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Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.

Huang L, Beiting DP, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Lee NA, Lee JJ, Appleton JA - PLoS Pathog. (2015)

Bottom Line: The eosinophil-mediated effect operates in the absence of adaptive immunity.Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur.Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.

View Article: PubMed Central - PubMed

Affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.

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IL-4/STAT6 signaling in eosinophils is required for larval growth.(A) Body size (area) of larvae, 17dpi. ΔdblGATA mice received PBS or 5 × 106 eosinophils every 48 h between 5 and 9 dpi or 11 and 15 dpi (oral infection). (B)–(C), ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg/STAT6-/- mice every 48 h from 5–9 dpi. (B) Total body larval burdens in muscle, 28 dpi. (C) Body size (area) of larvae, 17 dpi. (D) ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (E) ΔdblGATA mice received PBS or 5 × 106 eosinophils from uninfected or infected IL-5Tg+ every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (F) Body size (area) of larvae recovered from C57BL/6 and IL-5-/- mice injected 25,000 NBL IV, 13 days post injection. (G) IL-4-/- mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 0–5 days post IV infection. Body size (area) of larvae, 13 days post injection. Each data set was collected from two experiments with similar results. Values represent mean ± SD; n = 4 mice. Significant differences were determined by ANOVA and Tukey’s test. *p < 0.05, **p < 0.001, ***p < 0.0001.
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ppat.1005347.g003: IL-4/STAT6 signaling in eosinophils is required for larval growth.(A) Body size (area) of larvae, 17dpi. ΔdblGATA mice received PBS or 5 × 106 eosinophils every 48 h between 5 and 9 dpi or 11 and 15 dpi (oral infection). (B)–(C), ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg/STAT6-/- mice every 48 h from 5–9 dpi. (B) Total body larval burdens in muscle, 28 dpi. (C) Body size (area) of larvae, 17 dpi. (D) ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (E) ΔdblGATA mice received PBS or 5 × 106 eosinophils from uninfected or infected IL-5Tg+ every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (F) Body size (area) of larvae recovered from C57BL/6 and IL-5-/- mice injected 25,000 NBL IV, 13 days post injection. (G) IL-4-/- mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 0–5 days post IV infection. Body size (area) of larvae, 13 days post injection. Each data set was collected from two experiments with similar results. Values represent mean ± SD; n = 4 mice. Significant differences were determined by ANOVA and Tukey’s test. *p < 0.05, **p < 0.001, ***p < 0.0001.

Mentions: We next determined the time during infection when eosinophils influence larval growth. Transfer of eosinophils to infected ΔdblGATA mice during two different intervals confirmed that larval growth was supported when eosinophils were transferred between days 5 and 9 post oral infection of recipients. In contrast, transfer between days 11 and 15 had no effect on larval growth (Fig 3A). Thus, normal growth of larvae required eosinophils to be available at a time coincident with, or immediately following arrival of larvae in muscle. In similar transfer experiments, survival of larvae was not dependent upon STAT6 in eosinophils (Fig 3B); however, only recipients of STAT6+/+ eosinophils supported larval growth (Fig 3C). Similarly, transfer of IL-4-/- eosinophils isolated from infected IL-5Tg+/IL-4-/- mice did not improve larval growth in ΔdblGATA mice (Fig 3D). Eosinophils isolated from uninfected IL-5Tg+ were as effective as those isolated from infected IL-5Tg+ mice in restoring larval growth in ΔdblGATA mice (Fig 3E). Thus, infection and the resulting immune response are not necessary for conditioning the eosinophil prior to transfer. Furthermore, growth of larvae in IL-5-/- infected mice was not impaired (Fig 3F). Thus, IL-5 is not required for the growth-supporting properties of eosinophils. Lastly, to test whether eosinophils were driving an amplified IL-4 response in recipient mice that in turn supported larval growth, eosinophils isolated from infected IL-5Tg+ mice were transferred to infected IL-4-/- mice. Improved larval growth was observed only in recipients of IL-4+/+ eosinophils (Fig 3G). Thus, larval growth requires only that eosinophils be derived from IL-4 competent donors and the mechanism does involve amplification of IL-4 production by other cells during infection.


Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.

