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These include corticosteroid treatment, CGD, and near-drowning episodes Hollis et al. The association between Francisella and CGD, in which neutrophils fail to produce fully functional NADPH oxidase and thus reactive oxygen radicals, obviously suggests a role for these mediators in human resistance to infection. The experimental literature now frequently refers to the immunosuppressive nature of infection with virulent Francisella the topic of another chapter in this issue , but naturally infected patients as well as vaccines eventually develop robust and readily measurable T and B cell responses to the bacterium.

These responses have been studied for many years, particularly in regions such as Scandinavia which have appreciable amounts of disease.

An outbreak of ulceroglandular tularemia in Sweden in — provided a unique opportunity to obtain peripheral blood cells from patients within days of infection, and perform large scale transcriptional profiling of human gene expression by microarray Andersson et al. Thus infection in humans may be characterized by both appropriate and subversive types of host reactions.

The major means to diagnose tularemia is still based on four-fold increase of serum antibodies to the bacterium between acute and convalescent sera. Robust specific IgM, IgG, and IgA serum antibodies, much of them directed against Francisella lipopolysaccharide LPS , can be detected roughly simultaneously about 6—10 days after the onset of symptoms, or about 2 weeks after infection. Antibody responses peak between 1 and 2 months after infection, and persist for about a decade before diminishing Koskela and Salminen, Large scale efforts using 2-D gel blotting Janovska et al.

No obvious immunodominant B cell epitopes have been revealed, however, and as a result panels of antigens have been proposed for diagnostic purposes Sundaresh et al.

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As a reference point for further discussion of immune responses generally, here we include a brief summary of human immune responses to the LVS strain. Usually administered by scarification, LVS has been studied in western countries and particularly in the U. These studies have mostly used investigational lots of LVS produced in the s by the Department of the Army; more recently, LVS was re-derived from the original lots, and newly manufactured under modern GMP conditions El Sahly et al.

Microarray studies of gene changes in PBLs from five volunteers obtained between 1 and 14 days after vaccination with LVS indicated a robust up-regulation of expression of pro-inflammatory mediators and genes involved in dendritic cell DC function, which peaked within 2 days Fuller et al.

Similar to natural infection, humans vaccinated with LVS develop specific IgM, IgA, and IgG antibodies in serum about 2 weeks after vaccination that persist for at least 1. However, as noted at the outset, anti-Francisella serum antibodies titers in vaccinated individuals have not been predictive of protection against virulent tularemia, and vaccination with killed bacteria that elicit anti-Francisella antibodies but no detectable cell-mediated immune responses has provided little or no benefits in human studies Francis and Felton, ; Foshay, ; Overholt et al.

Animal Models of Human Immunity to Francisella Detailed consideration of animal models of Francisella infection is well beyond the scope of this article, and a comprehensive recent review is available elsewhere Lyons and Wu, Nonetheless, because the bulk of data on immune responses is currently being generated using animal models of infection, here we include brief summaries of recent developments as they relate to modeling the immune responses of humans for summary, see Table 1.

Characteristics of human Francisella infections compared to current experimental animal models. Both LVS Vonkavaara et al. Both efforts focused on the ability of the model to identify bacterial virulence factors; mutations in bacterial genes important to virulence in mouse models, notably pathogenicity island genes including mglA and others regulated by mglA, clearly contributed to virulence in flies.

Given that deer flies are vectors of Francisella infection, however, it remains to be revealed whether the fly host biology discovered is applicable only to the vector, or also helpful in modeling human responses. Initial efforts to establish Francisella infection of zebrafish, another genetically tractable system that has a more complex immune system than Drosophila, have recently been reported as well.

In the last 3—4 years, new Francisella spp. There was no increase, and perhaps transient down-regulation, of iNOS, however Vojtech et al. Mammalian Infection Models For all the obvious reasons, the majority of immunological studies of Francisella have used mouse models.

The available data indicate that mice are a reasonable model of human immune responses, at least at a first approximation, but less satisfying as a model for pathogenicity. Inbred laboratory strains are readily susceptible to infection with all Francisella isolates tested to date; bacteria disseminate to the same target organs of the reticuloendothelial system, and infected tissues develop granulomatous pathologies that appear roughly comparable to lesions described in tissues of infected people.

