Cathepsins and Their Endogenous Inhibitors in Host Defense During Mycobacterium tuberculosis and HIV Infection

Abstract

The moment a very old bacterial pathogen met a young virus from the 80’s defined the beginning of a tragic syndemic for humanity. Such is the case for the causative agent of tuberculosis and the human immunodeficiency virus (HIV). Syndemic is by definition a convergence of more than one disease resulting in magnification of their burden. Both pathogens work synergistically contributing to speed up the replication of each other. Mycobacterium tuberculosis (Mtb) and HIV infections are in the 21st century among the leaders of morbidity and mortality of humankind. There is an urgent need for development of new approaches for prevention, better diagnosis, and new therapies for both infections. Moreover, these approaches should consider Mtb and HIV as a co-infection, rather than just as separate problems, to prevent further aggravation of the HIV-TB syndemic. Both pathogens manipulate the host immune responses to establish chronic infections in intracellular niches of their host cells. This includes manipulation of host relevant antimicrobial proteases such as cathepsins or their endogenous inhibitors. Here we discuss recent understanding on how Mtb and HIV interact with cathepsins and their inhibitors in their multifactorial functions during the pathogenesis of both infections. Particularly we will address the role on pathogen transmission, during establishment of intracellular chronic niches and in granuloma clinical outcome and tuberculosis diagnosis. This area of research will open new avenues for the design of innovative therapies and diagnostic interventions so urgently needed to fight this threat to humanity.

Spatial localization of cathepsins: Implications in immune activation and resolution during infections

“…CTS emerge therefore as relevant players in the extracellular space as full degrading enzymes of ECM components, but the paradigm is now changing to enzymes that can specifically modify other extracellular proteins. Their secretion and activity are often dysregulated during inflammatory responses including infection [recently reviewed in ( 28 )].…”

“…CTS secretion to ECM is usually high during infection. Microorganisms are sensed by innate immune receptors in mucosal cells that respond with an increased secretion of a myriad of proteases including antimicrobial peptides and CTS all having antimicrobial effects ( 28 , 104 , 107 ). This is the case of CTS K, highly expressed in intestinal Goblet cells, or CTS G, secreted from Paneth cells, that contributes to pathogen and microbiota control, and epithelial barrier repair ( 104 , 107 ).…”

“…This is the case of CTS K, highly expressed in intestinal Goblet cells, or CTS G, secreted from Paneth cells, that contributes to pathogen and microbiota control, and epithelial barrier repair ( 104 , 107 ). In bronchial mucosa a protective effect was attributed to CTSs B and L ( 28 ) while CTS S, expressed mainly in macrophages, may favor the motility of cilia by preventing unspecific binding with airway circulating proteins ( 6 ).…”

“…The extensive destruction of lung parenchyma in tuberculosis is related with high levels of CTSs K, S, and V ( 114 ). CTSs G and D favor autolysis inside tuberculosis granulomas contributing to their liquefaction and disruption thus facilitating pathogen dissemination ( 28 , 115 ).…”

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

“…Ultimately, endogenous protein inhibitors regulate the activity of mature cathepsins that escape endo/lysosomal vesicles and are present in the cytoplasm or extracellular space or bound to the plasma membrane. Several groups of endogenous inhibitors of cysteine, serine, and metallopeptidases have been shown to impair secreted or misdirected lysosomal cathepsins, including cystatins, serpins, and tissue inhibitors of metallopeptidases [ 61 , 62 ]. Nevertheless, certain exceptions, such as cystatins M and F, can enter the endo/lysosomal pathway and regulate intralysosomal peptidase activity [ 62 ].…”