Role of Dendritic Cells and Alveolar Macrophages in Regulating Early Host Defense against Pulmonary Infection withCryptococcus neoformans

Abstract

Successful pulmonary clearance of the encapsulated yeast Cryptococcus neoformans requires a T1 adaptive immune response. This response takes up to 3 weeks to fully develop. The role of the initial, innate immune response against the organism is uncertain. In this study, an established model of diphtheria toxin-mediated depletion of resident pulmonary dendritic cells (DC) and alveolar macrophages (AM) was used to assess the contribution of these cells to the initial host response against cryptococcal infection. The results demonstrate that depletion of DC and AM one day prior to infection results in rapid clinical deterioration and death of mice within 6 days postinfection; this effect was not observed in infected groups of control mice not depleted of DC and AM. Depletion did not alter the microbial burden or total leukocyte recruitment in the lung. Mortality (in mice depleted of DC and AM) was associated with increased neutrophil and B-cell accumulation accompanied by histopathologic evidence of suppurative neutrophilic bronchopneumonia, cyst formation, and alveolar damage. Collectively, these data define an important role for DC and AM in regulating the initial innate immune response following pulmonary infection with C. neoformans. These findings provide important insight into the cellular mechanisms which coordinate early host defense against an invasive fungal pathogen in the lung.Cryptococcus neoformans, an opportunistic fungal pathogen acquired through inhalation, causes significant morbidity and mortality primarily in patients with impairments in host defense, including those with AIDS, those with lymphoid or hematological malignancies, or those receiving immunosuppressive therapy secondary to autoimmune disease or organ transplantation (31,33,60). The development of a T1 antigenspecific immune response characterized by gamma interferon production and classical activation of macrophages is required to eradicate the organism (4,8,21,23,24,28). This adaptive immune response takes 2 to 3 weeks to develop and coincides with the CCR2-mediated recruitment of additional pulmonary dendritic cells (DC) and T cells to the lung (51,66,67). The role of initial, innate immune responses against the organism (prior to the development of adaptive immunity) is not well understood.Resident lung phagocytic cells, primarily DC and alveolar macrophages (AM), are likely the first immune cells exposed to C. neoformans upon inhalation of the organism into the lung. Both DC and AM express lectin receptors, including macrophage mannose receptor and DC-specific non-ICAM3 grabbing nonintergrin (DC-SIGN) (14, 15), which bind C. neoformans glycoantigens, including mannoproteins (42, 55). DC and AM phagocytose the organism in vitro and in vivo (29,34,63,77,78), and phagocytosis (and/or exposure to soluble glycoantigens or cryptococcal DNA) is associated with cytokine and chemokine production (5,29,40,48,49,55,61) and yeast lysis (77). It is unclear whether phagocytosis by resident DC and AM contributes to early clearance and/or the la...

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

“…[25][26][27][28][29] Yet, AMs also protect against deleterious and ineffective inflammation before the onset of adaptive immunity. 30 Previous studies 31,32 identified macrophage accumulation in the lungs of cryptococcal-infected mice during the effector phase (approximately 14 -28 dpi) of the host response. Impaired cryptococcal clearance in chemokine receptor 2 (CCR2)-deficient mice correlates strongly with diminished pulmonary macrophage accumulation.…”

Analysis of Cell Cycle and Replication of Mouse Macrophages after In Vivo and In Vitro Cryptococcus neoformans Infection Using Laser Scanning Cytometry

“…he interaction of the human pathogenic fungus Cryptococcus neoformans with macrophages is thought to be a key event in the outcome of cryptococcal infection (10,13,17,28,29). C. neoformans is a facultative intracellular pathogen and, once within a macrophage, C. neoformans can replicate intracellularly with outcomes that range from host cell lysis to nonlytic exocytosis (2,3,23).…”

Cryptococcal Interactions with the Host Immune System

“…Dendritic cells function as major antigenpresenting cells that constantly monitor the current antigen population and modulate adaptive immune responses accordingly (28). During cryptococcal infections, DCs are thought to be the major initiators of protective cell-mediated immunity (11,147). Not only are major antigens (e.g., mannoproteins and glycoantigens) for the activation of anticryptococcal T-cell responses dominantly presented by DCs (107,125), but also the induction of T-cell responses by DCs is much more efficient than by alveolar or peritoneal macrophages (125,180).…”