There is a major discrepancy between humans and mice in virulence and lethality, however. In mice, the LVS strain establishes a sublethal vaccinating infection when administered via skin inoculation, but kills mice at low doses when introduced by other routes, including intravenous IV , intramuscular, or intraperitoneal IP , and is intermediate for respiratory infections Elkins et al.

In contrast, as noted above, human Type B infections in particular are rarely lethal Staples et al. Human F. To date, there is only one report of Francisella infection of HLA-DR4 transgenic mice, with the goal of uncovering antigens recognized by human T cells Yu et al.

Over the years, other small animal models for Francisella infection have been developed using rats, guinea pigs, hamsters, voles, and rabbits. Several recent reports, coupled with older literature, indicate that infection of Fisher rats with different Francisella strains may better approximate the phenotype of human infections that these other models.

Both Fisher and Lewis rats are much more resistant to F.

Nonetheless, overall the hierarchy of susceptibility of rats appears to generally reflect human Francisella infections, and provide a more satisfying profile than that of mice. Thus this rat strain appears to provide both a useful model for both infection and immunological studies for further analyses.

Despite the practical appeal of small animal models, studies using non-human primates remain important not only for basic studies of host—pathogen interactions but for testing of drugs, vaccines, and therapeutics.

Historically, monkeys have been considered to be even more susceptible than humans to Francisella infection. Outbreaks of tularemia in various species of monkeys in both zoo and experimental colonies have been reported repeatedly Splettstoesser et al.

There is an extensive older literature using monkeys, particularly Rhesus monkeys, for both natural history and vaccination studies Lyons and Wu, ; Kugeler et al.

Most recently, interest in product development has spurred renewed efforts to establish non-human primate models using species currently available for experimental studies.

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Infected marmosets further exhibited production of pro-inflammatory cytokines, as well as increased numbers of the major lymphoid and myeloid cell subpopulations in lungs and blood Nelson et al. While it is premature to draw conclusions about the relative strengths and weaknesses of each of these approaches, further studies will no doubt provide data that informs the value of different non-human primate models for both pathogenesis and immunological studies.

For many years, only F.

Promising preclinical data reviewed in 29 and the demonstration of safety in several clinical trials on MSC treatment in adult lung diseases 36 , 37 have recently brought MSC therapy into clinical development for newborn lung disease.

Specifically, in a single-center, phase I dose-escalation feasibility trial, nine preterm infants Although functional endpoints are beyond the scope of phase I clinical trials, it was noticed that MSC administration was associated with a reduction in inflammatory markers from baseline in the tracheal aspirates of treated infants, and lower BPD severity from the historical case-matched comparison group It is important to note that, although clinical trials are progressing, we lack complete understanding of the mechanism s underlying the therapeutic properties of MSCs.

Earlier hope that MSCs could repair lung tissue by engrafting with high efficiency in the injured lung and transdifferentiating to pneumocytes was subsequently proven to be rather premature and claims supporting it were based on equivocal evidence. The substantial physiologic improvements in the recipient lung following MSC transplantation, in the absence of significant engraftment of donor cells has led to the generally accepted notion that the MSC therapeutic action is mainly through paracrine mechanisms 34 , 39 , Interestingly, we found that treatment with the BMSC secretome specifically BMSC-conditioned media , provided a superior therapeutic capacity over MSCs themselves, providing greater protection in preventing alveolar simplification and preserving the lung architecture They noted that the BMSC-conditioned media accelerated wound healing and enhanced endothelial cord formation in vitro and that human umbilical cord MSC-conditioned media afforded short- and long-term therapeutic benefits without adverse lung effects in a rat model of hyperoxia-induced BPD 35 , 43 , Although the paracrine mode of MSC action is a generally accepted notion, we have not yet clearly defined the precise bioactive moiety responsible for their therapeutic efficacy.

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The complex MSC secretome contains proteins of diverse functions, nucleic acids, morphogens, free fatty acids, genetic information including small non-coding RNA and membrane components Over the last several years a number of these bioactive molecules have been reported to represent the active component s of the MSC secretome, but, in general, studies attempting to recapitulate the effects of MSC-conditioned media in vivo through the administration of the isolated candidate molecule did not yield consistent and reproducible results.

