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Cytokine-activated macrophages (MΦ) employ reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) to combat pathogens. The requirement for ROI for an effective host response to experimental leprosy using mice which have a disruption in the 91-kD subunit of the NAPDH oxidase cytochrome b ( phox91−/−) was examined. Mycobacterium leprae multiplication in phox91−/− foot pads (FP) was elevated early in infection but subsequently arrested similarly to control mice within a noninvasive granuloma. Using a modified lepromin test model, a similar cellular composition in the M. leprae-induced FP granuloma in both strains with lymphocyte infiltration consisting primarily of CD4+CD44hiCD62Llo effector cells was found. Of great interest was the disparity in the T cell population between the granuloma and the draining lymph node which contained predominantly naïve CD4+CD44loCD62Lhi cells and was, therefore, not representative of the infection site. TH1 cytokines, chemokines and inducible nitric oxide synthase were comparably expressed in the FP of both strains. When infected in vitro, normal MΦ from B6 and phox91−/− mice supported bacterial viability, whereas IFNγ-activated MΦ killed M. leprae in a RNI-dependent manner, emphasizing that ROI was dispensable. These data show that phox91−/− mice generate a strong adaptive immune response and control long-term infection with M. leprae. [ABSTRACT FROM AUTHOR]

Mycobacterium leprae infection was evaluated in interferon-γ knockout (GKO) mice. At 4 months, growth of the bacilli in the footpads of GKO mice plateaued a log[sub 10] higher than that in control mice. Control mice exhibited mild lymphocytic and histiocytic infiltrates, whereas GKO mice developed large, unorganized infiltrates of epithelioid macrophages and scattered CD4 and CD8 T cells. Flow cytometric analysis of popliteal lymph node cells demonstrated similar profiles of T cells; however, GKO cells exhibited an elevated proliferative response to M. leprae antigen. Expression of inducible nitric oxide synthase mRNA was decreased in GKO mice, whereas macrophage inflammatory protein-1α and interleukin-4 and -10 mRNA expression were augmented. Control and GKO activated macrophages inhibited bacterial metabolism and produced nitrite. Thus, although deficient in an important Th1 cytokine, GKO mice possess compensatory mechanisms to control M. leprae growth and feature elements resembling mid-borderline leprosy in humans. [ABSTRACT FROM AUTHOR]