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In the present study, we demonstrate that all mice survived when a low dose of Penicillium marneffei was instilled intratracheally, while severe infection induced by instillation of 1 × 108 and 1× 107 colony-forming units (CFU) killed all and 50% of mice, respectively, within 14 days, although the number of live microorganisms in the lungs of these animals was found to decrease with time. The cellular inflammatory responses in the lungs were much more striking in mice with severe infection than in animals infected with a low dose of microorganisms. The number of leucocytes, macrophages, neutrophils and lymphocytes in the lungs increased progressively during infection, and were more than 50 times higher on day 11 than in the control count. CD4+ T cells were the predominant cells in the lungs, and played an important role in hyperinflammatory host reactions, because neutralizing anti-CD4 MoAb increased the survival rate in infected mice despite the presence of a high number of live microorganisms in the lungs. Our results indicate that severe infection with P. marneffei induces fatal hyperinflammatory host reactions, mediated to a large extent by CD4+ T cells, although the infection is well controlled. However, the contribution of endogenous tumour necrosis factor-alpha (TNF-α) remains unsubstantiated, since administration of neutralizing anti-TNF-α MoAb in the present study failed to prolong survival in infected mice.