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Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency.

Flesch IE, Randall KL, Hollett NA, Di Law H, Miosge LA, Sontani Y, Goodnow CC, Tscharke DC - Immunol. Cell Biol. (2015)

Bottom Line: Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV).A better understanding of these mechanisms is required to underpin the development of more specific therapies.Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads.

View Article: PubMed Central - PubMed

Affiliation: Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.

ABSTRACT
DOCK8 deficiency in humans and mice leads to multiple defects in immune cell numbers and function. Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV). The underlying mechanism of the specific susceptibility to these chronic cutaneous viral infections is currently unknown, largely because the effect of DOCK8 deficiency has not been studied in suitable models. A better understanding of these mechanisms is required to underpin the development of more specific therapies. Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads. Furthermore, DOCK8-deficient mice showed a lack of CD4(+) T-cell infiltration into HSV-infected skin.

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Pathogenesis of HSV infection in DOCK8 deficient miceCohorts of DOCK8 deficient mice and matched DOCK8+/+ littermates were inoculated with HSV-1 strain KOS on the flank by tattoo. (A) Lesion morphology at 7 dpi at the peak of the infection. (B) Lesion size and (C) weight change in groups of 5 DOCK8pri/ipri mice and 4 DOCK8+/+ littermates. Data have been independently repeated twice. (D) Left and middle, virus titers in DRG and skin at 7 dpi, right is the amount of virus obtained from latently-infected DRG after 5 days of explant culture to induce reactivation. In all cases, data are combined from two independent experiments, each point represents a single mouse and lines indicate means. (E) Lesion size in groups of 7 Dock8E1886X/E1886X and 4 matched wild-type mice. Statistical significance (Mann Whitney) is noted with a p value or ns for p>0.05).
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Figure 1: Pathogenesis of HSV infection in DOCK8 deficient miceCohorts of DOCK8 deficient mice and matched DOCK8+/+ littermates were inoculated with HSV-1 strain KOS on the flank by tattoo. (A) Lesion morphology at 7 dpi at the peak of the infection. (B) Lesion size and (C) weight change in groups of 5 DOCK8pri/ipri mice and 4 DOCK8+/+ littermates. Data have been independently repeated twice. (D) Left and middle, virus titers in DRG and skin at 7 dpi, right is the amount of virus obtained from latently-infected DRG after 5 days of explant culture to induce reactivation. In all cases, data are combined from two independent experiments, each point represents a single mouse and lines indicate means. (E) Lesion size in groups of 7 Dock8E1886X/E1886X and 4 matched wild-type mice. Statistical significance (Mann Whitney) is noted with a p value or ns for p>0.05).

Mentions: Cohorts of DOCK8pri/pri and wild-type mice were inoculated by tattoo with HSV-1 strain KOS on the flank of shaved and depilated mice14. In this model of primary HSV infection, virus moves to the innervating dorsal root ganglia (DRG) concurrent with the initial skin infection. Replication in the peripheral nervous system leads to virus spreading back to the skin at sites within the inoculated dermatome that are distinct from the site of inoculation producing a characteristic ‘zosteriform’ lesion (Fig 1A) 15, 16. In immunocompetent mice, HSV is limited to the skin and innervating peripheral nervous system and acute infection is controlled by 7-8 days post infection (dpi), but loss of control can lead to central nervous system involvement or dissemination15. HSV lesions in DOCK8pri/pri mice initially formed at a similar rate to those in wild type littermates, but then continued to increase in size until 8 dpi, reaching a significantly larger size (Fig. 1A & B). By contrast wild type littermates began to control lesions by 6 dpi, such that the peak size was lower and lesions resolved more quickly. Despite the difference in lesion size there was no significant difference in weight-loss sustained by the DOCK8pri/pri mice compared with wild type controls and no mice succumbed to disease (Fig 1C). Qualitatively the lesions in DOCK8pri/pri and wild type mice looked similar with the exception of size, and the tumourous lesions found in DOCK8 deficient human patients were not seen. We speculate that this might be due to the mouse not recapitulating the atopic features of DOCK8-deficiency in humans, for example DOCK8-deficient mice do not exhibit hyper-IgE, even when aged (KLR, unpublished). While the lesions in DOCK8 deficient patients are clearly distinct from those associated with eczema herpeticum, it is possible that the superimposition of these two conditions leads to a unique lesion morphology.


Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency.

