The deadly face of felid killer cells: The cytotoxic proteins and their genes

Abstract

Natural killer cells and cytotoxic T lymphocytes are the main cell populations of the immune system able to directly kill target cells via cytotoxic granules. Different mammalian species may differ in specific features of their pore‐forming protein (perforin) and granule‐bound serine proteases (granzymes). One perforin gene (PRF1) and four genes encoding granzymes A, B, H, and K (GZMA, GZMB, GZMH, GZMK) were identified in the reference genomes of felids. The objective of this work was to characterize the genes PRF1, GZMA and GZMB in a panel of 17 felid species by next‐generation re‐sequencing. A search of available felid genomes (17 species) retrieved the coding sequences of these genes for comparison to our data. Both sets of sequences or their combinations (23 species) were used for phylogenetic and selection analyses. Nucleotide PRF1, GZMA and GZMB sequences showed high similarities between felid species (over 95% identity). All trees derived from coding sequences expressed phylogenetic relationships corresponding to the zoological taxonomy of the Felidae, except GZMA. No effects of positive selection were detected in the genes studied, however, effects of purifying selection were observed for PRF1 and GZMA. The conservation of PRF1 is in agreement with its critical biological function. The differentiation observed between granzyme sub‐families may reflect an adaptation to pathogen variation. The need to maintain important gene functions and at the same time cope with various pathogens may lead to an equilibrium between positive and negative selective pressures acting on GZMB. The within‐species variability in wild felid populations merits further investigation.

The immunological advantage of owned cats over stray cats: a comparative study of perforin and granzymes gene expressions

“…Our study also clearly demonstrated the importance of the GZMA gene for cats. Taken together, our study and previous studies [6,7,30,31] indicate that there are important immune system differences between pet cats and dog species, although not between breeds and related species. While stray dogs gain an immunological advantage in the fi ght against diseases [30], the opposite is true for cats: owned cats gain an immunological advantage compared to stray cats.…”

“…In another study examining 17 different felid species, nucleotide sequences of PRF1, GZMA and GZMB showed high similarities. All trees derived from coding sequences expressed phylogenetic relationships corresponding to the zoological taxonomy of the Felidae, except GZMA [6]. Bubenikova et al [31] found no signifi cant differences between different cat breeds for PRF1, GZMA, and GZMB genes.…”

“…Granzymes cause the death of the infected cell by activating apoptotic pathways and degrading both cell and viral DNA inside the cell. Two of the most important of these granzymes are granzyme A (GZMA) and granzyme B (GZMB) [5][6][7]. GZMA, which is the most abundant granzyme in cytotoxic granules that enter the cell, differs from many other granzymes by initiating a caspase-independent apoptosis mechanism.…”

Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke

“…GZMB can also be produced and released by NK cells. 59 Moreover, neutrophils and T cells are known to release other proteases, such as MMP9 and MMP2, that contribute to BBB damage and dysfunction. 48,49 Employing specific knock-out mice for GZMB or NE will help address this scientific question.…”