Huang L, Beiting DP, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Lee NA, Lee JJ, Appleton JA - PLoS Pathog. (2015)

IL-4/STAT6 signaling in eosinophils is required for larval growth.(A) Body size (area) of larvae, 17dpi. ΔdblGATA mice received PBS or 5 × 106 eosinophils every 48 h between 5 and 9 dpi or 11 and 15 dpi (oral infection). (B)–(C), ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg/STAT6-/- mice every 48 h from 5–9 dpi. (B) Total body larval burdens in muscle, 28 dpi. (C) Body size (area) of larvae, 17 dpi. (D) ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (E) ΔdblGATA mice received PBS or 5 × 106 eosinophils from uninfected or infected IL-5Tg+ every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (F) Body size (area) of larvae recovered from C57BL/6 and IL-5-/- mice injected 25,000 NBL IV, 13 days post injection. (G) IL-4-/- mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 0–5 days post IV infection. Body size (area) of larvae, 13 days post injection. Each data set was collected from two experiments with similar results. Values represent mean ± SD; n = 4 mice. Significant differences were determined by ANOVA and Tukey’s test. *p < 0.05, **p < 0.001, ***p < 0.0001.
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ppat.1005347.g003: IL-4/STAT6 signaling in eosinophils is required for larval growth.(A) Body size (area) of larvae, 17dpi. ΔdblGATA mice received PBS or 5 × 106 eosinophils every 48 h between 5 and 9 dpi or 11 and 15 dpi (oral infection). (B)–(C), ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg/STAT6-/- mice every 48 h from 5–9 dpi. (B) Total body larval burdens in muscle, 28 dpi. (C) Body size (area) of larvae, 17 dpi. (D) ΔdblGATA mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (E) ΔdblGATA mice received PBS or 5 × 106 eosinophils from uninfected or infected IL-5Tg+ every 48 h from 5–9 dpi. Body size (area) of larvae, 17dpi. (F) Body size (area) of larvae recovered from C57BL/6 and IL-5-/- mice injected 25,000 NBL IV, 13 days post injection. (G) IL-4-/- mice received PBS or 5 × 106 eosinophils from infected IL-5Tg+ or IL-5Tg+/IL-4-/- mice every 48 h from 0–5 days post IV infection. Body size (area) of larvae, 13 days post injection. Each data set was collected from two experiments with similar results. Values represent mean ± SD; n = 4 mice. Significant differences were determined by ANOVA and Tukey’s test. *p < 0.05, **p < 0.001, ***p < 0.0001.
Mentions: We next determined the time during infection when eosinophils influence larval growth. Transfer of eosinophils to infected ΔdblGATA mice during two different intervals confirmed that larval growth was supported when eosinophils were transferred between days 5 and 9 post oral infection of recipients. In contrast, transfer between days 11 and 15 had no effect on larval growth (Fig 3A). Thus, normal growth of larvae required eosinophils to be available at a time coincident with, or immediately following arrival of larvae in muscle. In similar transfer experiments, survival of larvae was not dependent upon STAT6 in eosinophils (Fig 3B); however, only recipients of STAT6+/+ eosinophils supported larval growth (Fig 3C). Similarly, transfer of IL-4-/- eosinophils isolated from infected IL-5Tg+/IL-4-/- mice did not improve larval growth in ΔdblGATA mice (Fig 3D). Eosinophils isolated from uninfected IL-5Tg+ were as effective as those isolated from infected IL-5Tg+ mice in restoring larval growth in ΔdblGATA mice (Fig 3E). Thus, infection and the resulting immune response are not necessary for conditioning the eosinophil prior to transfer. Furthermore, growth of larvae in IL-5-/- infected mice was not impaired (Fig 3F). Thus, IL-5 is not required for the growth-supporting properties of eosinophils. Lastly, to test whether eosinophils were driving an amplified IL-4 response in recipient mice that in turn supported larval growth, eosinophils isolated from infected IL-5Tg+ mice were transferred to infected IL-4-/- mice. Improved larval growth was observed only in recipients of IL-4+/+ eosinophils (Fig 3G). Thus, larval growth requires only that eosinophils be derived from IL-4 competent donors and the mechanism does involve amplification of IL-4 production by other cells during infection.

Bottom Line: The eosinophil-mediated effect operates in the absence of adaptive immunity.Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur.Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.

View Article: PubMed Central - PubMed

Affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.

Show MeSH
Related in: MedlinePlus