Pleiotropic Roles of Type 1 Interferons in Antiviral Immune Responses

Abstract

Since Isaac's and Lindenmann's seminal experiments over 50 years ago demonstrating a soluble factor generated from heat killed virus-stimulated chicken embryos could inhibit live influenza virus replication, the term interferon has been synonymous with inhibition of virus replication. While the antiviral properties of type 1 interferon (IFN-I) are undeniable, recent studies have reported expanding and somewhat unexpected roles of IFN-I signaling during both acute and persistent viral infections. IFN-I signaling can promote morbidity and mortality through induction of aberrant inflammatory responses and recruitment of inflammatory innate immune cell populations during acute respiratory viral infections. During persistent viral infection, IFN-I signaling promotes containment of early viral replication/dissemination, however, also initiates and maintains immune suppression, lymphoid tissue disorganization, and CD4 T cell dysfunction through modulation of multiple immune cell populations. Finally, new data are emerging illuminating how specific IFN-I species regulate immune pathology and suppression during acute and persistent viral infections, respectively. Systematic characterization of the cellular populations that produce IFN-I, how the timing of IFN-I induction and intricacies of subtype specific IFN-I signaling promote pathology or immune suppression during acute and persistent viral infections should inform the development of treatments and modalities to control viral associated pathologies.

Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies

“…Indeed, besides their beneficial direct antiviral effect, type I IFN may be deleterious when released at high levels and for a prolonged period. These effects include increase of inflammatory mediator release, depletion of T cells, destruction of the secondary lymphoid architecture, and inhibition of hematopoiesis, all of them likely occurring also during severe Ebola virus disease in humans 37 , 38 . Reversely, treatment with favipiravir reduces viral replication, which downregulates IFNα and other cytokines release and confers a nearly similar level of cell protection while limiting the deleterious effect of the inflammatory response.…”

Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy

“…In melanoma, while early IFN-I activation correlates with an effective PD-1 blockade ( 5 , 26 ), prolonged IFN-I signaling seems to favor resistance ( 27 ). This apparent discrepancy might not be surprising since, during persistent viral infections, IFN-I displays protective effects in early stages and becomes detrimental upon continued signaling activation in the chronic phase ( 28 ). Interestingly, CML patients in remission who stopped IFN-α treatment because of good clinical response developed higher protective T-cell memory response than patients who continued therapy ( 29 ).…”

Interferon gamma-induced protein 10 (IP-10) and cardiovascular disease in African Americans

“…Such chronic viral infection leads to induction of antiviral cytokines, such as type I and type II interferons (IFN), and may promote lowgrade inflammation, immune dysfunction, and hypercoagulability. [6,7] IFN signaling induces a network of interferon-inducible genes, which orchestrate both innate and adaptive immunity in defense against viruses. [8] While IFN is not readily measurable in plasma, interferon gamma-inducible protein 10 (IP-10, also known as C-X-C motif chemokine 10 or CXCL10) may serve as a surrogate chemokine marker for chronic activation of the IFN-1 pathway, distinct from the acute inflammation cascade which is marked by chemokines such as IL-6 and IL-8.…”