Interferonlike factors from antigen- and mitogen-stimulated human leukocytes with antirickettsial and cytolytic actions on Rickettsia prowazekii. Infected human endothelial cells, fibroblasts, and macrophages.

Abstract

Unique features of the primary site of rickettsial replication in typhus fevers, i.e., within the endothelial cells of small blood vessels in tissues, suggest that effector mechanisms, other than those dependent on phagocytosis by activated macrophages with enhanced microbicidal properties, most likely are necessary to explain the cell-mediated immune control of intracellular rickettsial replication in these sites. Theoretically, such mechanisms might involve contact between infected endothelial cells and activated T lymphocyte subpopulations or macrophages or immunologically induced soluble factors or lymphokines. Support for the existence of at least one of these alternative effector mechanisms is presented here for Rickettsia prowazekii. Cultures of human blood leukocytes, upon immunologically specific stimulation with R. prowazekii antigen or nonspecific stimulation with the mitogen phytohemagglutinin, produce soluble factor(s) in the supernatant fluid which, in culture, have (a) an intracellular antirickettsial action on R. prowazekii-infected human endothelial cells, fibroblasts, and macrophages, and (b) a specific cytolytic action on R. prowazekii-infected, but not uninfected bystander, human fibroblasts. Neither action is demonstrable in R. prowazekii-infected chicken embryo fibroblasts. The factor(s) has no direct antimicrobial action on extracellular rickettsiae and is inactivated by heating at 56 degree C for 1 h or by acid treatment at pH 2. Expression of the antirickettsial action requires new host cell messenger transcription and protein synthesis, whereas the cytolytic action does not. The circumstances of production and action and the properties of the factor(s) responsible for the intracellular antirickettsial, and perhaps also the cytolytic action are consistent with those of immune interferon (IFN-gamma).

Mechanisms of Intracellular Killing ofRickettsia conoriiin Infected Human Endothelial Cells, Hepatocytes, and Macrophages

“…Immunity to rickettsiae involves complex interactions of CD4 and CD8 T lymphocytes, macrophages, natural killer cells, B lymphocytes, antibodies, cytokines, and chemokines (6,8,9,11,17,18,19,22,28,29,48,50,55). Animal models have provided substantial information regarding some of these immune mechanisms against Rickettsia species, indicating that cellular mechanisms are of paramount importance, particularly T lymphocytes and the cytokines TNF-␣ and IFN-␥ (8, 9, 17, 22, 50).…”

Establishment of a Novel Endothelial Target Mouse Model of a Typhus Group Rickettsiosis: Evidence for Critical Roles for Gamma Interferon and CD8 T Lymphocytes

“…The other contemporary studies of immunity that have defined the importance of IFN-␥ in rickettsial killing and the existence of a subpopulation of T lymphocytes that is a potentially important mediator of immunity to typhus group rickettsial infections have been performed exclusively in vitro. Investigations demonstrating that IFN-␥ and TNF-␣ activate the intracellular killing of R. prowazekii by nitric oxide-dependent and nitric oxideindependent mechanisms have been conducted principally in fibroblasts and macrophages, which are non-targets and minor targets, respectively, in R. prowazekii and R. typhi infections rather than in the principal target of infection, the endothelium (Turco and Winkler, 1983a, 1983bWisseman and Waddell, 1983). The importance of IFN-␥ in immunity to typhus group rickettsiae had not been evaluated in vivo before the present study.…”

Production of and in vitro response to interleukin 2 in the acquired immunodeficiency syndrome.

“…Although T cells from patients with the acquired immunodeficiency syndrome (AIDS)' display a variety of defects in vitro (1), the failure to properly secrete gamma interferon (IFN-"y) in response to specific microbial antigen seems particularly relevant to the immunopathogenesis of AIDS-related opportunistic infections (2).2 In addition to its well-recognized antiviral effects (3), for example, IFN-'y also appears to play a pivotal role in a number of antigen-initiated cellular immune reactions (reviewed in reference 4), including the capacity to induce macrophages and other potential host defense cells to kill or inhibit both intraand extracellular pathogens (5)(6)(7)(8)(9)(10)(11)(12)(13). While interleukin 2 (IL-2), another soluble product (lymphokine) secreted by sensitized T cells (14)(15)(16), does not share IFN-'y's ability to activate macrophages directly (6), it nevertheless has been of considerable interest in AIDS research (17)(18)(19)(20)(21)(22)(23) because of its broad immunoregulatory effects, which include the stimulation and perhaps regulation of IFN--y production (24)(25)(26)(27)(28)(29).…”