Control of Virus Reactivation Arrests Pulmonary Herpesvirus-induced Fibrosis in IFN-γ Receptor–deficient Mice

Mora, Ana L.; Torres-González, Edilson; Rojas, Mauricio; Xu, Jianguo; Ritzenthaler, Jeffrey D.; Speck, Samuel H.; Roman, Jesse; Brigham, Kenneth L.; Stecenko, Arlene A.

doi:10.1164/rccm.200610-1426oc

Cited by 73 publications

(117 citation statements)

References 49 publications

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“…Although gHV-68 infection is not identical to infection with EBV or HHV-8, and FITC inoculation does not recapitulate all aspects of IPF fibrogenesis, this model can be used to better understand particular cell types or profibrotic factors critical to virus-induced augmentation of fibrosis. The studies by Mora and colleagues in Th2-biased mice suggested that antiviral therapies may improve fibrotic outcomes by limiting viral reactivation (13). In contrast, our studies suggest that viral reactivation is not critical to the augmentation of fibrosis in wild-type mice at least during early latency; thus, antiviral drugs may not be as effective as previously hoped.…”

Section: Discussioncontrasting

confidence: 69%

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Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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Rationale: No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied. Objectives: To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis. Methods: Mice were infected with murine gherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis. Measurements and Main Results: gHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-b1, and cysteinyl leukotrienes in alveolar epithelial cells. Conclusions: Latent gherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

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Section: Discussioncontrasting

confidence: 69%

“…In addition, we have recently shown that lytic gHV-68 infection can exacerbate established pulmonary fibrosis (11). The mechanisms identified to contribute to lytic virus-induced exacerbation of fibrosis have included Th2 bias, persistent reactivation, alternative activation of macrophages, and fibrocyte recruitment (11)(12)(13).…”

mentioning

confidence: 99%

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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“…Ϫ/Ϫ mice were treated with the viral DNA polymerase inhibitor cidofovir (25,26). We identified a dosage (8 mg/kg) that effectively reduced MHV68 lung titers to wild-type levels (Fig.…”

Section: Cd8mentioning

confidence: 99%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

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CD8؉ T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8؉ T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1 ؊/؊ mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8 ؉ T cell response. To test this, IFNAR1 ؊/؊ mice were infected with MHV68 and the CD8 ؉ T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8 ؉ T cells, and MHV68-specific CD8 ؉ T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-␣), gamma IFN (IFN-␥), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8 ؉ T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1؊/؊ mice failed to improve CD8 ؉ T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8 ؉ T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8 ؉ T cell response. IMPORTANCE The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8 T he gammaherpesvirus-directed CD8ϩ T cell response is critical to the control of replication and reactivation associated with Epstein-Barr virus (EBV) infection, and individuals with either genetic or acquired immunodeficiencies are highly susceptible to EBV-associated diseases (1-3). Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4, 5). In addition, CD8 ϩ T cells prevent in vivo tumor outgrowth of B cell cancer lines immortalized by murine gammaherpesvirus 68 (MHV68), a wellcharacterized virus model for EBV (6). Thus, CD8ϩ T cells can suppress gammaherpesvirus-associated malignancies. The promise of immunotherapy and vaccine development relies on our understanding of factors that promote a highly effective gammaherpesvirus-directed CD8 ϩ T cell response. CD8 ϩ T cells responding to their cognate antigen require three signals for survival and differentiation: antige...

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“…These infected animals develop progressive lung fibrosis that shares common features observed in IPF lungs, including patchy and subpleural fibrosis, high levels of transforming growth factor (TGF)-␤ production, the presence of myofibroblast transformation, hyperplasia and epithelial mesenchymal transition of alveolar epithelial cells, and the activation of alveolar macrophages by the alternative pathway. [15][16][17][18] Our previous studies demonstrated that lytic replication in the chronic phase of infection is critical for fibrotic progression in IFN␥R Ϫ/Ϫ mice infected with MHV68. The administration of the antiviral drug cidofovir starting at 45 days post infection (dpi) reduced virus replication and halted fibrotic progression.…”

mentioning

confidence: 99%

“…The administration of the antiviral drug cidofovir starting at 45 days post infection (dpi) reduced virus replication and halted fibrotic progression. 16 Infection with a recombinant MHV68 that lacks v-cyclin, a gene that functions to control reactivation, developed vasculitis and fibrosis at the onset of the chronic phase (day 15) but failed to drive fibrosis in the late chronic phase (day 150). 16,19 In C57BL/6 mice, lytic MHV68 infection has been used as a cofactor to exacerbate established pulmonary fibrosis.…”

mentioning

confidence: 99%

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

Krug

Torres-González

Qin

et al. 2010

The American Journal of Pathology

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and IPF. Based on those observations, we have developed a mouse model in which interferon (IFN)␥R؊/؊ mice infected intranasally with murine gammaherpesvirus 68 (MHV68) develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor (NF)-B signaling is required to efficiently establish gammaherpesvirus, latency we infected IFN␥R Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease of unknown cause, with no proven effective therapy other than lung transplantation.1 Although the cellular and molecular pathways that drive the pathogenesis of IPF are complex and not fully delineated, increasing evidence suggests that a key event in its pathogenesis is ongoing alveolar epithelial injury in association with an abnormal host repair response. Several studies have implicated viral infections as an important factor in IPF pathogenesis. Specifically, Epstein-Barr virus (EBV) DNA and protein have been detected in 40 to 70% of lung tissue of IPF patients, compared with 10 to 17% of lung controls.2-7 Our group has detected viral DNA for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and Cytomegalovirus herpesvirus in Ͼ95% of lung samples of IPF patients, with statically higher frequency compared with patients with non-IPF lung diseases. 5 We have developed a model of chronic herpesvirusinduced pulmonary fibrosis infection using the herpesvirus murine gammaherpesvirus 68 (MHV68), a natural pathogen of wild murid rodents that has strong genetic and biological similarities with the human gammaherpesviruses EBV and KSHV. 8 -10 In immunocompetent animals, intranasal infection with MHV68 leads to an acute phase of lytic replication in the lung. Within several weeks, infectious virus is undetectable, and latent virus

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Control of Virus Reactivation Arrests Pulmonary Herpesvirus-induced Fibrosis in IFN-γ Receptor–deficient Mice

Cited by 73 publications

References 49 publications

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

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Control of Virus Reactivation Arrests Pulmonary Herpesvirus-induced Fibrosis in IFN-γ Receptor–deficient Mice

Cited by 73 publications

References 49 publications

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

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Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection