Treg depletion attenuates the severity of skin disease from ganglionic spread after HSV-2 flank infection

Fernandez, Marian A.; Yu, Uet; Zhang, Geoff G. Z.; White, R. W.; Sparwasser, Tim; Alexander, Stephen I.; Jones, Cheryl

doi:10.1016/j.virol.2013.08.027

Cited by 15 publications

(14 citation statements)

References 53 publications

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“…Since adult DEREG mice do not develop autoimmunity after Treg depletion as it was observed in other mouse strains [28]–[30], this model is suitable to study the role of Tregs during infection without the side effects of autoimmune activation, as it was demonstrated in several models of chronic infection [6], [25], [31]–[33].…”

Section: Introductionmentioning

confidence: 84%

Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden, but Prevents Autoimmunity

et al. 2014

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The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.

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Section: Introductionmentioning

confidence: 84%

Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden, but Prevents Autoimmunity

et al. 2014

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“…During HSV-1 and HSV-2 infection of mice, cells phenotypically resembling MDSCs infiltrated the cornea (34) and skin (40,164). In one study, increased herpes simplex keratitis (HSK) and viral titers were observed in HSV-1-infected Kit W-sh mice (that lack CD31 + mast cells), compared to wildtype mice (130).…”

Section: Dna Virusesmentioning

confidence: 99%

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

2017

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Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.

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“…Female adult C57BL/6 mice, 6 to 8 weeks of age, were purchased from the Animal Resource Centre (Perth, Australia) and acclimatized, and experiments were conducted with the approval of the Children's Medical Research Institute/Children's Hospital at Westmead animal ethics committee. To mimic the route of HSV infection in humans, we used an epicutaneous flank scarification skin infection model as previously described (34). Briefly, mice were anesthetized, the left flank was shaved and depilated (Nair), and then the mice were infected topically by applying 10 l of virus (1 ϫ 10 6 PFU) or PBS within a 2-mm 2 area on the flank skin, which was scarified 20 times using an 18-guage needle, and a dressing was applied after 1 h for 24 h to facilitate infection.…”

Section: Figmentioning

confidence: 99%

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Diefenbach

Davis

Miranda-Saksena

et al. 2016

J Virol

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The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address this, we used an in vitro pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1. IMPORTANCEHerpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we have defined how a key viral protein plays a role in both axonal transport and spread of the virus from nerve cells to the skin. Deletion of the US9 gene, encoding the conserved type II transmembrane viral envelope protein pUS9 (1) (Fig. 1), has been undertaken in a range of Alphaherpesvirinae subfamily members, and neuronal spread has been assessed in several biological models. The relative contribution of pUS9 to neuronal spread within this subfamily was found to differ. Equine herpesvirus type 1 (EHV-1) and bovine herpesvirus type 1 (BHV-1) pUS9 can complement for the loss of pUS9 in swine pathogen pseudorabies virus (PrV) (1). In contrast, varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1) pUS9 are unable to complement for a loss of pUS9 in PrV (1). In PrV (2-5), BHV-1 (6), and BHV-5 (7), pUS9 plays a major role in axonal sorting and/or anterograde axonal transport. For PrV there is also evidence for pUS9-independent anterograde axonal transport of some viral components (8, 9). In HSV-1 the contribution of pUS9 to th...

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Treg depletion attenuates the severity of skin disease from ganglionic spread after HSV-2 flank infection

Cited by 15 publications

References 53 publications

Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden, but Prevents Autoimmunity

Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden, but Prevents Autoimmunity

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

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