Legionella pneumophila is an important cause of epidemic and sporadic human pneumonia. Intact recruited and immune inflammatory host defenses are essential for successful containment of this infection in man and animals. Critical interactions between cellular host defenses and Legionella can only be inferred, but not proven from study of clinical material. In vitro studies with human calls are, of necessity, limited by the selection of an artificial environment for culture. We have developed a model of Legionella pneumonia in rodents, which matches the human disease well. We have combined experiments performed in vitro and in vivo to supplement, rather than to supplant the studies that are being performed in other laboratories with human cells. The primary infection can be divided into phases: 1) initial unimpeded bacterial growth, 2) containment, and 3) clearance and resolution. A resident alveolar macrophage (AM) that is permissive for bacterial growth characterizes susceptible species and is probably necessary for productive infection. Neutrophils (PMNL), in contrast, provide the first protective defense against the bacteria. When examined in vitro phagocytes in the airspaces continue to support growth of Legionella during the phase of resolution (a time when specific immunological mechanisms have been activated), but they are less permissive than resident cells. We have demonstrated protection against rechallenge in animals that have survived prior sublethal infection. This protective effect can be reproduced partially by passive transfer of antibody into naive recipients. We propose studies to increase our understanding of immunological mechanisms in the successful containment of a primary infection and in acquired resistance to re-infection. We will characterize the humoral and cellular immune response in the Lewis rat and in Strain 2 guinea pigs. Subsequently, we will examine the effects of immunosuppression and reconstitution in animals that demonstrate innate or acquired resistance. We will explore the role of the stimulated or activated macrophage in the resistance to reinfection. These studies will increase our knowledge of immunity to an important human pathogen, but will also add to our knowledge of host defenses against an important class of human pathogens, pathogenic intracellular bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI020365-04
Application #
3129977
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1983-08-01
Project End
1990-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405