Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

Alisha Chetty; Matthew G. Darby; Pia M. Vornewald; Mara Martín-Alonso; Anna Filz; Manuel Ritter; Henry J. McSorley; Lindi Masson; Katherine Smith; Frank Brombacher; Matthew K. O'Shea; Adam F. Cunningham; Bernhard Ryffel; Menno J. Oudhoff; Benjamin G. Dewals; Laura E. Layland; William G. C. Horsnell

doi:10.1016/j.chom.2021.02.004

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

Alisha Chetty, Matthew G. Darby, Pia M. Vornewald, Mara Martín-Alonso, Anna Filz, Manuel Ritter, Henry J. McSorley, Lindi Masson, Katherine Smith, Frank Brombacher, Matthew K. O'Shea, Adam F. Cunningham, Bernhard Ryffel, Menno J. Oudhoff, Benjamin G. Dewals, Laura E. Layland (Lead / Corresponding author), William G. C. Horsnell (Lead / Corresponding author)

Cell Signalling and Immunology

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Abstract

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

Original language	English
Pages (from-to)	579-593.e5
Number of pages	21
Journal	Cell Host & Microbe
Volume	29
Issue number	4
Early online date	12 Mar 2021
DOIs	https://doi.org/10.1016/j.chom.2021.02.004
Publication status	Published - 14 Apr 2021

Keywords

HSV-2
IL-33
IL-5
Nippostrongylus brasiliensis
eosinophils
epithelial ulceration
helminths
systemic immunity
vagina

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2021.02.004Licence: CC BY

Final Published VersionFinal published version, 8.1 MBLicence: CC BY

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Chetty, A., Darby, M. G., Vornewald, P. M., Martín-Alonso, M., Filz, A., Ritter, M., McSorley, H. J., Masson, L., Smith, K., Brombacher, F., O'Shea, M. K., Cunningham, A. F., Ryffel, B., Oudhoff, M. J., Dewals, B. G., Layland, L. E., & Horsnell, W. G. C. (2021). Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection. Cell Host & Microbe, 29(4), 579-593.e5. https://doi.org/10.1016/j.chom.2021.02.004

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title = "Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection",

abstract = "How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.",

keywords = "HSV-2, IL-33, IL-5, Nippostrongylus brasiliensis, eosinophils, epithelial ulceration, helminths, systemic immunity, vagina",

author = "Alisha Chetty and Darby, {Matthew G.} and Vornewald, {Pia M.} and Mara Mart{\'i}n-Alonso and Anna Filz and Manuel Ritter and McSorley, {Henry J.} and Lindi Masson and Katherine Smith and Frank Brombacher and O'Shea, {Matthew K.} and Cunningham, {Adam F.} and Bernhard Ryffel and Oudhoff, {Menno J.} and Dewals, {Benjamin G.} and Layland, {Laura E.} and Horsnell, {William G. C.}",

note = "This study was supported by German Research Foundation (DFG) within the “German-Africa Cooperation Projects in Infectiology” (grant LA 2746/2 ); CNRS of Orl{\'e}ans (France) and European funding in Region Centre-Val de Loire ( FEDER no 2016-00110366 BIO-TARGET and EX005756 BIO-TARGET II); and the Poliomyelitis Research Foundation (PRF; 17/08). A.C., W.G.C.H., L.E.L., A.F., M.R., and L.M. were supported by the DFG ; A.C. was supported by the National Research Foundation of South Africa (NRF, grant 120685 ). P.M.V., M.M.-A., and M.J.O. were supported by the Research Council of Norway (Centre of Excellence ( 223255/F50 ), and Young Research Talent ( 274760 ). B.G.D. is a senior research associate of the F.R.S.-FNRS, Belgium. This research was funded in part by the Wellcome Trust (grant: 203135/Z/16/Z ). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.",

year = "2021",

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doi = "10.1016/j.chom.2021.02.004",

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Chetty, A, Darby, MG, Vornewald, PM, Martín-Alonso, M, Filz, A, Ritter, M, McSorley, HJ, Masson, L, Smith, K, Brombacher, F, O'Shea, MK, Cunningham, AF, Ryffel, B, Oudhoff, MJ, Dewals, BG, Layland, LE & Horsnell, WGC 2021, 'Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection', Cell Host & Microbe, vol. 29, no. 4, pp. 579-593.e5. https://doi.org/10.1016/j.chom.2021.02.004

TY - JOUR

T1 - Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

AU - Chetty, Alisha

AU - Darby, Matthew G.

AU - Vornewald, Pia M.

AU - Martín-Alonso, Mara

AU - Filz, Anna

AU - Ritter, Manuel

AU - McSorley, Henry J.

AU - Masson, Lindi

AU - Smith, Katherine

AU - Brombacher, Frank

AU - O'Shea, Matthew K.

AU - Cunningham, Adam F.

AU - Ryffel, Bernhard

AU - Oudhoff, Menno J.

AU - Dewals, Benjamin G.

AU - Layland, Laura E.

AU - Horsnell, William G. C.

N1 - This study was supported by German Research Foundation (DFG) within the “German-Africa Cooperation Projects in Infectiology” (grant LA 2746/2 ); CNRS of Orléans (France) and European funding in Region Centre-Val de Loire ( FEDER no 2016-00110366 BIO-TARGET and EX005756 BIO-TARGET II); and the Poliomyelitis Research Foundation (PRF; 17/08). A.C., W.G.C.H., L.E.L., A.F., M.R., and L.M. were supported by the DFG ; A.C. was supported by the National Research Foundation of South Africa (NRF, grant 120685 ). P.M.V., M.M.-A., and M.J.O. were supported by the Research Council of Norway (Centre of Excellence ( 223255/F50 ), and Young Research Talent ( 274760 ). B.G.D. is a senior research associate of the F.R.S.-FNRS, Belgium. This research was funded in part by the Wellcome Trust (grant: 203135/Z/16/Z ). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

PY - 2021/4/14

Y1 - 2021/4/14

N2 - How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

AB - How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

KW - HSV-2

KW - IL-33

KW - IL-5

KW - Nippostrongylus brasiliensis

KW - eosinophils

KW - epithelial ulceration

KW - helminths

KW - systemic immunity

KW - vagina

UR - http://www.scopus.com/inward/record.url?scp=85104076754&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2021.02.004

DO - 10.1016/j.chom.2021.02.004

M3 - Article

C2 - 33857419

SN - 1931-3128

VL - 29

SP - 579-593.e5

JO - Cell Host & Microbe

JF - Cell Host & Microbe

IS - 4

ER -

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

Abstract

Keywords

ASJC Scopus subject areas

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MICA: Modulation of IL-33-dependent Responses Using Parasite Products (Transfer)

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