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

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

doi:10.1016/j.chom.2021.02.004

Cited by 26 publications

(25 citation statements)

References 81 publications

(82 reference statements)

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“…In a recent study, coinfection of mice with N. brasiliensis was shown to exacerbate intravaginal Herpes simplex virus-2 (HSV-2) mediated epithelial ulceration in the female genital tract (FGT). 72 N. brasiliensis infection alone was shown to induce recruitment of eosinophils to the FGT. However, following HSV-2 coinfection of the vaginal epithelium, local eosinophilia was enhanced, which caused damage to the virally infected vaginal epithelium.…”

Section: Detrimental Outcomesmentioning

confidence: 92%

“…This immunopathological exacerbation occurred independently of IL-4Rα and instead depended on an IL-33/IL-5/eosinophil axis. 72 Thus, a helminth infection that alters systemic immunity and affects the milieu of distant tissues, despite not actively colonizing those tissues, can also worsen the outcome of local viral infections ( Table 4 ).…”

Section: Detrimental Outcomesmentioning

confidence: 99%

“…Consistent with this, coinfection of mice with N. brasiliensis , a worm that does not colonize the female genital tract (FGT), was shown to exacerbate intravaginal HSV-2 induced immunopathology in the FGT. 72 According to the hypothesis of different tissue niche, this combination of helminth–virus interactions should have been beneficial. However, N. brasiliensis induced alterations in systemic immunity causing a recruitment of eosinophils to FGT regions, and upon viral infection, local eosinophilia was enhanced causing damage to virally infected epithelium.…”

Section: Determinants Of Coinfection Outcomesmentioning

confidence: 99%

“…However, N. brasiliensis induced alterations in systemic immunity causing a recruitment of eosinophils to FGT regions, and upon viral infection, local eosinophilia was enhanced causing damage to virally infected epithelium. 72 The nature of antiviral immunity (immunopathological) in the helminth/HSV-2 study played a dominant role over tissue tropism and worsened outcomes. This study highlights that the helminth-virus coinfection process is complex and indicates that in some instances one particular determinant may play a dominant role in determining the coinfection outcome.…”

Section: Determinants Of Coinfection Outcomesmentioning

confidence: 99%

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Helminth–virus interactions: determinants of coinfection outcomes

2021

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Viral infections are often studied in model mammalian organisms under specific pathogen-free conditions. However, in nature, coinfections are common, and infection with one organism can alter host susceptibility to infection with another. Helminth parasites share a long coevolutionary history with mammalian hosts and have shaped host physiology, metabolism, immunity, and the composition of the microbiome. Published studies suggest that helminth infection can either be beneficial or detrimental during viral infection. Here, we discuss coinfection studies in mouse models and use them to define key determinants that impact outcomes, including the type of antiviral immunity, the tissue tropism of both the helminth and the virus, and the timing of viral infection in relation to the helminth lifecycle. We also explore the current mechanistic understanding of how helminth-virus coinfection impacts host immunity and viral pathogenesis. While much attention has been placed on the impact of the gut bacterial microbiome on immunity to infection, we suggest that enteric helminths, as a part of the eukaryotic macrobiome, also represent an important modulator of disease pathogenesis and severity following virus infection.

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Section: Detrimental Outcomesmentioning

confidence: 92%

Section: Detrimental Outcomesmentioning

confidence: 99%

Section: Determinants Of Coinfection Outcomesmentioning

confidence: 99%

Section: Determinants Of Coinfection Outcomesmentioning

confidence: 99%

See 2 more Smart Citations

Helminth–virus interactions: determinants of coinfection outcomes

2021

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“…In contrast, dysregulation or deficiency of IFN-g in HSV-2-infected individuals and mice has been observed to promote a Th2 cytokine response through IL-10 in humans and IL-4 in mice, which is unable to facilitate viral clearance (26,91). Th2 cytokine driven immune responses to vaginal HSV-2 infection in mice have also been described as pathogenic (102). Thus, type II IFNs are critical mediators of T cell-mediated viral clearance, and prevent pathogenic Th2 immunity during primary and secondary HSV-2 infection.…”

Section: T Cellsmentioning

confidence: 99%

Immunoregulatory Functions of Interferons During Genital HSV-2 Infection

et al. 2021

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Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections that disproportionately impacts women worldwide. Currently, there are no vaccines or curative treatments, resulting in life-long infection. The mucosal environment of the female reproductive tract (FRT) is home to a complex array of local immune defenses that must be carefully coordinated to protect against genital HSV-2 infection, while preventing excessive inflammation to prevent disease symptoms. Crucial to the defense against HSV-2 infection in the FRT are three classes of highly related and integrated cytokines, type I, II, and III interferons (IFN). These three classes of cytokines control HSV-2 infection and reduce tissue damage through a combination of directly inhibiting viral replication, as well as regulating the function of resident immune cells. In this review, we will examine how interferons are induced and their critical role in how they shape the local immune response to HSV-2 infection in the FRT.

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