Mouse Models for Cytomegalovirus Infections in Newborns and Adults

Brizić, Ilija; Lisnić, Berislav; Krstanović, Fran; Brune, Wolfram; Hengel, Hartmut; Jonjić, Stipan

doi:10.1002/cpz1.537

Cited by 13 publications

(9 citation statements)

References 92 publications

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“…MCMV is a natural mouse pathogen and therefore perfectly suited for studies in the mouse model (Brizic et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…For stock production, viruses were propagated in 10.1 fibroblasts and the supernatants were collected. Viral particles were pelleted by ultracentrifugation, resuspended, and purified by ultracentrifugation through a sucrose cushion (Brizic et al, 2022). For in vitro experiments, virus titration was performed on 10.1 cells by using the median tissue culture infective dose (TCID50) method.…”

Section: Virusesmentioning

confidence: 99%

“…Centrifugal enhancement of infection (30 min at 1000×g) was used for high-MOI infections. For in vivo experiments, virus stocks were titrated on M2-10B4 cells by standard plaque assay (Brizic et al, 2022).…”

Section: Virusesmentioning

confidence: 99%

“…Serum was harvested 1.5 and 3 days post-infection. Viral titers in organs were determined by plaque assay on M2-10B4 cells as described (Brizic et al, 2022). IL-18 serum concentrations were measured by ELISA as described above.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…Therefore, many viruses have developed countermeasures to prevent or delay programmed cell death (Upton and Chan, 2014;Verburg et al, 2022). Human cytomegalovirus (HCMV), a medically significant pathogen (Griffiths et al, 2015), and murine cytomegalovirus (MCMV), a related mouse pathogen used to study viral pathogenesis in vivo (Brizic et al, 2022), are prototypic β-herpesviruses with large genomes and protracted replication cycles. As such, they should be particularly vulnerable to cellular defense mechanisms such as PCD.…”

Section: Introductionmentioning

confidence: 99%

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A cytomegalovirus inflammasome inhibitor curbs proinflammatory cytokine release and pyroptosis

Brune

Deng

Ostermann

2023

Preprint

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In response to viral infection, cells can initiate programmed cell death (PCD), leading to a reduction in the release of viral progeny. Viruses have therefore evolved specific mechanisms to curb PCD. Cytomegaloviruses (CMVs) are particularly sophisticated manipulators of cellular defenses and are known to encode potent inhibitors of apoptosis and necroptosis. However, a CMV inhibitor of pyroptosis, the third major PCD form, has not been identified. Encoding such an inhibitor should be important for the virus as the three PCD pathways are not separate entities but interconnected pathways. Here we identify the murine CMV M84 protein as an inhibitor of pyroptosis and proinflammatory cytokine release. M84 interacts with the pyrin domain of the inflammasome components AIM2 and ASC to block Caspase-1 activation, release of interleukin 1β (IL-1β) and IL-18, cleavage of Gasdermin D, and pyroptosis of macrophages. Growth attenuation of an M84-deficient MCMV in macrophages was rescued by knockout of either Aim2 or Asc or by treatment with a Caspase-1 inhibitor, and its attenuation in infected mice was partially rescued in Asc knockout mice. These results demonstrate that viral inhibition of the inflammasome-pyroptosis pathway is important to promote viral replication and dissemination in vivo.

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“…MCMV is a natural mouse pathogen and therefore perfectly suited for studies in the mouse model (Brizic et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Section: Virusesmentioning

confidence: 99%

Section: Virusesmentioning

confidence: 99%

Section: Animal Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A cytomegalovirus inflammasome inhibitor curbs proinflammatory cytokine release and pyroptosis

Brune

Deng

Ostermann

2023

Preprint

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Immune surveillance of cytomegalovirus in tissues

Mihalić,

Železnjak,

Lisnić

et al. 2024

Cell Mol Immunol

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Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.

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Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells

Rožmanić,

Lisnić,

Pribanić Matešić

et al. 2023

Nat Commun

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Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA Ifng-as1 expression. Moreover, the bone marrow’s capacity to efficiently generate new NK cells is reduced, explaining the prolonged negative effects of perinatal infection on NK cells. This study demonstrates that viral infections in early life can profoundly impact NK cell biology, including long-lasting impairment in NK cell functionality.

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Mouse Models for Cytomegalovirus Infections in Newborns and Adults

Cited by 13 publications

References 92 publications

A cytomegalovirus inflammasome inhibitor curbs proinflammatory cytokine release and pyroptosis

A cytomegalovirus inflammasome inhibitor curbs proinflammatory cytokine release and pyroptosis

Immune surveillance of cytomegalovirus in tissues

Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells

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