OVERVIEW Tuberculosis, caused by Mycobacterium tuberculosis (Mtb) is the world’s most deadly infectious disease, recently overtaking HIV.  Despite being curable, progress in the fight against tuberculosis (TB) has been slow: treatment takes at least 6 months of taking multiple antibiotics, and the only available vaccine doesn’t protect most people.  In the Javid lab, we strongly believe that studying the fundamental biology of Mtb is necessary before we can improve current treatment and preventative strategies.

In addition to our focus on TB, our lab has an interest in regulation of gene translation in other systems: including unique aspects of the translational apparatus in human beings.  We welcome expressions of interest from curious, passionate people who want to join us in a collaborative journey of discovery.


Adaptive Mistranslation

 

All biological processes involve error, and the translation of the genetic code into functional proteins is no exception. However, the error rate in gene translation, mistranslation, appears to vary according to cellular context and environment, suggesting regulation. Our group and others have recently shown that mistranslation can actually be adaptive under certain conditions. In particular, Mycobacterium tuberculosis subpopulations or strains with increased mistranslation rates have remarkably increased tolerance to the first-line antibiotic rifampicin. We have recently identified small molecules, e.g. kasugamycin, which can specifically decrease mistranslation rates: intriguingly, treating Mtb-infected mice with kasugamycin suggests that Mtb uses mistranslation to adapt to the host environment: but what triggers stimulate adaptive mistranslation in vivo and in what contexts mistranslation is adaptive are not yet known.

Recent representative publications:

  • Swarnava Chaudhuri, Liping Li, Matthew Zimmerman, Yuemeng Chen, Yu-Xiang Chen, Melody N. Toosky, Michelle Gardner, Miaomiao Pan, Yang-Yang Li, Qingwen Kawaji, Jun-Hao Zhu, Hong-Wei Su, Amanda J. Martinot, Eric J. Rubin, Veronique Dartois* and Babak Javid* (2018): “Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation” eLife 7: e36782 PMID: 30152756
  • Hong-Wei Su, Jun-Hao Zhu, Hao Li, Rong-Jun Cai, Christopher Ealand, Xun Wang, Yu-Xiang Chen, Masood ur Rehman Kayani, Ting F. Zhu, Danesh Moradigaravand, Hairong Huang, Bavesh D. Kana and Babak Javid# (2016): “The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity” Nature Microbiology. 1(11) 16147 PMID: 27564922
Regulation of gene translation “Epigenetic regulation”, i.e. regulation of cellular processes that are not due to changes in DNA, are mostly thought to involve transcriptional regulation, i.e. regulating mRNA expression either directly or via ncRNA etc.  However, it’s becoming increasingly clear that the translation process itself is highly regulated.  We are interested in how gene translation, predominantly in mycobacteria, but also in humans and model organisms such as Drosophila contributes to adaptation to cellular and other stressors.  One specific focus is how different types of ribosomes – alternate ribosomes – may generate differential translational landscapes in response to environmental stimuli.

Recent representative publications:

  • Lluis Ribas de Pouplana, Manuel A S Santos, Jun-Hao Zhu, Philip J Farabaugh & Babak Javid# (2014): “Protein mistranslation: Friend or foe?” Trends in Biochemical Sciences 39(8) 355-362. PMID: 25023410
Mechanisms of antibiotic tolerance Not all bacteria in a drug-susceptible isogenic population respond the same to antibiotics: some subpopulations are killed more slowly, or not all, and this is termed antibiotic tolerance.  Antibiotic tolerance is thought to be the reason that tuberculosis treatment takes at least 6 months, and even then, a significant proportion of patients relapse – without developing drug resistance.  We are interested in studying mechanisms of antibiotic tolerance in Mtb predominantly, but also other pathogens.  We recently identified that in mycobacteria, rifampicin exposure initiates tolerance to itself via upregulation of its cellular target, RpoB.  We have also shown that adaptive mistranslation contributes critically to rifampicin tolerance.  We are now using forward genetics to identify other pathways of antibiotic tolerance in TB.

Recent representative publications:

  • Jun-Hao Zhu, Biwei Wang, Miaomiao Pan, Yu-Na Zeng, Hesper Rego and Babak Javid# (2018): “Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription” Nature Communications 9(1): 4218. PMID: 30310059
Humoral immunity to tuberculosis and host-pathogen interactions We and others recently re-examined the role of humoral (antibody) immunity to tuberculosis.  Previous studies in animals had suggested that it wasn’t very important, but we chose to look in human beings: specifically, healthcare workers in a TB hospital that would have been heavily exposed to Mtb on a daily basis as part of their work.  We found that some of these workers made antibody responses, directed against the cell-surface of Mtb, that protect against the pathogen in vitro and in vivo.  We are now attempting to isolate the monoclonal antibodies mediating protection, and characterise their function.

Recent representative publications:

  • Hao Li and Babak Javid# (2018): “Tuberculosis and antibodies: finally coming of age?” Nature Reviews Immunology 18 591-6. PMID: 29872140
  • Hao Li, Xing-xing Wang, Bin Wang, Lei Fu, Guan Liu, Yu Lu, Min Cao, Hairong Huang* and Babak Javid* (2017): “Latently and uninfected healthcare workers exposed to tuberculosis make protective antibodies against Mycobacterium tuberculosis”. PNAS 114 (19): 5023-5028. PMID: 28438994