Bacterial pathogenesis; Group A streptococcus and Legionella
Group A streptococci (Streptococcus pyogenes) cause pharyngitis, scarlet fever, toxic shock syndrome, and a range of skin and soft tissue infections, ranging from mild superficial infections to rapidly invasive deep tissue infections (so-called "flesh-eating" disease). Several streptococcal virulence factors that are essential for the evolution of necrotic skin disease are negatively regulated by a two-component system, designated CsrR/CsrS. Dr. Engleberg's laboratory has demonstrated that spontaneous mutations in these two regulatory proteins emerge in vivo in experimental animals and are associated with more severe disease. These mutants overproduce bacterial capsule and several exotoxins, they enhance the growth and survival of wildtype streptococci that coexist at the site of infection, and they synergize with wildtype bacteria to produce larger, more necrotic lesions and death. Dr. Engleberg is interested in determining to what extent the course of streptococcal infection in animals and humans depends upon the emergence of these spontaneous mutants. Additional goals include the elucidation of the CsrRS-regulated genes that are most responsible for the enhanced virulence and the mechanisms by which they are controlled.
Legionella pneumophila, the causal agent of Legionnaires’ disease, is normally found in a variety of aquatic environments, most often as parasites of free-living unicellular organisms such as amoebae. Legionella that infect and are released from amoebae are more invasive and survive better in human macrophages, an essential step in the development of Legionnaires’ disease. Dr. Engleberg and his colleagues have found that L. pneumophila is more virulent in animals when inoculated together with amoebae. Studies are focused on determining the reason for the enhencement and establishing the role of amoebae in aerosols that infect humans.
Engleberg, N.C., Heath, A., Miller, A., Rivera, R., and DiRita, V.J. Spontaneous mutations in the CsrRS two-component regulatory system of Streptococcus pyogenes result in enhanced virulence in a murine model of skin and soft tissue infection. J. Infect. Dis. 2001; 183:1043-1054.
Heath, A., DiRita, V.J., Barg, N.L., and Engleberg, N.C. A two-component regulatory system, CsrR/CsrS, represses expression of three Streptococcus pyogenes virulence factors, hyaluronic acid capsule, streptolysin S, and pyrogenic exotoxin B. Infect. Immun. 1999; 67:5298-5305.
Brieland, J., McClain, M., LeGendre, M., and Engleberg, C. Intrapulmonary Hartmannella vermiformis: a potential niche for Legionella pneumophila replication in a murine model of legionellosis. Infect. Immun. 1997; 65:4892-4896