Raymond
Donnelly, Darragh Duffy, Adriana Forero,
Amariliz Rivera-Medina, Ram Savan, and
Nikaia Smith. The Viewpoint was also inspired by the guest session on type III IFNs
at the American Association of Immunologists 2020 meeting, which was canceled due
to COVID-19; we appreciate the support for
this session provided by the Interferon and
Cytokine and Interferon Society. The figure
was created using BioRender.com.
L. Prokunina-Olsson, O.O. Onabajo, and
T.R. O’Brien are supported by the Intramural Research Program of the National Cancer
Institute/National Institutes of Health. H.M.
Lazear is supported by National Institutes of
Health grant R01AI39512. H. Piontkivska is
supported by National Institutes of Health
grant R21AG064479-01 and a Brain Health
Research Institute Pilot Award from Kent
State University. C. Odendall is supported
by a Sir Henry Dale Fellowship from the
Royal Society and the Wellcome Trust
(206200/Z/17/Z). A. Wack is supported by
the Francis Crick Institute, which receives
its core funding from Cancer Research UK
(FC001206), the UK Medical Research
Council (FC001206) and the Wellcome Trust
(FC001206). R.E. Dickenson is supported by
a studentship from the UK Medical Research
Council. N. Alphonse is supported by a studentship from the King’s College London/
Francis Crick Institute partnership. I. Zanoni
is supported by National Institutes of
Health grants 1R01 AI121066, 1R01DK115217,
and NIAID-DAIT-NIHAI201700100. The
content of this publication and the opinions
expressed reflect those of the individual
authors solely and do not necessarily reflect
the views or policies of the US Department
of Health and Human Services, the National
Institutes of Health, or corresponding research institutes.
L. Prokunina-Olsson and T.R. O’Brien are
coinventors on patents related to IFN-λ4
that are held by the National Cancer Institute. J.S. Glenn is the founder and a board
member of Eiger BioPharmaceuticals, Inc.,
which produces peg-IFN-λ1. S.V. Kotenko is
an inventor on patents and patent applications related to IFN-λs that are held by
Rutgers University. Other authors declare
no competing financial interests related to
this work.
References
Blazek, K., et al. 2015. J. Exp. Med. https://doi.org/
10.1084/jem.20140995
Broggi, A., et al. 2017. Nat. Immunol. https://doi
.org/10.1038/ni.3821
Broggi, A., et al. 2020. J. Exp. Med. https://doi.org/
10.1084/jem.20190295
Crotta, S., et al. 2013. PLoS Pathog. https://doi.org/
10.1371/journal.ppat.1003773
Davidson, S., et al. 2015. J. Interferon Cytokine Res.
https://doi.org/10.1089/jir.2014.0227
Davidson, S., et al. 2016. EMBO Mol. Med. https://
doi.org/10.15252/emmm.201606413
Espinosa, V., et al. 2017. Sci. Immunol. https://doi
.org/10.1126/sciimmunol.aan5357
Forero, A., et al. 2019. Immunity. https://doi.org/
10.1016/j.immuni.2019.07.007
Galani, I.E., et al. 2017. Immunity. https://doi.org/
10.1016/j.immuni.2017.04.025
Journal of Experimental Medicine
https://doi.org/10.1084/jem.20200653
Downloaded from http://rupress.org/jem/article-pdf/217/5/e20200653/1042205/jem_20200653… by Kent State University user on 16 November 2020
their activation exacerbates inflammation.
It also remains to be seen whether IFN-λ
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
(Zhang et al., 2020 Preprint), although this
varies between clinical studies. Type I IFNs
are known to be detrimental in select bacterial infection models (Davidson et al.,
2015). For example, Ifnlr−/− mice show improved bacterial control in virus–bacteria
superinfection models (Planet et al., 2016),
and ectopic induction of IFN-λ production
proved to be detrimental in mice previously
infected with influenza (Rich et al., 2019).
While type I IFNs often suppress antibacterial action of immune cells, IFN-λ may employ other routes to facilitate bacterial
superinfection, such as reduction in neutrophil recruitment (Blazek et al., 2015; Rich
et al., 2019) and/or neutrophil bactericidal
activities (Broggi et al., 2017). Although
mouse models do not fully recapitulate human diseases with respect to IFN-λ activities, animal studies give a mandate to
carefully evaluate the use of IFN-λ 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-λ, it may come at the cost of
efficacy. Indeed, IFN-λ 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-λ antiviral action for lack of IFNLR1.
While IFN-λ 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-λ.
Although not yet used in active COVID19 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-λ1.
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
3 of 4
Goel, R.R., et al. 2020. Proc. Natl. Acad. Sci. USA.
https://doi.org/10.1073/pnas.1916897117
Klinkhammer, J., et al. 2018. eLife. https://doi.org/
10.7554/eLife.33354
Kotenko, S.V., et al. 2003. Nat. Immunol. https://
doi.org/10.1038/ni875
Mehta, P., et al. 2020. Lancet. https://doi.org/10
.1016/S0140-6736(20)30628-0
Muir, A.J., et al. 2014. J. Hepatol. https://doi.org/10
.1016/j.jhep.2014.07.022
Planet, P.J., et al. 2016. MBio. https://doi.org/10
.1128/mBio.01939-15
Prokunina-Olsson, L., et al. 2013. Nat. Genet.
https://doi.org/10.1038/ng.2521
Rich, H.E., et al. 2019. Infect. Immun. https://doi
.org/10.1128/IAI.00114-19
Sheppard, P., et al. 2003. Nat. Immunol. https://doi
.org/10.1038/ni873
Ye, L., et al. 2019. Nat. Rev. Immunol. https://doi
.org/10.1038/s41577-019-0182-z
Zhang, G., et al. 2020. medRxiv. https://doi.org/10
.1101/2020.03.02.20030452 (Preprint posted
March 6, 2020)
Downloaded from http://rupress.org/jem/article-pdf/217/5/e20200653/1042205/jem_20200653… by Kent State University user on 16 November 2020
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