Tuberculosis is a global epidemic that annually accounts for more than 3 million deaths worldwide. Because of the capacity of M. tuberculosis to establish a latent infection, an estimated 2 billion people worldwide are infected with M. tuberculosis. Immunodeficiency caused by malnutrition, old age or HIV infection enhances development of active disease, either from a primary infection or more likely from reactivation of a latent infection. However, the environmental cues responsible for initiating latent infection in the host are not clearly understood. We previously showed that the gas carbon monoxide (CO) produced by host macrophages triggers a dormancy response in mycobacteria mediated by a bacterial two-component system. We also showed that carbon monoxide is well tolerated by mycobacteria, suggesting that mycobacteria can resist CO toxicity, and further have recently discovered a novel gene in M. tuberculosis that affords such resistance. We are currently characterizing the role of this gene in CO resistance, including its precise biochemical mechanism, interacting partners, metabolic effects and role in pathogenesis. Furthermore, we are identifying additional CO resistance genes and characterizing their functions and role in pathogenesis.
In addition to studying the role of carbon monoxide in M. tuberculosis pathogenesis, we are broadly interested in the metabolic and physiologic adaptations of M. tuberculosis during latency. Because successful M. tuberculosis infection occurs as a consequence of complex interactions with the host, we also are studying unique cellular and immunologic responses of the host that facilitate M. tuberculosis survival. Our hope is to identify novel microbial and host factors that can be inhibited or modulated to improve the treatment or prevention of tuberculosis.
- Medical School
- Cornell University Medical College (2001)
- University of California, San Francisco (2003), Internal Medicine
- University of California at San Francisco (2007), Infectious Diseases
- Innate immune response to intracellular pathogens
- Microbial pathogenesis
- Mucosal immunology
- Mycobacterium tuberculosis
- Role of carbon monoxide (CO) in host-pathogen interactions
- Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection.
- Nair VR, Franco LH, Zacharia VM, Khan HS, Stamm CE, You W, Marciano DK, Yagita H, Levine B, Shiloh MU Cell Rep 2016 Jul
- Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection.
- Scharn CR, Collins AC, Nair VR, Stamm CE, Marciano DK, Graviss EA, Shiloh MU J. Immunol. 2016 Jun 196 11 4641-9
- Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis.
- Collins AC, Cai H, Li T, Franco LH, Li XD, Nair VR, Scharn CR, Stamm CE, Levine B, Chen ZJ, Shiloh MU Cell Host Microbe 2015 Jun
- Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus.
- Stamm CE, Collins AC, Shiloh MU Immunol. Rev. 2015 Mar 264 1 204-19
- The ubiquitin ligase parkin mediates resistance to intracellular pathogens.
- Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS Nature 2013 Sep 501 7468 512-6
- cor, a Novel Carbon Monoxide Resistance Gene, Is Essential for Mycobacterium tuberculosis Pathogenesis.
- Zacharia VM, Manzanillo PS, Nair VR, Marciano DK, Kinch LN, Grishin NV, Cox JS, Shiloh MU MBio 2013 4 6
- EBV-driven HIV-associated diffuse large B-cell lymphoma causing profound lactic acidosis.
- Prokesch BC, Shiloh MU Blood 2014 Aug 124 6 842
- Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages.
- Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS Cell Host Microbe 2012 May 11 5 469-80
- Effect of carbon monoxide on Mycobacterium tuberculosis pathogenesis.
- Zacharia VM, Shiloh MU Med Gas Res 2012 2 1 30
- Mycobacterium tuberculosis MycP1 protease plays a dual role in regulation of ESX-1 secretion and virulence.
- Ohol YM, Goetz DH, Chan K, Shiloh MU, Craik CS, Cox JS Cell Host Microbe 2010 Mar 7 3 210-20
Honors & Awards
- The Department of Internal Medicine Chairs Pilot Awards
A Synthetic Lethal Genetic Interaction Map in Mycobacterium tuberculosis (2015-2017)
- UTSW High Impact/High Risk Award
Research award for development of a novel M. tuberculosis vaccine (2012)
- Disease Oriented Clinical Scholar, UTSW
- NIH/NIAID K08 award
- Sandler Family Foundation Discovery Award
Research award for highly innovative research (2006)
- Giannini Family Foundation Research Fellowship, 2005-2008
Honors research fellows in the state of California (2005)
- American Association of Immunologists (2014)
- American Society of Microbiology (2013)
- Infectious Disease Society of America (2010)