Flesch IE, Randall KL, Hollett NA, Di Law H, Miosge LA, Sontani Y, Goodnow CC, Tscharke DC - Immunol. Cell Biol. (2015)

Pathogenesis of HSV infection in DOCK8 deficient miceCohorts of DOCK8 deficient mice and matched DOCK8+/+ littermates were inoculated with HSV-1 strain KOS on the flank by tattoo. (A) Lesion morphology at 7 dpi at the peak of the infection. (B) Lesion size and (C) weight change in groups of 5 DOCK8pri/ipri mice and 4 DOCK8+/+ littermates. Data have been independently repeated twice. (D) Left and middle, virus titers in DRG and skin at 7 dpi, right is the amount of virus obtained from latently-infected DRG after 5 days of explant culture to induce reactivation. In all cases, data are combined from two independent experiments, each point represents a single mouse and lines indicate means. (E) Lesion size in groups of 7 Dock8E1886X/E1886X and 4 matched wild-type mice. Statistical significance (Mann Whitney) is noted with a p value or ns for p>0.05).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496291&req=5

Figure 1: Pathogenesis of HSV infection in DOCK8 deficient miceCohorts of DOCK8 deficient mice and matched DOCK8+/+ littermates were inoculated with HSV-1 strain KOS on the flank by tattoo. (A) Lesion morphology at 7 dpi at the peak of the infection. (B) Lesion size and (C) weight change in groups of 5 DOCK8pri/ipri mice and 4 DOCK8+/+ littermates. Data have been independently repeated twice. (D) Left and middle, virus titers in DRG and skin at 7 dpi, right is the amount of virus obtained from latently-infected DRG after 5 days of explant culture to induce reactivation. In all cases, data are combined from two independent experiments, each point represents a single mouse and lines indicate means. (E) Lesion size in groups of 7 Dock8E1886X/E1886X and 4 matched wild-type mice. Statistical significance (Mann Whitney) is noted with a p value or ns for p>0.05).
Mentions: Cohorts of DOCK8pri/pri and wild-type mice were inoculated by tattoo with HSV-1 strain KOS on the flank of shaved and depilated mice14. In this model of primary HSV infection, virus moves to the innervating dorsal root ganglia (DRG) concurrent with the initial skin infection. Replication in the peripheral nervous system leads to virus spreading back to the skin at sites within the inoculated dermatome that are distinct from the site of inoculation producing a characteristic ‘zosteriform’ lesion (Fig 1A) 15, 16. In immunocompetent mice, HSV is limited to the skin and innervating peripheral nervous system and acute infection is controlled by 7-8 days post infection (dpi), but loss of control can lead to central nervous system involvement or dissemination15. HSV lesions in DOCK8pri/pri mice initially formed at a similar rate to those in wild type littermates, but then continued to increase in size until 8 dpi, reaching a significantly larger size (Fig. 1A & B). By contrast wild type littermates began to control lesions by 6 dpi, such that the peak size was lower and lesions resolved more quickly. Despite the difference in lesion size there was no significant difference in weight-loss sustained by the DOCK8pri/pri mice compared with wild type controls and no mice succumbed to disease (Fig 1C). Qualitatively the lesions in DOCK8pri/pri and wild type mice looked similar with the exception of size, and the tumourous lesions found in DOCK8 deficient human patients were not seen. We speculate that this might be due to the mouse not recapitulating the atopic features of DOCK8-deficiency in humans, for example DOCK8-deficient mice do not exhibit hyper-IgE, even when aged (KLR, unpublished). While the lesions in DOCK8 deficient patients are clearly distinct from those associated with eczema herpeticum, it is possible that the superimposition of these two conditions leads to a unique lesion morphology.

Bottom Line: Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV).A better understanding of these mechanisms is required to underpin the development of more specific therapies.Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads.

View Article: PubMed Central - PubMed

Affiliation: Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.

ABSTRACT
DOCK8 deficiency in humans and mice leads to multiple defects in immune cell numbers and function. Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV). The underlying mechanism of the specific susceptibility to these chronic cutaneous viral infections is currently unknown, largely because the effect of DOCK8 deficiency has not been studied in suitable models. A better understanding of these mechanisms is required to underpin the development of more specific therapies. Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads. Furthermore, DOCK8-deficient mice showed a lack of CD4(+) T-cell infiltration into HSV-infected skin.

Show MeSH
Related in: MedlinePlus