This led to the hypothesis that the therapeutic vector of the MSC secretome was represented by moieties of higher molecular complexity, and in particular, the subclass of extracellular vesicles EVs termed exosomes.

Recent validation of this hypothesis in several preclinical studies creates the promise that exosomes may represent a novel and exciting approach to treating neonatal lung diseases.

Originally assumed to represent a mechanism for the cell to jettison unwanted moieties, the secretion of EVs, and particularly the subclass generated via the endosomal sorting machinery, is now considered to represent an effective method for cell-to-cell communication via the transfer of cellular components 15 , 46 — In turn, exosomes are at the forefront of active research themes for diagnostic, prognostic and therapeutic applications across multiple disciplines As the consequence of a relatively new multi-disciplinary research field, the nomenclature and classification of these vesicles remains abstract.

These sub-classes of vesicles were grouped based on their biogenesis and biophysical properties such as size, density and predominant protein markers. Exosome biogenesis and nomenclature has been extensively reviewed 45 , 46 , 50 — With limitations in current technology, the field currently lacks the ability to analyze exosomes at a single vesicle level. Thus, it is becoming increasingly difficult to uphold one terminology over another.

For the purposes of this review we will just note that it can be particularly misleading to attempt to classify EV subpopulations by size alone, since isolation manipulations often break up larger EVs, generating an artificial heterogeneity in the smaller size subclasses.

Thus, our study has identified a novel LPS modification important for microbial virulence. A mutant lacking this modification may be used as a live attenuated vaccine against tularemia.

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Introduction Francisella tularensis, one of the deadliest respiratory pathogens in existence, is considered a potential biological weapon because it is readily aerosolized and exhibits a high degree of infectivity and lethality in humans. An attenuated live vaccine strain LVS has been developed but has not been licensed as a vaccine because of an incomplete understanding of the basis for its attenuated virulence and associated side effects. There has been a widespread research effort aimed at elucidating Francisella pathogenesis and identifying components for rational vaccine design.

After intranasal infection of mice, F.

This initial delay in inflammation contributes to the ability of F. To suppress the early proinflammatory cytokine response, F. Lipopolysaccharide LPS of F. LPS, the major component of Gram-negative bacterial outer membranes 12 , 13 , itself has three components: i lipid A, a glucosamine-based glycolipid; ii a core oligosaccharide ketosidically linked to lipid A by an eight-carbon sugar, 3-deoxy-d-manno-octulosonic acid Kdo ; and iii the O-antigen polysaccharide comprising multiple repeating units of a complex tetrasaccharide.

The lipid A of many bacterial species such as Escherichia coli is a powerful stimulant of Toll-like receptor 4 TLR4 -mediated innate immune responses. In contrast, F.Insulin resistance and vascular and metabolic programming in adults The conditions altering vascular function during fetal and neonatal life, such as hyperglycemia, 69 gestational diabetes, 70,71 insulin resistance, 72 or hyperoxia 73 promote the development of cardiovascular, metabolic, and endocrine diseases in adult life.

This would explain the associations found between catch-up growth and an increased risk of metabolic syndrome and postnatal obesity.

Except as expressly permitted in this Agreement, Licensee shall not use, modify, copy or distribute the Content or Modifications. The exact mechanism for the occurrence of HBP in children born to mothers with metabolic changes during pregnancy is not fully understood. BPD is a multifactorial chronic lung disorder that occurs almost exclusively in preterm infants receiving supplemental oxygen and mechanical ventilation.

However, as noted earlier, there is a striking lack of crucial pro-inflammatory cytokines during the first 48 h of murine pulmonary Francisella infection.

This trend is likely attributed to advancements in medical care that favor the survival of extremely preterm infants. In a different study, F. Interestingly, we found that treatment with the BMSC secretome specifically BMSC-conditioned media , provided a superior therapeutic capacity over MSCs themselves, providing greater protection in preventing alveolar simplification and preserving the lung architecture Although the paracrine mode of MSC action is a generally accepted notion, we have not yet clearly defined the precise bioactive moiety responsible for their therapeutic efficacy.