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The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections.

Egli A, Santer DM, O'Shea D, Tyrrell DL, Houghton M - Emerg Microbes Infect (2014)

Bottom Line: Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection.It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines.In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.

View Article: PubMed Central - PubMed

Affiliation: Infection Biology, Department of Biomedicine, University Hospital of Basel , 4031 Basel, Switzerland ; Clinical Microbiology, University Hospital of Basel , 4031 Basel, Switzerland.

ABSTRACT
Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.

No MeSH data available.


Related in: MedlinePlus

(A) Sequence alignment of IFNLs. An amino-acid sequence alignment of human IFNL1–4 is shown. Red letters indicate significant differences. Green letters indicate common cysteines. Helices and exons are indicated with boxes. (B) Sequence alignment overlay for different IFNLs. Amino acids of significance are highlighted.
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fig1: (A) Sequence alignment of IFNLs. An amino-acid sequence alignment of human IFNL1–4 is shown. Red letters indicate significant differences. Green letters indicate common cysteines. Helices and exons are indicated with boxes. (B) Sequence alignment overlay for different IFNLs. Amino acids of significance are highlighted.

Mentions: The high degree of amino-acid sequence similarities within IFNL1–3 suggests a common ancestor gene.21 IFNL2 and 3 share 96% sequence similarity, whereas IFNL1 is less similar and also differs in terms of the pattern of disulfide bridges.25 IFNL4 arises as a consequence of a frameshift mutation generating a new gene not normally expressed, and demonstrates only a 40.8% similarity to IFNL3. Figure 1A shows a sequence alignment of all IFNLs. Figure 1B highlights the differences in side chains between IFNL1–3 in three-dimensional structures. Despite almost identical sequences, IFNL3 and IFNL2,9,26,27 have markedly different anti-viral activities. IFNL3 demonstrates the highest anti-viral activity as measured by HepG2 challenge with encephalomyocarditis virus. IFNL3 had a 16-fold lower half-maximal effective concentration (EC50) compared to IFNL2 and two-fold lower EC50 value relative to IFNL1.28 Additionally ISG induction (Mx1 and IRF9) by IFNL3 was significantly higher compared to IFNL1 and IFNL2.29


The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections.

Egli A, Santer DM, O'Shea D, Tyrrell DL, Houghton M - Emerg Microbes Infect (2014)

(A) Sequence alignment of IFNLs. An amino-acid sequence alignment of human IFNL1–4 is shown. Red letters indicate significant differences. Green letters indicate common cysteines. Helices and exons are indicated with boxes. (B) Sequence alignment overlay for different IFNLs. Amino acids of significance are highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126180&req=5

fig1: (A) Sequence alignment of IFNLs. An amino-acid sequence alignment of human IFNL1–4 is shown. Red letters indicate significant differences. Green letters indicate common cysteines. Helices and exons are indicated with boxes. (B) Sequence alignment overlay for different IFNLs. Amino acids of significance are highlighted.
Mentions: The high degree of amino-acid sequence similarities within IFNL1–3 suggests a common ancestor gene.21 IFNL2 and 3 share 96% sequence similarity, whereas IFNL1 is less similar and also differs in terms of the pattern of disulfide bridges.25 IFNL4 arises as a consequence of a frameshift mutation generating a new gene not normally expressed, and demonstrates only a 40.8% similarity to IFNL3. Figure 1A shows a sequence alignment of all IFNLs. Figure 1B highlights the differences in side chains between IFNL1–3 in three-dimensional structures. Despite almost identical sequences, IFNL3 and IFNL2,9,26,27 have markedly different anti-viral activities. IFNL3 demonstrates the highest anti-viral activity as measured by HepG2 challenge with encephalomyocarditis virus. IFNL3 had a 16-fold lower half-maximal effective concentration (EC50) compared to IFNL2 and two-fold lower EC50 value relative to IFNL1.28 Additionally ISG induction (Mx1 and IRF9) by IFNL3 was significantly higher compared to IFNL1 and IFNL2.29

Bottom Line: Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection.It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines.In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.

View Article: PubMed Central - PubMed

Affiliation: Infection Biology, Department of Biomedicine, University Hospital of Basel , 4031 Basel, Switzerland ; Clinical Microbiology, University Hospital of Basel , 4031 Basel, Switzerland.

ABSTRACT
Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.

No MeSH data available.


Related in: MedlinePlus