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Human polymorphonuclear leukocyte-mediated cytotoxicity against varicella-zoster virus-infected fibroblasts
Abstract:
Polymorphonuclear leukocytes (PMN) were studied for their ability to mediate cytotoxicity against varicella-zoster virus (VZV)-infected and uninfected human fibroblasts in 51Cr release assays. PMN were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) against VZV-infected targets. Maximal ADCC was obtained with effector-to-target ratios of 100:1 and 18 h of incubation. Percent 51Cr release for 26 normal adults was 14.1 +/- 0.6 (mean +/- standard error) in the presence of pooled human seropositive sera (final dilution, 1:100) and 0.5 +/- 0.6 in the presence of pooled human seronegative sera. Addition of phorbol myristate acetate (PMA) enhanced PMN-mediated cytotoxicity against VZV-infected and uninfected targets. PMA-stimulated cytotoxicity was optimal with PMA concentrations of 200 ng/ml and effector-to-target ratios of 10:1, and antibody was not required; killing was detected as early as 3 h after incubation and was maximal after 18 h. Highly purified PMN were capable of mediating both ADCC and PMA-stimulated lysis. Catalase completely inhibited PMA-stimulated PMN cytotoxicity, but had no effect on PMN-mediated ADCC. PMN from patients with chronic granulomatous disease were capable of mediating ADCC, but not PMA-stimulated killing, against VZV-infected targets. Thus, PMN could kill VZV-infected targets by two different mechanisms: ADCC, which required antibody but not hydrogen peroxide (H2O2), and PMA-stimulated cytotoxicity, which required H2O2 but not antibody.
Insights
Polymorphonuclear leukocytes (PMN) can kill varicella-zoster virus (VZV)-infected cells through antibody-dependent cellular cytotoxicity (ADCC) or phorbol myristate acetate (PMA)-stimulated mechanisms. PMA-stimulated killing relies on hydrogen peroxide (H2O2), unlike ADCC.
Area of Science:
- Immunology
- Virology
Background:
- Polymorphonuclear leukocytes (PMN) play a crucial role in the immune response.
- Varicella-zoster virus (VZV) causes significant human disease.
- Understanding PMN cytotoxicity mechanisms against VZV is vital for therapeutic strategies.
Purpose of the Study:
- To investigate the mechanisms by which PMN mediate cytotoxicity against VZV-infected human fibroblasts.
- To differentiate between antibody-dependent cellular cytotoxicity (ADCC) and phorbol myristate acetate (PMA)-stimulated cytotoxicity in PMN.
Main Methods:
- Utilized 51Cr release assays to quantify PMN-mediated cytotoxicity against VZV-infected and uninfected human fibroblasts.
- Investigated the role of antibodies and PMA in enhancing PMN cytotoxicity.
- Assessed the impact of catalase and hydrogen peroxide (H2O2) on different cytotoxicity pathways.
- Examined PMN function in patients with chronic granulomatous disease.
Main Results:
- PMN effectively mediated antibody-dependent cellular cytotoxicity (ADCC) against VZV-infected targets, requiring antibody but not H2O2.
- PMA significantly enhanced PMN cytotoxicity against both VZV-infected and uninfected targets, independent of antibody but dependent on H2O2.
- PMA-stimulated cytotoxicity was inhibited by catalase, while ADCC was unaffected.
- PMN from chronic granulomatous disease patients showed impaired PMA-stimulated killing but intact ADCC.
Conclusions:
- PMN possess distinct mechanisms for killing VZV-infected cells: ADCC and PMA-stimulated cytotoxicity.
- ADCC relies on antibody, whereas PMA-stimulated lysis depends on H2O2 production by PMN.
- These findings elucidate the multifaceted role of PMN in antiviral defense against VZV.