Group B streptococci (GBS) are the most common cause of neonatal sepsis, meningitis, and pneumonia in developed countries. They are also recognized as important pathogens in postpartum women and in immunocompromised adults. Surface proteins of GBS and other Gram-positive pathogens are known to be important determinants of immunity and may be useful targets for the development of vaccines for the prevention of human infection. The alpha C protein of GBS is a protective antigen containing a novel series of tandem repeats a novel series of tandem repeats that are identical at the nucleotide level. Naturally occurring isolates of GBS display heterogeneity in the number of repeats within their alpha C proteins; he has previously shown that such variation is related to the susceptibility of GBS to opsonization for phagocytic killing by antibodies specific to the alpha C protein. Recently, human isolates of GBS have been noted that, in passage from mother to neonate, appear to have undergone mutation in the gene encoding the alpha C protein that led to a reduction in the number of tandem repeats in the gene. These mutations result in the loss of susceptibility of these isolates to opsonophagocytic killing by alpha-specific antibodies. This phenomenon can be duplicated in laboratory animals made immune to the alpha C protein. Thus, variation of the repeat number within the alpha C protein causes antigenic variation in GBS and allows evasion of host immunity. These findings have important implications for the pathogenesis of GBS infection and for the design of effective protein-based GBS vaccines. The long-term goal of this project is to understand the molecular and immunologic bases for these observations.
The first aim i s to study GBS that escape from host immunity in an animal model and that contain mutations in the alpha C protein genes. The investigator will examine these isolates for altered behavior in test systems of alpha-specific antibody-mediated immunity.
The second aim i s to express tandem repeat variant alpha C protein genes in alpha-negative GBS and study the effects of alpha C protein expression on the biologic behavior of the bacteria. The next aim is to examine the immunologic properties induced by variation in the number of repeats within the alpha C protein by studying artificially derived constructs of alpha C proteins that differ only with respect to the repeat number.
The final aim i s to examine the genetic changes underlying these mutations by cloning and sequencing several representative examples of these repeat-variant alpha C protein genes. Understanding the nature of evasion of host immunity by repeat number antigenic variation will lead to a better understanding of infection by GBS and the many other microbial pathogens which express repeat-containing antigens. Such progress may lead to improvements in the design of protective vaccines.
|Klinzing, David C; Ishmael, Nadeeza; Dunning Hotopp, Julie C et al. (2013) The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus. Microbiology 159:1521-34|
|Klinzing, David C; Madoff, Lawrence C; Puopolo, Karen M (2009) Genomic analysis identifies a transcription-factor binding motif regulating expression of the alpha C protein in Group B Streptococcus. Microb Pathog 46:315-20|
|Baron, Miriam J; Wong, Sandra L; Nybakken, Kent et al. (2009) Host glycosaminoglycan confers susceptibility to bacterial infection in Drosophila melanogaster. Infect Immun 77:860-6|
|Pannaraj, Pia S; Kelly, Joanna K; Rench, Marcia A et al. (2008) Alpha C protein-specific immunity in humans with group B streptococcal colonization and invasive disease. Vaccine 26:502-8|
|Yang, Hsiao-Hui; Mascuch, Samantha J; Madoff, Lawrence C et al. (2008) Recombinant group B Streptococcus alpha-like protein 3 is an effective immunogen and carrier protein. Clin Vaccine Immunol 15:1035-41|