The study of human genetic and infectious diseases still strongly relies on animal models. As many genetic and infectious diseases involve the interplay of a number of cell and tissue types, we remain incapable of modelling them with simple cell and tissue culture systems, despite their usefulness especially in early research. The use of mammals such as mice could be reduced with the use of alternative animal models such as zebrafish or fruit fly. For some applications, a fish model can even be better suited than mice, Uusi-Mäkelä explains.
Uusi-Mäkelä’s thesis applies genetically modified zebrafish in modelling human disease genetics. In the thesis, a zebrafish model for a rare human disease FINCA, and two genetically modified models for studying the genetics of human tuberculosis were generated.
FINCA disease was recently identified in Finland. FINCA-patients presented mutations in a gene coding for a previously unknown NHLRC2 protein. The patients were born healthy, but before two years of age succumbed to an unknown multi organ disease.
For research, the causative relationship of the disease and the suspected gene needs to be established in animal models. However, producing a mouse model appeared futile as the knockout mice died before birth. In zebrafish, silencing nhlrc2 resulted in tissue degeneration in the mid brain region of larval zebrafish. These changes were considered to resemble the neurodegeneration observed in the human patients’ brain, which supports the role of NHLRC2 in FINCA. The study was completed in collaboration with researchers from the University of Oulu.
In case of infectious disease genetics, zebrafish has proven useful in modelling human tuberculosis infection. Both human and zebrafish are naturally susceptible to mycobacterial infections, such as tuberculosis, unlike for example mice. The so-called fish tuberculosis of zebrafish presents genetic and mechanistic similarities with human tuberculosis. Research with two zebrafish mutant lines showed that inflammasome signalling is essential for immune defence in mycobacterial infection. In contrast, the gene intelectin 3 was found to be dispensable for mycobacterial infection.
"Our studies were able to determine the significance of each of the identified genes in disease. Overall, the studies presented the applicability of zebrafish in human disease studies. In the best scenario, alternative model organisms such as zebrafish can be used to generate reliable data, and to decrease the number of mammals needed for research", Uusi-Mäkelä concludes.
Uusi-Mäkelä has since transferred to Karolinska Institute in Stockholm, to study pneumococcal infections in Birgitta Henriques Normark’s research group.
The doctoral dissertation of M. Sc. Meri Uusi-Mäkelä in the field of Experimental Immunology titled Zebrafish as a model for human genetic and infectious diseases will be publicly examined in the Faculty of Medicine and Health Technology at Tampere University at 12 o’clock on Wednesday 8th of June in the Arvo F114 lecture hall of the Tampere University Arvo building, address: Arvo Ylpön katu 34, Tampere. The Opponent will be Professor Marko Salmi from the University of Turku. The Custos will be Professor Mika Rämet.
Photo: Jukka Lehtiniemi