A primary subcutaneous infection with Paracoccidioides brasiliensis leads to immunoprotection or exacerbated disease depending on the route of challenge

In human and experimental paracoccidioidomycosis the severe disease is characterized by depressed cellular immunity whereas the mild disease is associated with persistent T cell immunity. Since the subcutaneous route of antigen inoculation is an efficient inducer of cellular immunity, we decided to study this route of infection and verify its effect on a lethal secondary infection of susceptible hosts. It was observed that the s.c. infection induces positive delayed type hypersensitivity (DTH) responses in 9 different mouse strains, is a self healing process and susceptible mice develop more intense DTH reactions than resistant mice to Paracoccidioides brasiliensis infection. Unexpectedly, the previous s.c. infection of susceptible mice led to immunoprotection or disease exacerbation depending on the route of fungal challenge. Immunoprotection was achieved after intraperitoneal challenge and was associated with persistent cell-mediated immunity and a mixed type-1/type-2 immunity. Exacerbated disease was found after intravenous challenge, was associated with cellular immunity anergy and prevalent type-2 immune response. As a whole, our work demonstrates that susceptibility to P. brasiliensis infection cannot be ascribed to intrinsic inability to mount cellular immune responses, that a single immunization procedure can result in opposite disease outcomes and immunoprotection can be achieved by a balanced Th1/Th2 immunity.