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Streptococcus sanguinis is a major component of the oral flora and an important cause of infective endocarditis. Although S. sanguinis is naturally competent, genome sequencing has suggested significant differences in the S. sanguinis competence system relative to those of other streptococci. An S. sanguinis mutant possessing an in-frame deletion in the comC gene, which encodes competence-stimulating peptide (CSP), was created. Addition of synthetic CSP induced competence in this strain. Gene expression in this strain was monitored by microarray analysis at multiple time-points from 2.5 to 30 min after CSP addition, and verified by quantitative reverse transcription-polymerase chain reaction. Over 200 genes were identified whose expression was altered at least two-fold in at least one time point, with the majority upregulated. The 'late' response was typical of that seen in previous studies. However, comparison of the 'early' response in S. sanguinis with that of other oral streptococci revealed unexpected differences with regard to the number of genes induced, the nature of those genes, and their putative upstream regulatory sequences. Streptococcus sanguinis possesses a comparatively limited early response, which may define a minimal streptococcal competence regulatory circuit.

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OBJECTIVE: To examine the memory immunity expressed in the lung in response to a low-dose aerosol challenge. DESIGN: Memory-immune C57BL/6 mice were generated by infection followed by drug treatment with isoniazid and rifabutin. Both memory-immune and naive mice were then rechallenged via both the aerosol and intravenous routes. The growth of bacteria in target organs, the expression of cytokines within these organs and the ability of T cells to recognize selected mycobacterial protein antigens were determined over time. RESULTS: There was a finite delay before immunity was expressed in the lungs of the memory-immune mice. This was in contrast to the immediate control of bacterial growth seen in the liver of intravenously challenged mice. In both cases, the expression of interferon-gamma (IFN-gamma) mRNA in the target organ correlated with the control of bacterial growth. Memory immunity in the spleen and lung differed: whereas splenic T cells strongly recognized the major Ag85 protein, the 45 kDa protein, and a synthetic peptide representing the ESAT molecule, only the Ag85 molecule was recognized by T cells harvested from thoracic lymph nodes after pulmonary rechallenge. CONCLUSIONS: Immunity, as mediated by IFN-gamma, is expressed more slowly following an aerosol rechallenge and appears to be restricted in terms of antigen specificity. Moreover, very strong levels of memory immunity can prevent progressive disease in the lungs, but cannot prevent the establishment of secondary infection.

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Previous work in this laboratory has led to the development of the hypothesis that the increased susceptibility of old mice to tuberculosis infection reflects a limited ability by immune CD4 mediator cells to accumulate at sites of bacterial implantation. To test this hypothesis with very low dose infections, the present study documented the course of a low-dose aerogenic infection with virulent Mycobacterium tuberculosis Erdman against time in the target organs of young (3-month-old) and old (24-month-old) B6D2F1 hybrid mice. The results of the study indicated that the infection was controlled by the two groups of mice at similar rates, although the bacterial load in the old mice was eventually somewhat higher. Despite these similarities, some subtle differences between the young and old mice were also evident and included evidence of increased hematogenous spread of the infection from the lungs to other organs in the old mice. Interestingly, very poor expression of the cytokine interleukin-12 was observed in the lungs of infected old mice, leading to the hypothesis that the poor CD4 response in such animals could be partially attributed to the lack of this Th1-type, CD4 T-cell-enhancing cytokine. In this regard, treatment of old mice with exogenous interleukin-12 increased resistance and promoted gamma interferon secretion by CD4 T cells from these mice, although the effects were generally modest. These data suggest that old mice possess CD4-independent compensatory mechanisms by which to deal with low-dose pulmonary tuberculosis infections, although such mechanisms are less efficient than those seen in young animals.

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The early phase of acquired cellular immunity to Mycobacterium tuberculosis infection is mediated by the emergence of protective CD4 T lymphocytes that secrete cytokines including interferon-gamma (IFN-gamma), a molecule which is pivotal in the expression of resistance to tuberculosis. Recent evidence demonstrates that infection with M. tuberculosis induces peripheral blood mononuclear cells to release the cytokine interleukin-12 (IL-12), a molecule that promotes the emergence of T-helper type-1 (Th1), IFN-gamma-producing T cells. We demonstrate here that IL-12 mRNA expression was induced by M. tuberculosis infection both in vivo and in vitro and that exogenous administration of IL-12 to mice transiently resulted in increased resistance to the infection. IL-12 also increased the production of IFN-gamma by both splenocytes derived from infected animals treated in vivo and by antigen-stimulated CD4 cells from untreated infected animals, with maximal effects at times associated with the expansion of antigen-specific CD4 T cells in vivo. In the absence of a T-cell response, as seen in SCID mice or nude mice, IL-12 only slightly augmented the moderate bacteriostatic capacity of these immunocompromised mice. Neutralization of IL-12 by specific monoclonal antibodies resulted in a reduction in granuloma integrity and slowing of the capacity of the animal to control bacterial growth.

