Mycobacterium bovis strain bacillus Calmette-Guérin-induced liver granulomas contain a diverse TCR repertoire, but a monoclonal T cell population is sufficient for protective granuloma formation.

Granuloma formation is a form of delayed-type hypersensitivity requiring CD4(+) T cells. Granulomas control the growth and dissemination of pathogens, preventing host inflammation from harming surrounding tissues. Using a murine model of Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) infection we studied the extent of T cell heterogeneity present in liver granulomas. We demonstrate that the TCR repertoire of granuloma-infiltrating T cells is very diverse even at the single-granuloma level, suggesting that before granuloma closure, a large number of different T cells are recruited to the lesion. At the same time, the TCR repertoire is selected, because AND TCR transgenic T cells (Valpha11/Vbeta3 anti-pigeon cytochrome c) are preferentially excluded from granulomas of BCG-infected AND mice, and cells expressing secondary endemic Vbeta-chains are enriched among AND cells homing to granulomas. Next, we addressed whether TCR heterogeneity is required for effective granuloma formation. We infected 5CC7/recombinase-activating gene 2(-/-) mice with recombinant BCG that express pigeon cytochrome c peptide in a mycobacterial 19-kDa bacterial surface lipoprotein. A CD4(+) T cell with a single specificity in the absence of CD8(+) T cells is sufficient to form granulomas and adequately control bacteria. Our study shows that expanded monoclonal T cell populations can be protective in mycobacterial infection.

The impact of early initiation of highly active antiretroviral therapy on the human immunodeficiency virus type 1-specific CD8 T cell response in children.

This cross-sectional study investigated the effect of early highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV) type 1-specific CD8 T cell responses in children. HIV-1-specific CD8 T cell responses were quantified using an enzyme-linked immunospot assay to measure interferon-gamma-secreting cells. HIV-1-infected children were classified by time of HAART initiation prior to age 1 year or after age 2 years as early (n=24) or late (n=28) treated. The magnitude and breadth of the HIV-1-specific CD8 T cell response was significantly lower in children receiving early compared with late HAART treatment (P=.0007 and.0001, respectively). However, total CD8 T cell responses in the early HAART treatment group did not differ significantly from those of age-matched non-HAART-treated controls (n=30). Thus, the reduced magnitude and breadth of the HIV-1-specific CD8 T cell response in early HAART-treated children is due to their younger age.

Endocardial abscesses in children: case report and review of the literature.

The rarity of perivalvular abscesses arising as a complication of bacterial endocarditis in the pediatric population limits its recognition and awareness of its often malignant course. The diagnosis depends on a combination of clinical criteria, including persistent fever and bacteremia, the presence of an atrioventricular block and persistent embolic phenomenon, and transthoracic or transesophageal echocardiographic confirmation. Because of the infrequency of perivalvular abscesses in children, there is no consensus on a treatment strategy. Early detection and intervention with antibiotics and surgical debridement are recommended to decrease the morbidity and mortality associated with this disease. A case of a 14-year-old boy with an aortic root abscess is presented, along with review of other cases reported in the last 20 years in children in relation to risk factors, clinical features, diagnosis, therapy, and mortality.

Mucosal DNA vaccine immunization against measles with a highly attenuated Shigella flexneri vector.

An intranasal vaccine vector would elicit protective immunity at the respiratory mucosa, the portal of entry and the primary site for replication for measles virus (MV) and other respiratory viruses. In a murine model of pulmonary Shigella, we demonstrate here that a candidate-attenuated Shigella vaccine vector is safely tolerated in IFN-gamma deficient mice at an inoculum that is 1 million-fold higher than the inoculum of the wild-type parent strain that would be lethal for greater than 90% of these mice. Also, following intranasal inoculation, the Deltaasd Shigella harboring a DNA MV vaccine plasmid induces a vigorous MV-specific Th1-type (both CD8+ CTL and IFN-gamma) and, to a lesser degree, Th2-type responses among splenocytes in addition to low levels of IgG and IgA in the serum. Priming for MV-specific CTL responses was possible in mice that had prior infection with a wild-type Shigella of the same serotype. Remarkably, mice immunized by the intranasal route with attenuated Shigella harboring the DNA MV vaccine plasmid had a level of MV-specific CTL activity among splenocytes that was comparable with levels observed in mice immunized by the i.p. route with attenuated Salmonella typhi harboring the same DNA vaccine plasmid, despite the fact that Shigella remained localized to the lungs, yet Salmonella disseminated to the spleen following inoculation. Thus, Deltaasd Shigella represents a very useful vector for delivery of DNA vaccines to mucosal lymphoid tissues.

Recombinant bacille Calmette-Guérin expressing the measles virus nucleoprotein protects infant rhesus macaques from measles virus pneumonia.

Measles virus infection continues to be a major cause of infant mortality. There is a need for a measles vaccine that can be administered at birth in the presence of maternal neutralizing antibody. Infant rhesus monkeys were immunized with recombinant bacille Calmette-Guérin expressing the full-length measles virus nucleoprotein (BCG-N) and subsequently challenged with measles virus. Nucleoprotein-specific lymphocyte proliferative responses were detected in the absence of anti-N antibody after vaccination. Vaccination with BCG-N did not prevent systemic measles virus infection; however, there was a significant reduction of lung inflammation after challenge. Virus titers in lymph nodes were significantly lower, and the duration of nasopharyngeal viral shedding was shorter in some vaccinated monkeys after challenge. These results suggest that measles virus-specific T cells were primed by BCG-N vaccination and that they prevented virus-induced lung pathology.

Recombinant bacille Calmette-Guérin priming against measles.

Live attenuated measles virus (MV) vaccines are ineffective in young infants because of neutralization by maternal antibody. An immunization strategy that may permit priming for T cell memory for MV in infants at or shortly after birth uses recombinant bacille Calmette-Guérin expressing the full-length MV nucleocapsid (N) protein (rBCG::N). C3H/He mice immunized with rBCG::N developed T cell responses and ELISA antibodies to the N protein and low levels of neutralizing antibody after intracranial infection with MV strain CAM/R40. There was considerable reduction in the virus titer recovered from brain homogenates, a decrease in the incidence and severity of histologic encephalitis, and a decrease in mortality in rBCG::N-printed C3H/He mice compared with control mice. Given the limitations of existing live attenuated MV vaccines, these results encourage the further testing of rBCG::N vaccines in primate models.