Vaccine-Mediated Mechanisms Controlling Replication of Francisella tularensis in Human Peripheral Blood Mononuclear Cells Using a Co-culture System

To quantify the efficacy of BCG vaccine against tuberculosis (TB). MEDLINE with index terms BCG vaccine, tuberculosis, and human. Experts from the Centers for Disease Control and Prevention and the World Health Organization, among others, provided lists of all known studies. A total of 1264 articles or abstracts were reviewed for details on BCG vaccination, concurrent vaccinated and unvaccinated groups, and TB outcome; 70 articles were reviewed in depth for method of vaccine allocation used to create comparable groups, equal surveillance and follow-up for recipient and concurrent control groups, and outcome measures of TB cases and/or deaths. Fourteen prospective trials and 12 case-control studies were included in the analysis. We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, and items to assess the potential for bias in study design and diagnosis. At least two readers independently extracted data and evaluated validity. The relative risk (RR) or odds ratio (OR) of TB provided the measure of vaccine efficacy that we analyzed. The protective effect was then computed by 1-RR or 1-OR. A random-effects model estimated a weighted average RR or OR from those provided by the trials or case-control studies. In the trials, the RR of TB was 0.49 (95% confidence interval [CI], 0.34 to 0.70) for vaccine recipients compared with nonrecipients (protective effect of 51%). In the case-control studies, the OR for TB was 0.50 (95% CI, 0.39 to 0.64), or a 50% protective effect. Seven trials reporting tuberculous deaths showed a protective effect from BCG vaccine of 71% (RR, 0.29; 95% CI, 0.16 to 0.53), and five studies reporting on meningitis showed a protective effect from BCG vaccine of 64% (OR, 0.36; 95% CI, 0.18 to 0.70). Geographic latitude of the study site and study validity score explained 66% of the heterogeneity among trials in a random-effects regression model. On average, BCG vaccine significantly reduces the risk of TB by 50%. Protection is observed across many populations, study designs, and forms of TB. Age at vaccination did not enhance predictiveness of BCG efficacy. Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy.

Francisella tularensis has been recognized as a human pathogen for almost 100 years and is the etiological agent of the zoonotic disease tularemia. Soon after its discovery, it became recognized as an important pathogen in several parts of the world, for example, in the United States and Soviet Union. The number of tularemia cases in the two countries peaked in the 1940s and has thereafter steadily declined. Despite this decline, there was still much interest in the pathogen in the 1950s and 1960s since it is highly infectious and transmissible by aerosol, rendering it a potent biothreat agent. In fact, it was one of the agents that was given the highest priority in the offensive programs of the United States and Soviet Union. After termination of the offensive programs in the 1960s, the interest in F. tularensis diminished significantly and little research was carried out for several decades. Outbreaks of tularemia during the last decade in Europe, for example, in Kosovo, Spain, and Scandinavia, led to a renewed public interest in the disease. This, together with a massive increase in the research funding, in particular in the United States since 2001, has resulted in a significant increase in the number of active Francisella researchers. This article summarizes, predominantly with a historical perspective, the epidemiology and clinical manifestations of tularemia and the physiology of F. tularensis.

The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines IL-1β and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella novicida. AIM2 activation by F. novicida requires bacteriolysis, yet whether this process is accidental or a host-driven immune mechanism remained unclear. Using siRNA screening for nearly 500 interferon-stimulated genes, we identified guanylate-binding proteins GBP2 and GBP5 as key AIM2 activators during F. novicida infection. Their prominent role was validated in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs target cytosolic F. novicida and promote bacteriolysis. Thus, besides their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.