Mycobacterium tuberculosis
uses its ESX-1 system to secrete EsxA and EspB into a host to cause disease. We show that EspK, a protein whose role in the ESX-1 machinery was thought to be nonessential, is needed by
M. tuberculosis
for optimal EsxA and EspB secretion.
Mycobacterium
tuberculosis (M. tb) uses its type-7 secretion
system ESX-1 to translocate key virulence
effector proteins. Taking a chemical genetics approach, we demonstrate
for the first time the importance of mycobacterial proteostasis to
ESX-1. We show that individual treatment with inhibitors of protein
synthesis (chloramphenicol and kanamycin) and protein degradation
(lassomycin and bortezomib), at concentrations that only reduce M. tb growth by 50% and less, specifically block ESX-1 secretion
activity in the tubercle bacillus. In contrast, the mycobacterial
cell-wall synthesis inhibitor isoniazid, even at a concentration that
reduces M. tb growth by 90% has no effect on ESX-1
secretion activity. We also show that chloramphenicol but not isoniazid
at subinhibitory concentrations specifically attenuates ESX-1-mediated M. tb virulence in macrophages. Taken together, the results
of our study identify a novel vulnerability in the ESX-1 system and
offer new avenues of anti-TB drug research to neutralize this critical
virulence-mediating protein secretion apparatus.
Domestic pigs share many similarities with humans in their pulmonary anatomy, physiology, and immunology. Accordingly, pigs have been shown to be valuable models to study human tuberculosis (TB). Here we examined the outcome of disease in domestic pigs challenged via two different routes with either the human-adapted TB bacillus Mycobacterium tuberculosis or the zoonotic bovine TB bacillus M. bovis in head-to-head comparisons. We found that pigs challenged intravenously with M. bovis AF2122/97 exhibited severe morbidity and rapid onset of mortality, accompanied by higher tissue bacterial burden and necrosis compared to pigs challenged similarly with M. tb Erdman. Concordantly, pigs challenged with aerosolized M. bovis AF2122/97 exhibited reduced weight gain and more severe pathology than pigs challenged similarly with M. tb Erdman. Moreover, pigs aerosol-challenged with M. bovis AF2122/97 exhibited a spectrum of granulomatous lesions ranging from small well-contained granulomas to caseous-necrotic lesions mimicking active TB disease in humans. In contrast, pigs aerosol-challenged with M. tb Erdman exhibited arrested granuloma development. Irrespective of challenge dose and pathological outcome however, peripheral IFN-γ responses were similar in both M. bovis AF2122/97 and M. tb Erdman challenged pigs. This study demonstrates domestic pigs can support infections with M. bovis and M. tb and develop pathology similar to what is observed in humans. And although M. bovis AF2122/97 appears to be more virulent than M. tb Erdman, both strains can be used to model TB in domestic pigs, depending on whether one wishes to recapitulate either acute and active TB or latent TB infections. Keywords: Tuberculosis, domestic pigs, animal model, active TB, latent TB
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