Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Young children are more likely to contract infection with and develop severe disease from the causative agent Mycobacterium tuberculosis (Mtb). These clinical observations likely reflect fundamental differences in the immune systems of young children and adults. Critical differences relevant to TB immunity include the propensity for infants and young children to develop TH2-type CD4+ T cells in response to immunogens and deficiencies in the development of TH1-type T cells in response to pathogens. Furthermore, parts of the world with a high prevalence of childhood TB also have heavy burdens of parasitic disease and AIDS, which may increase the propensity to develop TH2-type immunity and erodes TH1-type immunity, respectively. ? ? We propose to systematically define, in young children (~ 10 years old) from Uganda, where HIV and parasitic infections are common in children, these important differences relevant to the successful containment of Mtb infection.
The specific aims are: 1) To determine if severity of disease following Mtb infection in young children is associated with TH2-type Mtb-specific immunity, and conversely, if absence of disease following Mtb infection is associated with TH1-type Mtb-specific immunity. 2) To determine if immunologic immaturity is associated with the development of TH2-type Mtb-specific immunity following Mtb infection, and conversely if immunologic maturity is associated with the development of TH1-1ype Mtb-specific immunity following Mtb infection. 3) To determine if HIV co-infection affects the development of T cell immunity in children with tuberculosis. These studies may contribute to a more complete understanding of TB immunity in young children, and hence facilitate the development of an improved TB vaccine for this vulnerable population. ? ?
| Sinnott, Brian D; Park, Byung; Boer, Mardi C et al. (2016) Direct TLR-2 Costimulation Unmasks the Proinflammatory Potential of Neonatal CD4+ T Cells. J Immunol 197:68-77 |
| Lancioni, Christina; Nyendak, Melissa; Kiguli, Sarah et al. (2012) CD8+ T cells provide an immunologic signature of tuberculosis in young children. Am J Respir Crit Care Med 185:206-12 |
| Nyendak, Melissa R; Lewinsohn, Deborah A; Lewinsohn, David M (2009) New diagnostic methods for tuberculosis. Curr Opin Infect Dis 22:174-82 |
| Lewinsohn, Deborah A; Winata, Ervina; Swarbrick, Gwendolyn M et al. (2007) Immunodominant tuberculosis CD8 antigens preferentially restricted by HLA-B. PLoS Pathog 3:1240-9 |
| Gold, Marielle C; Robinson, Tammie L; Cook, Matthew S et al. (2007) Human neonatal dendritic cells are competent in MHC class I antigen processing and presentation. PLoS One 2:e957 |
| Gold, Marielle C; Donnelly, Erin; Cook, Matthew S et al. (2006) Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation. Pediatr Res 60:34-7 |
