Abstract
Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis (Mtb) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the M. bovis infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the M. bovis infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in M. bovis infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1β, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-β expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in M. bovis infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the M. bovis infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.
Highlights
Tuberculosis (TB) is a major health threat to human and animal populations causing high morbidity and mortality worldwide
To determine whether kallikrein-related peptidase 12 (KLK12) plays a role in the immune responses against the M. bovis infection, we investigated the expression of KLK12 in vivo and in vitro
We infected bone marrow derived macrophages (BMDMs) and RAW264.7 cells with M. bovis C68004 at a multiplicity of infection (MOI) of 10 and incubated for indicated time periods, i.e., 0, 6, 12, 18 and 24 h. qRT-PCR results indicated an elevated expression of KLK12 in a time-dependent manner (Figure 1D,F)
Summary
Tuberculosis (TB) is a major health threat to human and animal populations causing high morbidity and mortality worldwide. The disease is caused by the Mycobacterium tuberculosis complex (MTC) and M. bovis is an important member of MTC which is genetically more than 99% identical to. M. bovis can cause TB in human and multiple species of animals including cattle. Cells 2019, 8, 415 with a similar disease profile and host immune response. It is estimated that it infects more than 50 million cattle per annum with global economic losses of approximately $3 billion [3]. M. bovis is responsible for 2.8% of all human TB cases in Africa and it accounts for 7.6% of human TB cases in Mexico [4] while in a more recent study in Mexico, 30.2% of human TB was caused by M. bovis [5]
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