Perforin knockout mice, but not mice with MAIDS, show protection against experimental cytomegalovirus retinitis after adoptive transfer of immune cells with a functional perforin cytotoxic pathway

Dix, Richard D.; Ekworomadu, C. O.; Hernandez, E.; Cousins, Scott W.

doi:10.1007/s00705-004-0370-3

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…This is in contrast to perforin deficient mice, which failed to clear the virus (Kagi et al, 1995). Similarly, Fas was dispensable for control of MCMV induced retinitis (Dix et al, 2004). In fact, lpr mice were more efficient at controlling vaccinia virus replication (Seedhom et al, 2012).…”

Section: Apoptotic Mechanisms In Anti-viral Immunitymentioning

confidence: 99%

Staying Alive: Cell Death in Antiviral Immunity

2014

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Programmed cell death is an integral part of host defense against invading intracellular pathogens. Apoptosis, programmed necrosis, and pyroptosis each serve to limit pathogen replication in infected cells, while simultaneously promoting the inflammatory and innate responses that shape effective long-term host immunity. The importance of carefully regulated cell death is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in these pathways. Moreover, many viruses encode inhibitors of programmed cell death to subvert these host responses during infection, thereby facilitating their own replication and persistence. Thus, as both virus and cell vie for control of these pathways, the battle for survival has shaped a complex host-pathogen interaction. This review will discuss the multifaceted role programmed cell death plays in maintaining the immune system and its critical function in host defense, with a special emphasis on viral infections.

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Section: Apoptotic Mechanisms In Anti-viral Immunitymentioning

confidence: 99%

Staying Alive: Cell Death in Antiviral Immunity

2014

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“…We have used the MAIDS model of MCMV retinitis as an experimental model for AIDS-related HCMV retinitis to investigate humoral immunity (27), cellular immunity (28,29), cell death pathways (26), and a number of individual cytokines for their relative roles during retinal disease onset and development. Among the cytokines we have examined to date are tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), interleukin-2 (IL-2), IL-12, IL-4, IL-10, and IL-17 (22,23,(30)(31)(32)(33).…”

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confidence: 99%

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

Chien

Alston

Dix

2018

J Virol

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AIDS-related human cytomegalovirus retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. To study mechanisms of this disease, we used a clinically relevant animal model of murine cytomegalovirus (MCMV) retinitis with retrovirus-induced murine AIDS (MAIDS) that mimics the progression of AIDS in humans. We found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling 1 (SOCS1) and SOCS3, host proteins which hinder immune-related signaling by cytokines, including antiviral type I and type II interferons. The present study demonstrates that in the absence of retinal disease, systemic MCMV infection of mice without MAIDS, but not in mice with MAIDS, leads to mild stimulation of splenic SOCS1 mRNA. In sharp contrast, when MCMV is directly inoculated into the eyes of retinitis-susceptible MAIDS mice, high levels of intraocular SOCS1 and SOCS3 mRNA and protein are produced which are associated with significant intraocular upregulation of gamma interferon (IFN-γ) and interleukin-6 (IL-6) mRNA expression. We also show that infiltrating macrophages, granulocytes, and resident retinal cells are sources of intraocular SOCS1 and SOCS3 protein production during development of MAIDS-related MCMV retinitis, and SOCS1 and SOCS3 mRNA transcripts are detected in retinal areas histologically characteristic of MCMV retinitis. Furthermore, SOCS1 and SOCS3 are found in both MCMV-infected cells and uninfected cells, suggesting that these SOCS proteins are stimulated via a bystander mechanism during MCMV retinitis. Taken together, our findings suggest a role for MCMV-related stimulation of SOCS1 and SOCS3 in the progression of retinal disease during ocular, but not systemic, MCMV infection. Cytomegalovirus infection frequently causes blindness in untreated HIV/AIDS patients. This virus manipulates host cells to dysregulate immune functions and drive disease. Here, we use an animal model of this disease to demonstrate that cytomegalovirus infection within eyes during retinitis causes massive upregulation of immunosuppressive host proteins called SOCS. As viral overexpression of SOCS proteins exacerbates infection with other viruses, they may also enhance cytomegalovirus infection. Alternatively, the immunosuppressive effect of SOCS proteins may be protective against immunopathology during cytomegalovirus retinitis, and in such a case SOCS mimetics or overexpression treatment strategies might be used to combat this disease. The results of this work therefore provide crucial basic knowledge that contributes to our understanding of the mechanisms of AIDS-related cytomegalovirus retinitis and, together with future studies, may contribute to the development of novel therapeutic targets that could improve the treatment or management of this sight-threatening disease.

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“…This hypothesis was tested by comparing perforin mRNA levels of splenic T cells and MCMV-infected eyes collected from mice with MAIDS with perforin mRNA levels of splenic T cells and MCMV-infected eyes collected from healthy mice. In support of this hypothesis, perforin mRNA levels were dramatically reduced within splenic T cells and MCMV-infected eyes of retinitis-susceptible MAIDS mice when compared with retinitis-resistant healthy mice who showed consistently high amounts of perforin mRNA production within splenic T cells and MCMV-infected eyes [ 51 , 55 ].…”

Section: Insights Into Pathogenesismentioning

confidence: 98%

“…Whereas mice without MAIDS but deficient in the Fas/FasL cytotoxic pathway showed absolute (0%) resistance to MCMV retinitis as observed for healthy mice who were immunocompetent, mice without MAIDS but deficient in the perforin cytotoxic pathway showed significant susceptibility to MCMV retinitis at a frequency of >90% and at a level equivalent to that observed for mice with MAIDS [ 50 , 51 ]. Adoptive transfer studies were then performed to confirm our observation that the perforin cytotoxic pathway is more important than the Fas/FasL cytotoxic pathway in conferring protection against MCMV retinitis [ 54 , 55 ]. Splenic immune cells originating from MCMV-immunized healthy mice or MCMV-immunized gld mice when transferred to recipient PKO mice significantly reduced susceptibility to MCMV retinitis following challenge by subretinal MCMV inoculation.…”

Section: Insights Into Pathogenesismentioning

confidence: 99%

A Mouse Model That Mimics AIDS-Related Cytomegalovirus Retinitis: Insights into Pathogenesis

Carter

Dix

2021

Pathogens

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With the appearance of the worldwide AIDS pandemic four decades ago came a number of debilitating opportunistic infections in patients immunosuppressed by the pathogenic human retrovirus HIV. Among these was a severe sight-threatening retinal disease caused by human cytomegalovirus (HCMV) that remains today a significant cause of vision loss and blindness in untreated AIDS patients without access or sufficient response to combination antiretroviral therapy. Early investigations of AIDS-related HCMV retinitis quickly characterized its hallmark clinical features and unique histopathologic presentation but did not begin to identify the precise virologic and immunologic events that allow the onset and development of this retinal disease during HIV-induced immunosuppression. Toward this end, several mouse models of experimental cytomegalovirus retinitis have been developed to provide new insights into the pathophysiology of HCMV retinitis during AIDS. Herein, we provide a summary and comparison of these mouse models of AIDS-related HCMV retinitis with particular emphasis on one mouse model developed in our laboratory in which mice with a murine acquired immunodeficiency syndrome (MAIDS) of murine retrovirus origin develops a reproducible and well characterized retinitis following intraocular infection with murine cytomegalovirus (MCMV). The MAIDS model of MCMV retinitis has advanced the discovery of many clinically relevant virologic and immunologic mechanisms of virus-induced retinal tissue destruction that are discussed and summarized in this review. These findings may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections.

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Perforin knockout mice, but not mice with MAIDS, show protection against experimental cytomegalovirus retinitis after adoptive transfer of immune cells with a functional perforin cytotoxic pathway

Cited by 8 publications

References 18 publications

Staying Alive: Cell Death in Antiviral Immunity

Staying Alive: Cell Death in Antiviral Immunity

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

A Mouse Model That Mimics AIDS-Related Cytomegalovirus Retinitis: Insights into Pathogenesis

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