Human cytomegaloviral multifunctional protein kinase pUL97 impairs zebrafish embryonic development and increases
Salvador Cazorla-Vázquez1, Mirjam Steingruber2, Manfred Marschall2
1Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 12, 91052, Erlangen, Germany.
Abstract:
Cytomegalovirus is a worldwide-distributed human pathogen, which is the leading cause of congenital virus infection, affecting 0.5 to 2% of live births. To date, it is largely unclear which molecular mechanisms underlie the symptomatic outcomes. This is mainly due to species specificity and limited homology among cytomegalovirus genomes. As it is not possible to infect model organisms with human cytomegalovirus, the aim of this study was to develop a heterologous system allowing in the future the elucidation of the pathological role of individual viral proteins. As a model organism the zebrafish has been chosen due to its ease of manipulation and characterization as well as its large offspring. As cytomegalovirus model protein, pUL97 was characterized because it is multiply involved in virus-host interaction. Here, we show in zebrafish embryos, that (i) pUL97 can be expressed in zebrafish, (ii) increasing pUL97 expression levels quantitatively correlate with both minor and major pathological defects, (iii) pUL97 expression impairs cell cycle progression and induces cell death, (iv) active pUL97, but not an inactive mutant, induces excess mortality, and (v) co-administration of a pUL97 inhibitor reduces embryonic pathology. Collectively, these data indicate the suitability of zebrafish to elucidate the pathological role of human cytomegaloviral proteins.
Insights
Zebrafish embryos successfully express human cytomegalovirus protein pUL97, revealing its role in congenital virus infection pathology. Inhibiting pUL97 reduced embryonic defects, validating zebrafish as a model for studying viral protein functions.
Area of Science:
- Virology
- Developmental Biology
- Genetics
Background:
- Human cytomegalovirus (HCMV) is a major cause of congenital infections, but underlying molecular mechanisms remain unclear due to species specificity.
- Limited homology and inability to infect model organisms with HCMV hinder research into symptomatic outcomes.
Purpose of the Study:
- To develop a heterologous system for studying the pathological role of individual HCMV proteins.
- To investigate the function of HCMV protein pUL97 in a model organism.
Main Methods:
- Expression of HCMV pUL97 in zebrafish embryos.
- Quantitative analysis of pathological defects correlated with pUL97 expression levels.
- Assessment of pUL97's impact on cell cycle, cell death, and mortality.
- Evaluation of pUL97 inhibitor efficacy in reducing embryonic pathology.
Main Results:
- Zebrafish successfully express functional HCMV pUL97.
- Increased pUL97 expression correlates with dose-dependent pathological defects and increased embryonic mortality.
- pUL97 impairs cell cycle progression and induces cell death.
- A pUL97 inhibitor significantly reduces embryonic pathology.
Conclusions:
- Zebrafish embryos serve as a suitable model for elucidating the pathological roles of HCMV proteins.
- HCMV protein pUL97 plays a significant role in inducing embryonic pathology and mortality.
- This model system facilitates future research into HCMV pathogenesis and potential therapeutic targets.
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