Neutrophil role in pulmonary paracoccidioidomycosis depends on the resistance pattern of hosts

Abstract

The immunoprotective and immunomodulatory role of neutrophils during pulmonary infection of resistant (A/J) and susceptible (B10.A) mice to Paracoccidioides brasiliensis was investigated. First, comparative studies about early cellular influx to the lungs demonstrated higher numbers of neutrophils in susceptible rather than in resistant mice. Neutrophil depletion resulted in decreased survival times of susceptible but not resistant mice. In both mouse strains, depletion led to increased fungal burdens at Week 1 of infection; however, only susceptible mice remained with increased pulmonary fungal loads and presented a dramatic fungal dissemination to liver and spleen. At Week 1 of infection, treated and untreated B10.A and A/J mice were negative for delayed-type hypersensitivity (DTH) reactions, which remained negative for the susceptible strain. In contrast, from the second week onward, control and neutrophil-depleted, resistant mice became positive for DTH reactions. In B10.A mice, neutrophil depletion resulted in increased levels of interleukin (IL)-12 and IL-4 in the lungs, high levels of hepatic cytokines, and increased synthesis of T helper cell type 1 (Th1)- and Th2-regulated antibodies [immunoglobulin G1 (IgG1), IgA, and IgG3]. In neutrophil-depleted A/J mice, high levels of pulmonary IL-12 and granulocyte macrophage-colony stimulating factor were concomitant to diminished levels of hepatic cytokines and increased amounts of Th1-regulated isotypes (IgG2a, IgG2b, and IgG3). Differently from primary infection, neutrophil depletion did not alter immunoprotection in secondary paracoccidioidomycosis. As a whole, our data showed that the genetic patterns of hosts exert an important influence on the immunoprotective and immunoregulatory functions of neutrophils, which appear to be essential in situations devoid of cell-mediated immunity.