Michael Shiloh, M.D., Ph.D.

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)
Residency	University of California at San Francisco (2003), Internal Medicine
Fellowship	University of California at San Francisco (2007), Infectious Disease

• Primary Care - General Internal Medicine

• Primary Interests
• Internal Medicine

• Innate immune response to intracellular pathogens
• Microbial pathogenesis
• Mucosal immunology
• Mycobacterium tuberculosis
• Role of carbon monoxide (CO) in host-pathogen interactions

Featured Publications

Mycobacterium Tuberculosis Activates the DNA-Dependent Cytosolic Surveillance Pathway within Macrophages

Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS Cell Host Microbe 2012 11 5 469-80

Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection.

Shiloh MU, Manzanillo P, Cox JS Cell Host Microbe 2008 May 3 5 323-30

Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens.

Nathan C, Shiloh MU Proc. Natl. Acad. Sci. U.S.A. 2000 Aug 97 16 8841-8

Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase.

Shiloh MU, MacMicking JD, Nicholson S, Brause JE, Potter S, Marino M, Fang F, Dinauer M, Nathan C Immunity 1999 Jan 10 1 29-38

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

To catch a killer. What can mycobacterial models teach us about Mycobacterium tuberculosis pathogenesis?

Shiloh MU, DiGiuseppe Champion PA Curr. Opin. Microbiol. 2010 Feb 13 1 86-92

A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP.

Hisert KB, MacCoss M, Shiloh MU, Darwin KH, Singh S, Jones RA, Ehrt S, Zhang Z, Gaffney BL, Gandotra S, Holden DW, Murray D, Nathan C Mol. Microbiol. 2005 Jun 56 5 1234-45

Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia.

Grobmyer SR, Barie PS, Nathan CF, Fuortes M, Lin E, Lowry SF, Wright CD, Weyant MJ, Hydo L, Reeves F, Shiloh MU, Ding A Crit. Care Med. 2000 May 28 5 1276-82

Reactive nitrogen intermediates and the pathogenesis of Salmonella and mycobacteria.

Shiloh MU, Nathan CF Curr. Opin. Microbiol. 2000 Feb 3 1 35-42

Lethality of endotoxin in mice genetically deficient in the respiratory burst oxidase, inducible nitric oxide synthase, or both.

Nicholson SC, Grobmyer SR, Shiloh MU, Brause JE, Potter S, MacMicking JD, Dinauer MC, Nathan CF Shock 1999 Apr 11 4 253-8

• UTSW High Impact/High Risk Award
  Research award for development of a novel M. tuberculosis vaccine (2012)
• Disease Oriented Clinical Scholar, UTSW
  (2011)
• NIH/NIAID K08 award
  2008-2012 (2008)
• 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)

• Infectious Disease Society of America