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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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Eosinophils promote larval growth in an innate context.(A)–(C), C57BL/6, PHIL, Rag1-/-, PHIL/Rag1-/- and Rag2-/-γc-/- mice were injected IV with 25,000 NBL. (A) Body size (area) of larvae recovered from indicated strains 13 days post injection. (B) Body size (area) of larvae recovered from Rag1-/- and Rag2-/-γc-/- mice, 13 days post injection. (C) PHIL/Rag1-/- 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 = 3–4 mice. Significant differences were determined by Student’s t test or ANOVA and Tukey’s test. ***p < 0.0001.
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ppat.1005347.g004: Eosinophils promote larval growth in an innate context.(A)–(C), C57BL/6, PHIL, Rag1-/-, PHIL/Rag1-/- and Rag2-/-γc-/- mice were injected IV with 25,000 NBL. (A) Body size (area) of larvae recovered from indicated strains 13 days post injection. (B) Body size (area) of larvae recovered from Rag1-/- and Rag2-/-γc-/- mice, 13 days post injection. (C) PHIL/Rag1-/- 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 = 3–4 mice. Significant differences were determined by Student’s t test or ANOVA and Tukey’s test. ***p < 0.0001.

Mentions: We next tested the requirement for adaptive immunity in larval growth by measuring larvae in Rag1-/- mice. Notably, the morphology of nurse cells in Rag1-/- mice is comparable to those in WT mice. Larvae grew normally in Rag1-/- mice, while larval growth was impaired in PHIL/Rag1-/- mice (Fig 4A), indicating that eosinophils promote larval growth in an innate context. Type 2 innate lymphoid cells (ILC2) promote recruitment and activation of eosinophils. To investigate whether ILC2 contributed to larval growth by recruiting and activating eosinophils, we infected Rag2-/-γc-/- mice. Larval growth was not affected by the absence of ILC2 (Fig 4B), a result that is compatible with our previous finding that recruitment of eosinophils to infected muscle was normal in ILC2-ablated Rag2-/-γc-/- mice [9]. Lastly, transfer of IL-4-/- eosinophils failed to improve larval growth in PHIL/Rag1-/- mice (Fig 4C). Taken together, the findings show that eosinophils regulated larval growth in an innate context that was independent of ILC2. The effect depended upon eosinophils being derived from IL-4 competent mice.


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)

Eosinophils promote larval growth in an innate context.(A)–(C), C57BL/6, PHIL, Rag1-/-, PHIL/Rag1-/- and Rag2-/-γc-/- mice were injected IV with 25,000 NBL. (A) Body size (area) of larvae recovered from indicated strains 13 days post injection. (B) Body size (area) of larvae recovered from Rag1-/- and Rag2-/-γc-/- mice, 13 days post injection. (C) PHIL/Rag1-/- 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 = 3–4 mice. Significant differences were determined by Student’s t test or ANOVA and Tukey’s test. ***p < 0.0001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4697774&req=5

ppat.1005347.g004: Eosinophils promote larval growth in an innate context.(A)–(C), C57BL/6, PHIL, Rag1-/-, PHIL/Rag1-/- and Rag2-/-γc-/- mice were injected IV with 25,000 NBL. (A) Body size (area) of larvae recovered from indicated strains 13 days post injection. (B) Body size (area) of larvae recovered from Rag1-/- and Rag2-/-γc-/- mice, 13 days post injection. (C) PHIL/Rag1-/- 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 = 3–4 mice. Significant differences were determined by Student’s t test or ANOVA and Tukey’s test. ***p < 0.0001.
Mentions: We next tested the requirement for adaptive immunity in larval growth by measuring larvae in Rag1-/- mice. Notably, the morphology of nurse cells in Rag1-/- mice is comparable to those in WT mice. Larvae grew normally in Rag1-/- mice, while larval growth was impaired in PHIL/Rag1-/- mice (Fig 4A), indicating that eosinophils promote larval growth in an innate context. Type 2 innate lymphoid cells (ILC2) promote recruitment and activation of eosinophils. To investigate whether ILC2 contributed to larval growth by recruiting and activating eosinophils, we infected Rag2-/-γc-/- mice. Larval growth was not affected by the absence of ILC2 (Fig 4B), a result that is compatible with our previous finding that recruitment of eosinophils to infected muscle was normal in ILC2-ablated Rag2-/-γc-/- mice [9]. Lastly, transfer of IL-4-/- eosinophils failed to improve larval growth in PHIL/Rag1-/- mice (Fig 4C). Taken together, the findings show that eosinophils regulated larval growth in an innate context that was independent of ILC2. The effect depended upon eosinophils being derived from IL-4 competent mice.

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