Osteopontin (OPN, also known as Eta-1), a noncollagenous matrix protein produced by macrophages and T lymphocytes, is expressed in granulomatous lesions caused by Mycobacterium tuberculosis infection. In the present study, we compared plasma concentrations of OPN in patients with active pulmonary tuberculosis with those of healthy control subjects and patients with sarcoidosis, another disease associated with granuloma formation. Plasma OPN levels were significantly higher in patients with tuberculosis (n = 48) than in control subjects (n = 34) and patients with sarcoidosis (n = 20). OPN levels correlated well with severity of pulmonary tuberculosis, as indicated by the size of lung lesions on chest X-ray films. Furthermore, chemotherapy resulted in a significant fall in plasma OPN levels. In patients with tuberculosis, plasma OPN concentrations correlated significantly with those of interleukin (IL)-12. In vitro experiments showed that OPN production by peripheral blood mononuclear cells infected with Mycobacterium bovis bacillus Calmette-Guérin preceded the synthesis of IL-12 and interferon-gamma and that the neutralizing anti-OPN monoclonal antibody significantly reduced the production of IL-12 and interferon-gamma. Our results suggest that OPN may be involved in the pathologic process associated with active pulmonary tuberculosis by inducing IL-12-mediated type 1 T helper cell responses.

In the present study, the role of interferon-gamma (IFN-gamma) in the host resistance against Cryptococcus neoformans was examined using a murine model of pulmonary and disseminated infection. In this model, mice were infected intratracheally with live yeast cells, and the histological changes in the lungs and the number of microorganisms in the lung and brain were compared in mice treated and untreated with anti-IFN-gamma monoclonal antibody (mAb) to define the contribution of endogenously synthesized IFN-gamma in the natural course of infection. Administration of this mAb reduced the accumulation of inflammatory cells in the alveolar septa, peribronchial and perivascular areas, and promoted the expansive growth of microorganisms in the alveoli and destruction of alveolar structure. The neutralization of endogenous IFN-gamma by mAb increased the number of microorganisms in the lung and brain, and significantly shortened the survival time of infected mice. On the other hand, administration of IFN-gamma decreased the number of microorganisms in these organs, and significantly extended their survival time. Considered together, our results suggest that endogenous IFN-gamma protects mice from infection with C. neoformans by inducing a cellular inflammatory response, potentiating the clearance of microorganism from the lungs and preventing its dissemination into the central nervous system.

Previous investigations have demonstrated that macrophages play a critical role in the first‐line cellular defense mechanism against infection with Cryptococcus neoformans. In the present study, to elucidate the way in which anticryptococcal activity of macrophages is regulated at the site of infection, pulmonary intraparenchymal macrophages were directly analyzed for expression of their surface molecules and their phagocytic activities against the organism, and the effects of depletion of T cells and endogenous IFN‐γ in vivo on these parameters were examined. In the lungs of mice intratracheally inoculated with heat‐killed C. neoformans, macrophages were activated, as indicated by augmented expression of MHC class II, intercellular adhesion molecule‐1 (ICAM‐1) and Fc receptor (FcR), and about two‐thirds of macrophages were found to have ingested an average of 3.77 ± 0.12 yeast cells per macrophage. In mice depleted of both CD4+ and CD8+ T cells by injecting the specific monoclonal antibodies (mAbs) or anti‐IFN‐γ mAb, not only augmentation of the expression of macrophage activation markers but also phagocytosis of C. neoformans was significantly reduced. These results suggest that anticryptococcal activity of macrophages is regulated by IFN‐γ endogenously produced by T cells. Additionally, treatment with IFN‐γ were shown to significantly prolong the survival time of mice infected with viable C. neoformans. Additionally, preimmunization with heat‐killed C. neoformans significantly prolonged the survival time of mice which received the following infection.

Penicillium marneffei is one of the most important opportunistic infectious pathogens in AIDS patients in Thailand and Southeast Asia. However, very little is known about the host defence mechanisms against P. marneffei infection. In the present study, we established the first experimental murine model of chronic pulmonary and disseminated infection using P. marneffei, and examined the immunological response to such infection in euthymic and athymic mice. In this model, micro-organisms inoculated intratracheally multiplied progressively in the lungs and disseminated to the liver and spleen. However, the number of organisms decreased gradually in these organs. In contrast, congenitally athymic mice developed severe pulmonary and disseminated systemic mycosis. Pulmonary penicilliosis marneffei was associated with a marked cellular inflammatory response as evident by histological abnormalities and increased intraparenchymal leucocyte count. To confirm the importance of cell-mediated immunity in host resistance to P. marneffei infection, we transferred nylon wool non-adherent spleen cells into the athymic mice. Such treatment significantly reduced the number of yeasts in the organs of athymic mice. Taken together, our results demonstrate that the cell-mediated immunity play a central role in a host defence mechanism against infection with P. marneffei, and suggest that our new model may be a useful approach for studying the pathogenesis of this fungal disease.