Effect of genetic modifications by selection for immunological tolerance on fungus infection in mice

Two strains of mice genetically selected for extreme phenotypes of immunolo gical tolerance to ovalbumin, susceptible (TS) and resistant (TR), were exp erimentally infected with Sporothrix schenckii. The objective was to observ e whether the genetic modifications produced by the selection might be asso ciated with interstrain differences in adaptive immune and innate responses to infection. Therefore, we evaluated the LD50, CFU, phagocytic index, fun gicidal activity, pro-inflammatory cytokines, specific antibody titres, and the delayed-type hypersensitivity reactivity. TR mice were tenfold more su sceptible to infection than TS mice, as shown by LD50 (5 x 10(6) conidia i. v.). In TS mice, the resistance was a consequence of the tissue fungal load reduction, consistent specific T-cell-mediated immunity, and tumour necros is factor (TNF)-alpha activity at onset of infection. In TR mice, these res ponses were not precociously detected. Therefore, the absence of CD4(+) T-c ell response in the first week of infection might explain the non-clearance of pathogen in TR mice. However, TR mice did show an increase in TNF level and delayed-type hypersensitivity response after the first week post-infec tion; there was also expansion and increase in granulomatous foci and CFU i n the spleen. The expansion of granulomatous foci and the increase in TNF-a lpha and tissue fungal load to damaging levels induced severe tissue destru ction, general failure of the organs, cachexy and death in TR mice. The res ults show that genetic selection for extreme phenotypes of immunological to lerance also modified the responses to S. schenckii infection. (C) 2001 Edi tions scientifiques et medicales Elsevier SAS.