Our laboratory studies the ability of aerobic bacterial pathogens to exist in non-replicating states that are distinct from the replicating bacteria most often studied. We hypothesize that these states are central to the pathogens survival during latent infections and their ability to tolerate conventional drug treatment. The physiological state of Mycobacterium tuberculosis during latent infection has been a focus of our research. A primary reason for the continued threat from M. tuberculosis lies in its ability to establish an asymptomatic latent infection, which serves as a reservoir for future infections. One-third of the world's population is latently infected with tuberculosis and current treatment of latent infections is inefficient. Little is known about the nature of the latent state including the physiological and metabolic state of the bacilli. In vitro studies demonstrate M. tuberculosis, an obligate aerobe, has the ability to undergo a distinct physiologic adaptation to a non-respiring state in response to low O2 levels and or the presence of the respiratory stresses, nitric oxide (NO) and carbon monoxide (CO). The respiratory stress-induced state is marked by bacteriostasis, in addition to metabolic, chromosomal, and structural changes in the bacteria. These stresses instigate a rapid and dramatic induction of a set of 48 genes (DosR regulon) in M. tuberculosis. These genes are coordinately regulated and encode functions that are essential for survival in the absence of aerobic respiration. NO, CO and O2 levels modulate the induction of the DosR regulon and concurrently control bacterial respiration and growth. It appears that control of respiration by NO and CO production and O2 deprivation via granuloma formation are potent components of immune control of M. tuberculosis. However, the bacilli have evolved mechanisms to survive and persist during the growth arresting state produced by active immune pressure. Research in my laboratory utilizes genetic, microarray, metabolomic, biochemical, and animal studies to investigate the mechanisms employed by M. tuberculosis to survive during latent infection, with a particular focus on the role of the DosR regulon and the central metabolic processes essential in the absence of aerobic respiration.
A second project in our laboratory involves the study of the potential bioterrorism agent Burkholderia pseudomallei. B. pseudomallei and M. tuberculosis share striking similarities in their fundamental biology and disease characteristics. These organisms are aerobes although they maintain a repertoire of anaerobic metabolism genes. Both pathogens are responsible for granulomatous pulmonary infections and B. pseudomallei infections are often misdiagnosed as tuberculosis and often are characterized by large oxygen-restricted abscesses. Interestingly, both infections can also result in long periods of clinical latency. Perhaps the most important similarity for control of these infections is the necessity of months of antimicrobial treatment which often fails. Thus, a fraction of bacteria are capable of existing in a drug tolerant state. We hypothesize that a small portion of a B. pseudomallei population can shift into persistent state in response to respiratory stress and is tolerant to most antimicrobial therapy. The persistent state of B. pseudomallei and how it relates to drug tolerance is the focus of our B. pseudomallei research.