| Autor: |
Das M; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India., Sreedharan S; Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India.; School of Chemical and Biotechnology, (SASTRA)-Deemed to be University, Thanjavur 613401, India., Shee S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India., Malhotra N; National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India., Nandy M; National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India., Banerjee U; Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India., Kohli S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India., Rajmani RS; Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India., Chandra N; Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India., Seshasayee ASN; National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India., Laxman S; Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India., Singh A; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India. |
| Abstrakt: |
Iron-sulfur (Fe-S) biogenesis requires multiprotein assembly systems, SUF and ISC, in most prokaryotes. M. tuberculosis ( Mtb ) encodes a complete SUF system, the depletion of which was bactericidal. The ISC operon is truncated to a single gene iscS (cysteine desulfurase), whose function remains uncertain. Here, we show that Mtb Δ iscS is bioenergetically deficient and hypersensitive to oxidative stress, antibiotics, and hypoxia. Mtb Δ iscS resisted killing by nitric oxide (NO). RNA sequencing indicates that IscS is important for expressing regulons of DosR and Fe-S-containing transcription factors, WhiB3 and SufR. Unlike wild-type Mtb , Mtb Δ iscS could not enter a stable persistent state, continued replicating in mice, and showed hypervirulence. The suf operon was overexpressed in Mtb Δ iscS during infection in a NO-dependent manner. Suppressing suf expression in Mtb Δ iscS either by CRISPR interference or upon infection in inducible NO-deficient mice arrests hypervirulence. Together, Mtb redesigned the ISC system to "fine-tune" the expression of SUF machinery for establishing persistence without causing detrimental disease in the host. |
