Keywords
1. Kallikrein 12 and Macrophages
2. Mycobacterium bovis Immunity
3. Innate Resistance to Tuberculosis
4. Macrophage Autophagy and Apoptosis
5. Cytokine Regulation in Tuberculosis
As the world continues to grapple with the vast spectrum of infectious diseases that threaten public health, a significant spotlight remains on tuberculosis (TB), a disease caused by the Mycobacterium tuberculosis complex. Among this complex, Mycobacterium bovis (M. bovis) stands out as a notorious pathogen capable of crossing species barriers, resulting in bovine tuberculosis, which is not only a serious zoonotic concern but also a significant economic burden in the cattle industry. Complicating efforts to control this pathogen is the intricate interplay between the bacteria and the host’s immune system.
A groundbreaking study led by a dedicated team of researchers from the College of Veterinary Medicine at China Agricultural University, Beijing, has made a notable advance in understanding the immune response orchestrated by murine macrophages against M. bovis. The study, entitled “Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis,” was published in the journal “Cells” (DOI: 10.3390/cells8050415) and brings to light the critical role of Kallikrein 12 (KLK12) in the host’s defense mechanisms.
In this landmark research, Sabir Naveed, Tariq Hussain, and other esteemed colleagues provided compelling evidence that KLK12 is instrumental in modulating innate resistance in murine macrophages upon infection by M. bovis. The study meticulously demonstrates that KLK12 influences various immune response pathways, impacting cytokine production, apoptosis (programmed cell death), and autophagy – a cellular process of self-digestion used to eliminate pathogens.
The pathogens of focus, M. tuberculosis (Mtb) and M. bovis, are highly related and constitute a formidable challenge to public health. M. bovis, in particular, is responsible for tuberculosis in cattle, which can spill over into the human population, emphasizing the necessity of unraveling the molecular mechanisms governing host-pathogen interactions.
The research team, consisting of experts in the field, such as Yi Liao, Jie Wang, and Yinjuan Song, among others, harnessed an array of sophisticated techniques to dissect the intersection of KLK12 expression and macrophage function. Their experiments utilized the murine macrophage cell line RAW 264.7, and cultures derived from C57BL mice to explore the viability of M. bovis under varying conditions of KLK12 expression.
The team, determined to leave no stone unturned, addressed inquiries on multiple fronts. They measured cytokine concentrations, assessed microbial viability, and analyzed macrophage signal transduction. Eventually, their perseverance paid off, unraveling that KLK12 downregulation led to increased bacterial survival and a suboptimal cytokine response. Furthermore, KLK21’s involvement appeared to tweak both apoptotic and autophagy pathways, solidifying the enzyme’s reach and importance in immunity (Hussain et al., 2019).
This comprehensive exploration was made possible through supportive cooperation between the National Animal Transmissible Spongiform Encephalopathy Laboratory, the Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, and other contributors who ensured the integrity and success of this research initiative.
In contextualizing the implications of their findings, the study opens the doors to new therapeutic strategies against TB. By targeting KLK12, new drugs could potentially modulate macrophage responses to enhance their bactericidal activity. This breakthrough could transform TB treatment, especially in cases caused by M. bovis, which are notoriously more challenging due to their resistance to pyrazinamide, one of the core first-line anti-TB drugs.
Looking beyond tuberculosis, KLKs as a whole have caught the attention of the scientific community for their dynamic roles in various physiological and pathological processes. Emerging evidence, as cataloged by Yousef and Diamandis (2003), elucidates the diagnostic potential of this family of serine proteases in cancer. The functionality of KLKs spans the regulation of blood pressure, semen liquefaction, and skin desquamation, among other critical biological functions (Borgoño and Diamandis, 2004; Chao et al., 2010; Harvey et al., 2000).
In translational medicine, KLKs loom large; for instance, KLK6 exhibits transformative potential in treating Gaucher’s disease, a lysosomal storage disorder (Scarisbrick et al., 2011). Insights from studies such as Scarisbrick et al. (2016) and Cerqueira et al. (2015) underscore the pleiotropic effects of KLKs, implicating them in the pathogenesis and resolution of inflammatory and infectious diseases.
The study of KLK12 in macrophages infected with M. bovis also beckons a deeper understanding of the cytokine response firewalling the body against intruders. Diamandis and colleagues (Catalona et al., 1991; Diamandis and Yousef, 2002) underscored the role of cytokine-mediated communication in aligning and mobilizing the body’s defenses – a critical consideration as the curtains raise on KLK12’s entrée into the arena.
KLK12 may not be working alone; a family of fourteen other kallikreins could potentially join the fight, leading to a network of synergistic activities that amplify the immune response (Clements et al., 2004). As the hunt for innovative drug targets against TB continues, the revelation of how KLK12 tip the scales in favor of the host offers a promising direction for developing potent, enzyme-based therapeutics.
The exhaustive investigations conducted in this field present an optimistic future for combatting tuberculosis. From the dawning realization of the role of kallikreins in disease pathways to the cutting-edge research like that spearheaded by the China Agricultural University team, the step changes in our understanding of infectious disease defense mechanisms are indeed monumental.
With the ongoing work by researchers like Sabir Naveed, Tariq Hussain, and their colleagues around the globe, there’s a growing hope that diseases like tuberculosis, which have for so long cast a shadow over public health, might one day be relegated to the annals of history as ailments conquered by human ingenuity and scientific resolve. As today’s challenges in tuberculosis fight advance, so do the researchers, moving steadfastly into the light of discovery and closer towards a world with less of TB’s burden.
References
1. Hussain, T., Zhao, D., Shah, S. Z. A., Wang, J., Yue, R., Liao, Y., … & Zhou, X. (2019). Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis. Cells, 8(5), 415. https://doi.org/10.3390/cells8050415
2. Yousef, G. M., & Diamandis, E. P. (2003). The new human tissue kallikrein gene family: structure, function, and association to disease. Endocrine reviews, 24(2), 184-204. https://doi.org/10.1210/er.2002-0023
3. Borgoño, C. A., & Diamandis, E. P. (2004). The emerging roles of human tissue kallikreins in cancer. Nature reviews Cancer, 4(11), 876-890. https://doi.org/10.1038/nrc1474
4. Chao, J., Bledsoe, G., & Chao, L. (2006). Protective role of kallistatin in vascular and organ injury. Hypertension, 48(2), 245-254. https://doi.org/10.1161/01.HYP.0000231552.86044.41
5. Catalona, W. J., Smith, D. S., Ratliff, T. L., Dodds, K. M., Coplen, D. E., Yuan, J. J., … & Andriole, G. L. (1991). Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. New England Journal of Medicine, 324(17), 1156-1161. https://doi.org/10.1056/NEJM199104253241702
6. Clements, J., Hooper, J., Dong, Y., & Harvey, T. (2004). The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions. Biological chemistry, 385(7-8), 623-629. https://doi.org/10.1515/BC.2004.068