Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases

Brideau-Andersen, Amy; Huang, Xiaojian; Sun, Siu-Chi Chang; Chen, Teddy T.; Stark, Diane M.; Sas, Ian J.; Zadik, Linda; Dawes, Glenn; Guptill, Douglas R.; McCord, Robert; Govindarajan, Sridhar; Roy, A. K.; Yang, Sen; Gao, Judy; Chen, Yong Hong; Skartved, Niels Jørgen Østergaard; Pedersen, Annette K.; Lin, David; Locher, Christopher P.; Rebbapragada, Indrani; Jensen, A. S.; Bass, Steven; Nissen, Torben L. Straight; Viswanathan, Sridhar; Foster, Graham R.; Symons, Julian; Patten, Phillip A.

doi:10.1073/pnas.0609001104

Cited by 33 publications

(25 citation statements)

References 20 publications

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“…Alternatively, Katakura et al used the dextran sulfate sodium colitis model rather than the TNBS model and stimulated their mice with IFN-␤ rather than IFN-␣A. Although these two type I IFNs share the same receptor, there are a number of important biological differences between the various type I IFNs (28,29), which could contribute to the differences in our results relative to those of Katakura et al…”

Section: Ifn-␣a Treatment Ameliorates Tnbs Colitis In Cd73contrasting

confidence: 55%

Control of IFN-αA by CD73: Implications for Mucosal Inflammation

Louis

Robinson

MacManus

et al. 2008

The Journal of Immunology

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Inflammatory diseases influence tissue metabolism, altering regulation of extracellular adenine nucleotides, with a resultant protective influence of adenosine. Ecto-5′-nucleotidase (CD73) is a central surface enzyme generating extracellular adenosine. Thus, we hypothesized that CD73 is protective in mucosal inflammation as modeled by trinitrobenzene sulfonate (TNBS) colitis. Initial studies revealed a >3-fold induction of CD73 mRNA levels after TNBS colitis. Additionally, the severity of colitis was increased, as determined by weight loss and colonic shortening, in cd73−/− mice relative to cd73+/+ controls. Likewise, enteral administration of the selective CD73 inhibitor α,β-methylene ADP to cd73+/+ mice resulted in a similar increase in severity of TNBS colitis. Gene array profiling of cytokine mRNA expression, verified by real-time PCR, revealed a >90% down-regulation of IFN-αA in cd73−/− mice and α,β-methylene ADP-treated cd73+/+ mice, compared with cd73+/+ mice. Exogenous administration of recombinant IFN-αA partially protected TNBS-treated cd73−/− mice. Cytokine profiling revealed similar increases in both IFN-γ and TNF-α mRNA in colitic animals, independent of genotype. However, IL-10 mRNA increased in wild-type mice on day 3 after TNBS administration, whereas cd73−/− mice mounted no IL-10 response. This IL-10 response was restored in the cd73−/− mice by exogenous IFN-αA. Further cytokine profiling revealed that this IL-10 induction is preceded by a transient IFN-αA induction on day 2 after TNBS exposure. Together, these studies indicate a critical regulatory role for CD73-modulated IFNαA in the acute inflammatory phase of TNBS colitis, thereby implicating IFN-αA as a protective element of adenosine signaling during mucosal inflammation.

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Section: Ifn-␣a Treatment Ameliorates Tnbs Colitis In Cd73contrasting

confidence: 55%

Control of IFN-αA by CD73: Implications for Mucosal Inflammation

Louis

Robinson

MacManus

et al. 2008

The Journal of Immunology

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“…This information could potentially be informative for understanding the basis of the potency differences between the two IFN families, but also to establish a benchmark of activity for future IFN-λ engineering efforts. In the type I IFN system, several prior studies using gene shuffling show that affinity improvement also manifests as improved antiviral potency (Brideau-Andersen et al, 2007; Chang et al, 1999). However, a more comprehensive series of type I IFN engineering studies conclude that wild-type IFNs are already at an AV potency maximum, and there is little to gain from affinity maturation (Jaitin et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…We thus added the Lys152Arg mutation to each of the four variants from the HTP screen. In addition to these mutants, we biophysically and biochemically characterized the wild-type IFN-ω, IFN-ω (Lys152Arg), and a shuffled IFN-α mutant (Maxygen 9×25) that was previously reported to be biased toward antiviral activity (Brideau-Andersen et al, 2007). …”

Section: Resultsmentioning

confidence: 99%

“…Previous studies of the type I IFNs have demonstrated a modest 2-fold difference in antiviral potency between the highest affinity natural IFN (IFN-β) or engineered IFN such as IFN-α2 YNS (Kalie et al, 2007) relative to lower affinity ligands such as IFN-α2. However, one study reported engineering type I IFNs with >20-fold improved antiviral activities but relatively unchanged antiproliferative activities (Brideau-Andersen et al, 2007). This study measured antiproliferative activity using the Daudi cell line, which is more sensitive to antiproliferative effects, possibly leading to aberrant antiproli-ferative:antiviral ratios.…”

Section: Discussionmentioning

confidence: 99%

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The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity

Mendoza¹,

Schneider²,

Hoffmann³

et al. 2017

Immunity

108

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Summary Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rβ (IL-10Rβ), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rβ for cytokines has impeded efforts aimed at crystallizing cytokine-receptorcomplexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rβ uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.

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“…Although the multigenic nature of IFN-a has been known for over 20 years, the significance of this is still debatedi.e. whether these genes are expressed differentially in distinct cell types, whether they are inducible by different types of viruses or whether they are functionally specialized (Brideau-Andersen et al, 2007). For the rest of this review, we will not distinguish between IFN-a subtypes.…”

Section: Biology Of the Interferon Systemmentioning

confidence: 99%

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Randall

Goodbourn

2008

Journal of General Virology

1,387

1,420

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The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer. Biology of the interferon systemThe interferons (IFNs) are a group of secreted cytokines that elicit distinct antiviral effects. They are grouped into three classes called type I, II and III IFNs, according to their amino acid sequence. Type I IFNs (discovered in 1957;Isaacs & Lindenmann, 1957) comprise a large group of molecules; mammals have multiple distinct IFN-a genes (13 in man), one to three IFN-b genes (one in man) and other genes, such as IFN-v, -e, -t, -d and -k. The IFN-a and -b genes are induced directly in response to viral infection, whereas IFN-v, -e, -d and -k play less well-defined roles, such as regulators of maternal recognition in pregnancy. Thus, rather than use the term 'type I IFN', we will use IFN-a/b when referring to the virally induced cytokines. Although the multigenic nature of IFN-a has been known for over 20 years, the significance of this is still debatedi.e. whether these genes are expressed differentially in distinct cell types, whether they are inducible by different types of viruses or whether they are functionally specialized (Brideau-Andersen et al., 2007). For the rest of this review, we will not distinguish between IFN-a subtypes. Type III IFNs have been described more recently and comprise IFNl1, -l2 and -l3, also referred to as IL-2...

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Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases

Cited by 33 publications

References 20 publications

Control of IFN-αA by CD73: Implications for Mucosal Inflammation

Control of IFN-αA by CD73: Implications for Mucosal Inflammation

The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

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