A mouse model for tularemia

In this recent paper co-authored by a large group of Researchers at the Department of microbiology and immunolgy, UTMB, Galveston, it is demonstrated for the first time that mice infected via intranasal challenge with virulent Francisella tularensis strain SCHU S4 and then treated with levofloxacin developed protective immunity against subsequent lethal intranasal challenge with SCHU S4. Furthermore, sera from these protected mice was shown to be protective when passively transferred to normal, naive, mice. The full paper can be found at the site of the Journal VACCINE.

The ability to protect mice against respiratory infections with virulent Francisella tularensis has been problematic and the role of antibody-versus-cell-mediated immunity controversial. In this study, we tested the hypothesis that protective immunity can develop in mice that were given antibiotic therapy following infection via the respiratory tract with F. tularensis SCHU S4. We show that mice infected with a lethal dose of SCHU S4, via an intra-nasal challenge, could be protected with levofloxacin treatment. This protection was evident even when levofloxacin treatment was delayed 72h post-infection. At early time points after levofloxacin treatment, significant numbers of bacteria could be recovered from the lungs and spleens of mice, which was followed by a dramatic disappearance of bacteria from these tissues. Mice successfully treated with levofloxacin were later shown to be almost completely resistant to re-challenge with SCHU S4 by the intra-nasal route. Serum antibody appeared to play an important role in this immunity. Normal mice, when given sera from animals protected by levofloxacin treatment, were solidly protected from a lethal intra-nasal challenge with SCHU S4. The protective antiserum contained high titers of SCHU S4-specific IgG2a, indicating that a strong Th1 response was induced following levofloxacin treatment. Thus, this study describes a potentially valuable animal model for furthering our understanding of respiratory tularemia and provides suggestive evidence that antibody can protect against respiratory infections with virulent F. tularensis.

This mouse model could be helpful in identifying F. tularensis antigens that elicit the formation of protective antibodies. The model might also yield valuable insight into a number of questions still unanswered with regard to protective immunity against inhalation infection with virulent Francisella.

Human Dendritic Cells Phagocytose But Fail to Kill Francisella Tularensis

This paper on Tularemia was published in Journal of Leukocyte Biology in 2005. It described the interaction of Francicella tularensis (Ft) with human dendritic cells (DCs), and showed the importance of complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in the opsonophagocytosis of Ft by DCs.

Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1ß, and TNF-) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.

This paper wasfollowed by a paper that described in details the interactions between the complement sytem and Ft. The whole paper can be read Here if you subscribe to the journal. 

Complement Opsonins are deposited at the surafce of Francisella Tularensis, an intracellular Bacteria that Subverts Complement Activation

This recent article published in the Journal of leukocyte Biology in July 2008 describes how francisella tularencis (Ft), an intracellular bacteria subverts an important innate immune system module: the complement system. This paper provides a detailed analysis of the early complement activation pathways at the level of C3b/C4b. It is shown that Ft activates both the classical and alternative pathways of complement in non-immune human serum and that deposition of C3 appear to play a significant role in the phagocytosis of bacteria by immature human dendritic cells (DC). The analysis of complement activation pathways showed that the Ft exploits human complement in order to facilitate its own uptake by phagocytic cells, while, at the same time, it binds regulators of complement activation (RCAs) that promote its resistance to complement lysis. The preliminary results show that Ft expresses fH-binding proteins, which are proposed to be responsible for the resistance of Ft to complement-mediated killing. The summury for this article is reproduced here but the full article can be accessed at the Journal's page.

Francisella tularensis (Ft) is resistant to serum but requires complement factor C3-derived opsonins for uptake by phagocytic cells and subsequent intracellular growth. In this study, we show that C3 fragments, deposited on Ft, are detected by anti-C3d and -iC3b mAb and that the classical and the alternative pathways are involved in this event. This was demonstrated using C2-depleted sera and specific inhibitors of the classical-versus-alternative pathways of complement activation. Further, we demonstrate that factor C4b, which is crucial for the classical pathway, is deposited on the surface of Ft. In contrast, the C5b-C9 membrane attack complex (MAC) is not assembled on the surface of Ft, which may explain its resistance to complement killing.
Deposition of C3 opsonins leads to enhanced phagocytosis by human immature dendritic cells (DC), which leads to intracellular survival, growth, and DC death. Finally, we show that factor H (fH) can bind to the surface of Ft. We believe our data suggest that important virulence factors for Ft are its ability to bind fH and inactivate C3b to iC3b, which culminates in opsonin-induced uptake for subsequent intracellular growth. C3b inactivation also leads to inefficient MAC assembly, which contributes to the ability of this bacterium to resist complement lysis.

Published Articles--Genetic disorders

This article was originally written for Gale Encyclopedia of Genetic Disorders Part II. This quote is reproduced from http://www.healthline.com/.

Variations within the DNA sequence of a particular gene affect its function, and may cause or predispose an individual a particular disease. Alterations in the genome may increase the frequency of disorder and disease with entire populations.
Although there are many types of genetic disorders, a specific disorder does not have to be inheritable to have a genetic basis. For example, non-heritable disorders can also arise from mutations in somatic cells resulting from exposure to mutagenic factors in the environment. Mutations, whether inherited mutations that appear in every cell of the body, or random mutations affecting a particular cell, can cause groups of cells to grow out of control, or inhibit the processes (contact inhibition processes) that normally prevent this from happening.

http://www.healthline.com/galecontent/genetic-disorders-3