Microbial Persistence

Abstract

Microbial persistence is the term used to signify the phenomenon whereby microbes that are susceptible to a drug in vitro can nevertheless survive long continued exposure to it in vivo (1, 2).An unusual form of microbial persistence displayed by tubercle bacilli of human origin was described in previous reports from this laboratory (3-5). Relatively large populations of bacilli (one to three million cells) could be made to "vanish" uniformly from the tissues of mice that had received two compounds; the nicotinamide derivative pyrazinamide, and isoniazid, in appropriate time-dose relationships. The criteria for "vanishing" were failure to detect any bacilli by; microscopy, culture, or guinea pig inoculation of the tissues of the infected mice. The "vanishing" did not mean that the bacilli were totally eliminated from the tissues. On the contrary, after a 90 day treatment-free interval, culturable tubercle bacilli could be demonstrated in approximately one-third of the animals. The question immediately arose whether all of the tubercle bacilli had been eradicated in the other two-thirds of the animals in each experiment, or whether the bacilli were still present in them but were in a iatent state.By latent is meant a phase during which the infection is hidden beyond all diagnostic reach. In such a phase, the bacilli conceivably could be present in some altered form or they could be unaltered, but so few in number tl~t they escape detection. In view of the demonstrated sensitivity of the culture techniques employed, it seemed clear that at the most only a very few ~naltered bacilli could be present and escape detection. It was noted (4), however, that if a microbial alteration took the form of sterilization without death, fairly large populations, being nonculturable, might vanish from the tissues because of the insensitivity of microscopy as a detection technique. In the studies reported (3), acid-fast bacilli could not be found with any regularity on microscopy of tissue sections when the organ census was below I × 105 per ml and only

Microbial Persistence

“…The census of culturable tubercle bacilli in the homogenates of the lungs and spleens of periodically sacrificed sample subgroups is determined at the start of therapy or cortisone administration, during and at the completion of the period of drug administration, and at designated periods thereafter. As was previously reported (1), with a very few exceptions, no tubercle bacilli capable of multiplication in mice, guinea pigs, or cell-free or cell-containing cultures, were demonstrable at the point 12 wk after the start of drug administration or in the succeeding month. Variations of this basic model are set forth in the individual experiments below.…”

“…The basic model used in these experiments has been described in the preceding report (1) and in previous publications (2,3). In its essentials, it consists of: infecting large numbers of * This study was supported in part by Public Health Service Research Grant AI00635 from the National Institute of Allergy and Infectious Diseases; by grants from the National Tuberculosis Association-American Thoracic Society, the New York Tuberculosis and Health Association, and the Philip Hanson Hiss, Jr., Memorial Fund.…”

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

“…In humans, both M. tuberculosis and M. bovis [27] can give rise to a clinically latent form that can be reactivated decades after the initial exposure. It is not clear whether mycobacteria in the Cornell model, an antibiotics-induced model for latency in mice, go into a true dormant state [28,29]. After treatment, bacteria cannot be detected in these mice, but reappear after a certain amount of time.…”

“…So, even though cattle may be the species in which latency resembles human latency optimally, there is a long road to go before a bovine model of latent tuberculosis is available, for example for testing post exposure vaccines against latency antigens. Research aiming at the development of a bovine model of latent tuberculosis may include the use of mycobacteria that are attenuated in cattle, like M. tuberculosis [32,33], or experimental treatment of M. bovis-infected animals with antibiotics in a way that is comparable to the Cornell model in mice [28,29].…”

Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

“…In addition, Ag85A DNA vaccine showed a better therapeutic effect than IL-12N220L DNA vaccine, suggesting the potential use of Ag85A DNA vaccine in combination with chemotherapy as a therapeutic agent against TB for the prevention of TB reactivation as well as for the effective cure of TB in humans. 27 In contrast, the treatment of infected mice with INH and PZA for 6 months prevented the appearance of detectable bacterial numbers either at 30 or 42 weeks postinfection (2 or 14 weeks after the completion of 6-month chemotherapy) ( Table 1). In addition, even at 80 weeks postinfection (52 weeks after the completion of 6-month chemotherapy), no reactivation of M. tuberculosis was found in the lungs or spleens, indicating that chemotherapy over 6 months prevented M. tuberculosis reactivation.…”