Gram-negative enteric infections and Gram-positive organisms, including Streptococcus pneumoniae, Group A (GAS) and Group B (GBS) streptococci are leading causes of serious bacterial infections and contribute to neonatal deaths worldwide. In man and mouse the early B cell production of antibodies to these and similar organisms are essential for protection from infection and their blood-borne dissemination. However the adaptive immune system is compromised in early life and human infant protective antibody responses to polysaccharide (PS) take more than two years to develop. Our long range goal is to conduct carefully controlled studies of the neonatal immune response to multiple organisms of clear relevance to infant health. Our immediate goal is to use mouse models to study the interactions of the neonatal immune system with bacterial components that lead to long-lasting protection. The rationale behind our approach is that an understanding of the mechanisms controlling the plasticity of the neonatal repertoire will lead to new therapeutic or vaccination options for the treatment and prevention of infection by these organisms. Because mouse models provide unique opportunities for experimentation that cannot be performed in humans, we anticipate that this knowledge will help understand human infant responses to infection, aid in the development of more effective vaccine strategies, and help understand possible consequences of vaccine interference. These goals will be pursued by three aims: 1) to identify factors affecting the establishment of the B cell clonal repertoire to polysaccharides expressed by S. pneumoniae, S. pyogenes (GAS), S. agalactiae (GBS) and E. cloacae: 2) to identify phenotypic, subset distribution, and functional changes elicited in emerging B cells by exposure to these organisms: and 3) to isolate and determine the characteristics of mAbs derived from neonatally immunized adult mice that provide optimal protection to infection with these organisms. By choosing to study this multi-member panel, we will develop unique models in which we can study B cell clonal competition and other interactions during development. We have also developed a comprehensive panel of anti-idiotype antibodies and labeled antigens which permit us to accurately quantitate B cell clonal frequencies and trace by flow cytometry the development of single antigen-binding B cells in response to vaccination or after infection with our model organisms. In addition, we have constructed immunoglobulin transgenic mice with VH genes from hybridomas responding to the PS expressed by these organisms. Our findings are expected to have impact on the understanding of immune B cell memory development and its persistence throughout life. The likely future introduction of even more childhood vaccines makes it imperative that we better understand vaccine interference that may result from the effects of multiple vaccines, neonatal chronic infections, and co-infection on subsequent immune responses to further vaccination or infection.

Public Health Relevance

Gram-negative enteric infections and Gram-positive organisms, including Streptococcus pneumoniae, Group A (GAS) and Group B (GBS) streptococci are leading causes of serious neonatal bacterial infections. The proposed research is relevant to public health because an understanding of the mechanisms controlling the plasticity of the neonatal repertoire will lead to new therapeutic or vaccination options for the treatment and prevention of infection by these organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100005-03
Application #
8609548
Study Section
Special Emphasis Panel (ZAI1-LGR-I (J1))
Program Officer
Prabhudas, Mercy R
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$278,888
Indirect Cost
$88,521
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294