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Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.

Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, Culley FJ, Mack M, Akira S, Johansson C - J. Exp. Med. (2015)

Bottom Line: AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV.Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity.Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.

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Type I IFN production by AMs is dependent on MAVS. (A) GFP expression in AMs from the indicated strains of mice was assessed 18 h after mock (PBS), RSV, or UV-inactivated RSV (UV RSV) instillation. (B) Percentage and number of GFP+ AMs during the time course of RSV infection in Ifna6gfp/+ and Ifna6gfp/+ Mavs−/− mice. 0 h represents mock (PBS)-infected mice. (C) Secretion of IFN-α from primary AMs of the indicated genotypes after ex vivo exposure for 20 h to medium or the indicated MOIs of RSV or UV-RSV (MOI of 5; UV 5). (D) Analysis of IFN-α3 and IFN-β protein levels in lung homogenates from mice of the indicated genotypes at the indicated times p.i. (E and F) Levels of Ifnl and Ifng (E) and Rsad2, Oas1a, Eif2ak2, and Mx1 transcripts (F) in lung tissue from mock (0 h)- or RSV-infected mice of the indicated genotypes at the indicated times p.i. Flow cytometry plots in A represent four to five mice per group and are representative of at least two independent experiments. Data in B and D–F are presented as mean ± SEM of four to five mice per group and are representative of at least two independent experiments. Statistical significance of differences between indicated genotypes at each time point was determined by unpaired Student’s t test. Results in C are pooled from two independent experiments with at least three individual cultures per condition and presented as mean ± SEM. Statistical significance of differences between indicated groups was determined by unpaired Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
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fig3: Type I IFN production by AMs is dependent on MAVS. (A) GFP expression in AMs from the indicated strains of mice was assessed 18 h after mock (PBS), RSV, or UV-inactivated RSV (UV RSV) instillation. (B) Percentage and number of GFP+ AMs during the time course of RSV infection in Ifna6gfp/+ and Ifna6gfp/+ Mavs−/− mice. 0 h represents mock (PBS)-infected mice. (C) Secretion of IFN-α from primary AMs of the indicated genotypes after ex vivo exposure for 20 h to medium or the indicated MOIs of RSV or UV-RSV (MOI of 5; UV 5). (D) Analysis of IFN-α3 and IFN-β protein levels in lung homogenates from mice of the indicated genotypes at the indicated times p.i. (E and F) Levels of Ifnl and Ifng (E) and Rsad2, Oas1a, Eif2ak2, and Mx1 transcripts (F) in lung tissue from mock (0 h)- or RSV-infected mice of the indicated genotypes at the indicated times p.i. Flow cytometry plots in A represent four to five mice per group and are representative of at least two independent experiments. Data in B and D–F are presented as mean ± SEM of four to five mice per group and are representative of at least two independent experiments. Statistical significance of differences between indicated genotypes at each time point was determined by unpaired Student’s t test. Results in C are pooled from two independent experiments with at least three individual cultures per condition and presented as mean ± SEM. Statistical significance of differences between indicated groups was determined by unpaired Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.

Mentions: Next we dissected the pathway leading to type I IFN induction by lung AMs. Live virus was necessary as UV-inactivated RSV administered i.n. did not elicit GFP expression (Fig. 3 A). Importantly, live virus failed to induce a GFP signal in AMs from Ifna6gfp/+ mice deficient in the RLR adaptor protein MAVS (Ifna6gfp/+ Mavs−/− mice; Fig. 3 A). This was true at all time points examined, from 8 to 96 h p.i. (Fig. 3 B), demonstrating a key role for the RLR pathway in the AM response to RSV. Consistent with that notion, primary AMs isolated from Ifna6gfp/+ mice but not from Ifna6gfp/+ Mavs−/− mice secreted large amounts of IFN-α in response to increasing doses of RSV ex vivo (Fig. 3 C). The lack of IFN-α production by Ifna6gfp/+ Mavs−/− AMs was maintained even when the cells were stimulated with RSV up to multiplicities of infection (MOIs) of 20 (not depicted).


Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.

Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, Culley FJ, Mack M, Akira S, Johansson C - J. Exp. Med. (2015)

Type I IFN production by AMs is dependent on MAVS. (A) GFP expression in AMs from the indicated strains of mice was assessed 18 h after mock (PBS), RSV, or UV-inactivated RSV (UV RSV) instillation. (B) Percentage and number of GFP+ AMs during the time course of RSV infection in Ifna6gfp/+ and Ifna6gfp/+ Mavs−/− mice. 0 h represents mock (PBS)-infected mice. (C) Secretion of IFN-α from primary AMs of the indicated genotypes after ex vivo exposure for 20 h to medium or the indicated MOIs of RSV or UV-RSV (MOI of 5; UV 5). (D) Analysis of IFN-α3 and IFN-β protein levels in lung homogenates from mice of the indicated genotypes at the indicated times p.i. (E and F) Levels of Ifnl and Ifng (E) and Rsad2, Oas1a, Eif2ak2, and Mx1 transcripts (F) in lung tissue from mock (0 h)- or RSV-infected mice of the indicated genotypes at the indicated times p.i. Flow cytometry plots in A represent four to five mice per group and are representative of at least two independent experiments. Data in B and D–F are presented as mean ± SEM of four to five mice per group and are representative of at least two independent experiments. Statistical significance of differences between indicated genotypes at each time point was determined by unpaired Student’s t test. Results in C are pooled from two independent experiments with at least three individual cultures per condition and presented as mean ± SEM. Statistical significance of differences between indicated groups was determined by unpaired Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4419339&req=5

fig3: Type I IFN production by AMs is dependent on MAVS. (A) GFP expression in AMs from the indicated strains of mice was assessed 18 h after mock (PBS), RSV, or UV-inactivated RSV (UV RSV) instillation. (B) Percentage and number of GFP+ AMs during the time course of RSV infection in Ifna6gfp/+ and Ifna6gfp/+ Mavs−/− mice. 0 h represents mock (PBS)-infected mice. (C) Secretion of IFN-α from primary AMs of the indicated genotypes after ex vivo exposure for 20 h to medium or the indicated MOIs of RSV or UV-RSV (MOI of 5; UV 5). (D) Analysis of IFN-α3 and IFN-β protein levels in lung homogenates from mice of the indicated genotypes at the indicated times p.i. (E and F) Levels of Ifnl and Ifng (E) and Rsad2, Oas1a, Eif2ak2, and Mx1 transcripts (F) in lung tissue from mock (0 h)- or RSV-infected mice of the indicated genotypes at the indicated times p.i. Flow cytometry plots in A represent four to five mice per group and are representative of at least two independent experiments. Data in B and D–F are presented as mean ± SEM of four to five mice per group and are representative of at least two independent experiments. Statistical significance of differences between indicated genotypes at each time point was determined by unpaired Student’s t test. Results in C are pooled from two independent experiments with at least three individual cultures per condition and presented as mean ± SEM. Statistical significance of differences between indicated groups was determined by unpaired Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
Mentions: Next we dissected the pathway leading to type I IFN induction by lung AMs. Live virus was necessary as UV-inactivated RSV administered i.n. did not elicit GFP expression (Fig. 3 A). Importantly, live virus failed to induce a GFP signal in AMs from Ifna6gfp/+ mice deficient in the RLR adaptor protein MAVS (Ifna6gfp/+ Mavs−/− mice; Fig. 3 A). This was true at all time points examined, from 8 to 96 h p.i. (Fig. 3 B), demonstrating a key role for the RLR pathway in the AM response to RSV. Consistent with that notion, primary AMs isolated from Ifna6gfp/+ mice but not from Ifna6gfp/+ Mavs−/− mice secreted large amounts of IFN-α in response to increasing doses of RSV ex vivo (Fig. 3 C). The lack of IFN-α production by Ifna6gfp/+ Mavs−/− AMs was maintained even when the cells were stimulated with RSV up to multiplicities of infection (MOIs) of 20 (not depicted).

Bottom Line: AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV.Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity.Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.

Show MeSH
Related in: MedlinePlus