Kallikrein 13: a new player in coronaviral infections

Aleksandra Milewska; Katherine Falkowski; Magdalena Kalinska; Ewa Bielecka; Antonina Naskalska; Pawel Mak; Adam Lesner; Marek Ochman; Maciej Urlik; Jan Potempa; Tomasz Kantyka; Krzysztof Pyrc

Considering the small arsenal of tools available to researchers studying KLKs, only three 287 compounds were readily available. Treating HAE cultures with these inhibitors revealed that 288 only compounds designed to inhibit KLK13 hampered HCoV-HKU1 replication. However, the 289 great similarity between different KLKs makes one doubt the specificity of these inhibitors, 290 despite their performance in biochemical assays. Therefore, we decided to silence KLK13 in 291 HAE cultures. This abolished virus replication ex vivo, thereby confirming the importance of 292 KLK13 during infection. KLK13 is thought to be secreted and membrane-bound(82, 83). 293 This study showed that HCoV-HKU1 infection in HAE modulates the expression of 294 different KLKs, including KLK13. In our study, KLKs expression was tested using semi-295 quantitative PCR, and for that reason, we were unable to show the level of KLKs modulation 296 after HCoV-HKU1. However, the pattern of virus-induced expression of several KLKs could 297 be observed. KLK mechanism of activation is a complex process and until now it has only 298 been proven that most KLK genes are regulated by steroids and other hormones (84). It is also 299 important to remember, that KLK expression is regulated in a similar manner, and the induction 300 of a single gene usually results in overexpression of the whole cluster (85, 86). While one may 301 assume that the virus stimulates KLK13 production to promote the infection, this up-regulation 302 is likely a natural response of the damaged tissue, as KLKs were previously reported to take 303 part also in tissue regeneration (87-89). Further, increased expression of KLKs may be the 304 author/funder. All rights reserved. No reuse allowed without permission.