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We sought to understand the persistence and relevance of the long-lived immune response to early secretory antigenic target (ESAT-6) of Mycobacterium tuberculosis in humans. ESAT-6 is recognized by memory cells involved in protection of animals against tuberculosis (TB). Recent reports also showed that ESAT-6 response can be recovered in patients with TB and in those soon after anti-TB therapy. We chose 18 individuals who had recovered from pulmonary TB (some in remission for >5 years), and 14 bacille Calmette-Guérin-vaccinated healthy individuals for this study. The results showed that peripheral blood mononuclear cells of 10 (55.6%) of 18 patients with TB remission responded to ESAT-6 with stimulation indices >3.0, whereas none of the healthy controls responded. Functional analysis showed that 13 (72.2%) of 18 patients with TB remission produced significant amounts of IFN-gamma in response to ESAT-6, whereas only 1 (7.1%) of the 14 healthy control subjects did so. It appears that responses to ESAT-6 can persist in individuals who had recovered from pulmonary TB.

It has long been recognized that some viral infections result in generalized immune suppression. In acute infections, this period of suppressed immunity is relatively short. However, chronic infections associated with a prolonged period of immune suppression present far greater risks. Here, we examined the role of CD8 T cell responses following viral infection in immunity to systemic histoplasmosis. Although wild-type mice with systemic histoplasmosis were able to control the infection, those simultaneously infected with lymphocytic choriomeningitis virus clone 13 showed reduced immunity with greater fungal burden and high mortality. The immune suppression was associated with loss of CD4 T cells and B cells, generalized splenic atrophy, and inability to mount a granulomatous response. Removing the anti-viral CD8 T cells in the coinfected mice enabled them to reduce the fungal burden and survive the infection. Their lymphoid organs were replenished with CD4 T and B cells. In contrast to wild-type mice, perforin-deficient mice infected with lymphocytic choriomeningitis virus clone 13 and Histoplasma showed an absence of immunopathology, but the animals still died. These results show that CD8 T cells can suppress immunity through different mechanisms; although immunopathology is perforin-dependent, lethality is perforin-independent.

In summary, different approaches have been taken to understand cytokine responses to different fungal infections. Singer-Vermes and co-investigators indirectly examined cytokine responses to paracoccidioidomycosis by studying the types of cellular and humoral immune responses that were induced in resistant and susceptible mouse strains. Their results implicated Th1 cell responses in the resistant mouse strain and Th2 cell responses in the mouse strain susceptible to paracoccidioidomycosis. By measuring cytokine production and through cytokine depletion experiments, Wu-Hsieh showed that besides IFN gamma, TNF alpha was important in host defences against the intracellular pathogen, H. capsulatum. Both cytokines play important roles in the regulation of other cytokines. In histoplasmosis, the dynamics of the complex interactions amongst cytokines govern the efficiency of host clearance of the fungus from tissues. Ferrante and collaborators, examining TNF alpha and TNF alpha receptors on neutrophils presented data showing that TNF alpha plays an important role in the activation of neutrophils for anti-Candida activity. Through the detection of cytokine mRNAs with RT-PCR, Moser and co-workers found that cytokine mRNAs of macrophage origin were produced preferentially in the lungs of mice infected with Histoplasma or Blastomyces. A great challenge still lies ahead of us. It is well understood that the interactions of cytokines are extremely complex at the levels of the induction and expression of the immune responses as well as on effects on natural cellular defences. Work accomplished thus far has laid the ground work for future studies in the effort to dissect host cytokine responses and to understand the roles of cytokines in protection against fungal infections.

The study by use of immunocytochemical methods shows that the spleen of mouse infected intravenously by Histoplasma capsulatum is heavily infiltrated by macrophages. The CD4+ and CD8+ T cells are diffused and sparsely distributed throughout the spleen. It appears that experimental histoplasmosis in animals presents as a disease of the mononuclear phagocyte systems. Macrophages are important cells in controlling replication of intracellular H. capsulatum. Factors that affect the infiltration and activation of macrophages are, thus, important in host defense against histoplasmosis. Depletions of endogenous TNF-alpha in animals infected with sublethal dose of H. capsulatum results in death of these animals. The fungus burden in these animals is high and macrophages are not capable of restricting proliferations of the fungus. However, the role of TNF-alpha in histoplasmosis is not a direct activation of macrophages and is still yet to be defined. IFN-gamma has been shown to fully activate mouse peritoneal macrophages and partially activate splenic macrophages for anti-histoplasma activity. The importance of IFN-gamma in host defense against histoplasmosis is studied by use of resistant A/J and susceptible C57BL/6 mouse strains. There is a good correlation of early production of IFN-gamma by spleen cells of infected mice with the ability of the animals to clear the infection. Spleen cells of resistant A/J mice are more efficient than susceptible C57BL/6 mice in production of IFN-gamma. Recombinant inbred progeny of A/J and C57BL/6 mice are used to locate the genes that control resistance to histoplasmosis. Preliminary studies show that the resistance phenotype is controlled not by a single gene but by multiple genes.