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As mice age, spontaneous changes occur in the receptor repertoire of their T cells. The receptor repertoire of CD4+ T cells does not change with age. By contrast, however, the percentage of alpha beta+, CD8+ T cells bearing particular V elements varies considerably between individual aged mice, although it is remarkably consistent among individual young animals within a given strain. Changes of receptor V element use among CD8+ T cells in individual mice are unpredictable. However, when a large number of mice of the same strain is analyzed, strain-specific trends in V element skewing are found. Old C3H.SW and B10.BR mice have mono- or oligoclonal expansions of CD8+ T cells. These expansions of peripheral CD8+ T cells with age are probably due to deregulation of proliferation of individual CD8+ T cells after recognition of viral or environmental Ag, accompanied, perhaps, by partial transformation of particular T cell clones. Another phenomenon documented herein is the fact that the CD4/CD8 ratio drops steadily as a function of age. Shifts in CD4/CD8 ratio were not due to increased numbers of CD8+ T cells in spleen and lymph nodes, rather the CD4+ T cells disappeared from aging mice faster than CD8+ T cells.

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It has been noted previously that superantigens can under different circumstances stimulate activation, expansion, anergy, and/or deletion of reactive T cells in vivo and in vitro. Here, we present a detailed examination of the expansion and deletion of T cells in vivo in response to the superantigens staphylococcal enterotoxin A (SEA) in the B10.BR mouse. Mice were either acutely or chronically exposed to varying doses of SEA, and the relative level of T cells bearing SEA-reactive V beta elements was followed over time in lymphocytes purified from peripheral blood, lymph nodes, mesenteric lymph nodes, and spleen. In most cases, an initial sharp rise in the proportion of reactive T cells was followed by a dramatic decline. Cells of the CD4+ and CD8+ lineages displayed subtle differences in their kinetics of activation and deletion, as well as their sensitivity to different doses of SEA. Furthermore, cells bearing either of two V beta elements previously characterized as SEA-reactive showed some differences in their responses to SEA treatment. Acute exposure usually caused the disappearance of only 50% to 70% of reactive T cells; however, chronic exposure to SEA caused almost complete deletion of target T cells. Deletion was evident even in animals treated with very low doses of SEA, doses that were too small to cause any apparent T cell proliferation. Thus, proliferation does not appear to be a prerequisite for peripheral deletion of T cells.

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The Staphylococcus aureus enterotoxins are known to be potent T cell activators, stimulating cell proliferation and lymphokine production. Two additional S. aureus proteins, exfoliating toxin and toxic shock syndrome toxin, share these properties. Recently these molecules have been termed "super-antigens" because of their ability to bind to class II MHC molecules and thus form ligands that interact with TCR in an unconventional manner. In this paper we show that each toxin stimulates mouse T cells bearing receptors that include particular V beta regions, almost regardless of the other variable receptor components. In addition, different toxins have different specificities for V beta.

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Three primary theoretical models have been presented to explain child abuse: psychopathological, sociological, and ecological. Four hundred forty-seven later adolescents were surveyed to determine which approach was most consistent with their beliefs, attitudes and opinions. Overwhelmingly, adolescents indicated that their views were most closely aligned with the psychopathological model, followed by the ecological model. Subjects maintained that parental psychological factors and characteristics of victims contributed strongly to maltreatment. Societal factors were perceived as relatively unimportant causative agents or correlates of abuse. Findings are discussed in terms of implications for parent education programs.

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The occurrence and forms of violence experienced by adolescents in families and dating relationships were investigated. Subjects were 204 juniors and seniors enrolled in a high school in central Michigan. A primary aim of the study was to examine similarities between adolescents' experiences with dating violence and those reported by college students. Findings indicate that high school students encounter a considerable amount of violence in their families. Results also reveal a remarkable similarity between their dating experiences and those of college students, suggesting that there is a pattern to "relationship violence".

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