Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress

Abstract

Mycobacterium tuberculosis (Mtb) is the main pathogenic agent of tuberculosis (TB), a leading cause of death due to an infectious disease worldwide (WHO, 2018). About a third of the world's population is estimated to have latent TB infection, reflecting Mtb's ability to survive in the human host as bacterial subpopulations in heterogeneous states that range from replicative to non-replicative, with differing sensitivities to antibiotics (Gold and Nathan, 2017). Mtb can reside in acidic host environments, as evidenced by the avirulence of acid-susceptible mutants in mice and the activity of the front-line TB drug pyrazinamide, which becomes active against Mtb in vitro under acidic conditions (

Structural basis for aggregate dissolution and refolding by the Mycobacterium tuberculosis ClpB-DnaK bi-chaperone system

“…Anti-DnaK rabbit antisera (Harnagel et al, 2021) anti-ClpB rabbit antisera (Vaubourgeix et al, 2015) anti-SigA affinity purified antisera, EZBiolab…”

The Role of ClpB in Bacterial Stress Responses and Virulence

“…Besides promoting stress tolerance, ClpB plays an important role in invasiveness and/or host survival of multiple important bacterial pathogens (Table 1), such as Leptospira interrogans, Yersinia enterocolitica, Francisella noatunensis, F. tularensis, Piscirickettsia salmonis, Mycoplasma pneumoniae, Salmonella typhimurium, Mycobacterium tuberculosis, Porphyromonas gingivalis, Enterococcus faecalis, Listeria monocytogenes, and Staphylococcus aureus (Badger et al, 2000;Chastanet et al, 2004;Frees et al, 2004;Yuan et al, 2007;Capestany et al, 2008;Kannan et al, 2008;Conlan, 2011;de Oliveira et al, 2011; Lourdault et al, 2011;Alam et al, 2018Alam et al, , 2020Sangpuii et al, 2018;Harnagel et al, 2020;Kêdzierska-Mieszkowska and Arent, 2020;Tripathi et al, 2020). In the case of L. interrogans, the causative agent of the emerging zoonotic disease leptospirosis, a clpB mutant not only showed enhanced susceptibility to high temperature, nutrient-depletion, and oxidative stress, but was also attenuated in a gerbil animal model of acute leptospirosis (Lourdault et al, 2011;Kêdzierska-Mieszkowska and Arent, 2020).…”

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

“…Additionally, bacteria are constantly subject to stress conditions, including heat/cold shock, oxidative stress, osmotic shock, heavy metal toxicity, changes in hydrostatic pressure, the presence of drugs, as well as host organism mounted-stresses in response to infections such as chemical stresses (e.g. reactive oxygen and nitrogen species), the presence of antibiotics or the elevated temperature from fever ( Ehrt and Schnappinger, 2009 ; Dahl et al, 2015 ; Harnagel et al, 2020 ). The exposure of bacteria to these pressures as well as the complexity of metabolic changes that arise in response to these pressures can cause significant perturbations of bacterial proteostasis ( Morano et al, 2012 ; Gayán et al, 2017 ).…”

“…For example, DnaK/DnaJ and TF have overlapping sets of substrates and one can compensate for the absence of the other—but a combined deletion of both is lethal above 30°C ( Deuerling et al, 1999 ; Deuerling et al, 2003 ). Similarly, while the individual loss of neither HtpG (an Hsp90-homologue) nor ClpB (a disaggregase) is lethal to Mycobacterium tuberculosis , cells lacking both these chaperones become hypersensitive to host-like stresses and go into a nonreplicating state ( Harnagel et al, 2020 ). Tampering with the clearance of protein aggregates also has severe consequences for bacteria.…”

“…Tampering with the clearance of protein aggregates also has severe consequences for bacteria. For example, cells lacking the ClpB disaggregase become more sensitive to heat or oxidative stress ( Harnagel et al, 2020 ). Based on these observations, inhibitors targeting the chaperone system such as DnaK inhibitors ( Czihal et al, 2012 ) and HSP60/10 chaperonin system inhibitors ( Stevens et al, 2019 ) have been put forth as antibiotic strategies but it remains to be seen whether sufficient specificity toward bacterial chaperones over mammalian counterparts can be achieved.…”