Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans.
Autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response to Cryptococcus neoformans and Candida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing C. albicans. In contrast, LC3 was found in only a few vacuoles containing C. neoformans previously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagy in vitro by RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis of C. albicans and the fungistatic activity of J774.16 macrophage-like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity against C. neoformans when activated. In contrast, nonactivated ATG5-knockout BMMs actually restricted C. neoformans growth more efficiently, suggesting that macrophage autophagy plays different roles against C. neoformans, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis of C. neoformans, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenous C. albicans infection. In contrast, these mice manifested no increased susceptibility to C. neoformans, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling.
Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
André Moraes
AM
Nicola
Patrícia
P
Albuquerque
Luis R
LR
Martinez
Rafael Antonio
RA
Dal-Rosso
Carolyn
C
Saylor
Magdia
M
De Jesus
Joshua D
JD
Nosanchuk
Arturo
A
Casadevall
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000276:immunology / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014617:Vacuoles / Q000737:chemistry
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins