Gamma Interferon, Tumor Necrosis Factor Alpha, and Nitric Oxide Synthase 2, Key Elements of Cellular Immunity, Perform Critical Protective Functions during Humoral Defense against Lethal Pulmonary Yersinia pestis Infection

• Published in: Infection and Immunity Vol. 74; no. 6; pp. 3381 - 3386
• Main Authors: Parent, Michelle A, Wilhelm, Lindsey B, Kummer, Lawrence W, Szaba, Frank M, Mullarky, Isis K, Smiley, Stephen T
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.06.2006
• Subjects: Animals; Bacteriology; Biological and medical sciences; cell-mediated immunity; Fundamental and applied biological sciences. Psychology; humoral immunity; Immunity, Cellular; Interferon-gamma - physiology; interferons; Mice; Mice, Inbred C57BL; Microbial Immunity and Vaccines; Microbiology; Miscellaneous; nitric oxide synthase; Nitric Oxide Synthase Type II - physiology; plague; Plague - immunology; Plague Vaccine - immunology; Pneumonia, Bacterial - immunology; respiratory tract diseases; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - physiology; Yersinia pestis; Immunoprotection; Microbiology; Enzyme; Cytokine; Cellular immunity; Nitric-oxide synthase; Yersinia pestis; Infection; Bacteriosis; Bacteria; Oxidoreductases; Tumor necrosis factor α; Humoral immunity; Yersiniosis; Enterobacteriaceae; Gamma interferon
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00185-06

Pulmonary infection by Yersinia pestis causes pneumonic plague, a rapidly progressing and often fatal disease. To aid the development of safe and effective pneumonic plague vaccines, we are deciphering mechanisms used by the immune system to protect against lethal pulmonary Y. pestis infection. In murine pneumonic plague models, passive transfer of convalescent-phase sera confers protection, as does active vaccination with live Y. pestis. Here, we demonstrate that protection by either protocol relies upon both gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) cytokines classically associated with type 1 cellular immunity. In both protocols, abrogating IFN-γ or TNF-α activity significantly decreases survival and increases the bacterial burden in pulmonary, splenic, and hepatic tissues. Neutralization of either cytokine also counteracts challenge-induced, vaccination-dependent upregulation of nitric oxide synthase 2 (NOS2). Moreover, genetic depletion of NOS2 suppresses protection conferred by serotherapy. We conclude that IFN-γ, TNF-α, and NOS2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Y. pestis challenge. These observations strongly suggest that plague vaccines should strive to maximally prime both cellular and humoral immunity.