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Macrophage Autophagy in Immunity to Cryptococcus neoformans and Candida albicans André Moraes Nicola, Patrícia Albuquerque, Luis R. Martinez, Rafael Antonio Dal-Rosso, Carolyn Saylor, Magdia De Jesus, Joshua D. Nosanchuk and Arturo Casadevall Downloaded from Infect. Immun. 2012, 80(9):3065. DOI: 10.1128/IAI.00358-12. Published Ahead of Print 18 June 2012. Updated information and services can be found at: http://iai.asm.org/content/80/9/3065 http://iai.asm.org/ These include: SUPPLEMENTAL MATERIAL Supplemental material REFERENCES This article cites 51 articles, 17 of which can be accessed free on March 26, 2013 by ALBERT EINSTEIN COLL OF MED at: http://iai.asm.org/content/80/9/3065#ref-list-1 CONTENT ALERTS Receive: RSS Feeds, eTOCs, free email alerts (when new articles cite this article), more» Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/ Macrophage Autophagy in Immunity to Cryptococcus neoformans and Candida albicans André Moraes Nicola,* Patrícia Albuquerque,* Luis R. Martinez,* Rafael Antonio Dal-Rosso, Carolyn Saylor, Magdia De Jesus,* Joshua D. Nosanchuk, and Arturo Casadevall Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Downloaded from 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 opportu- nistic 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 mac- http://iai.asm.org/ rophages (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 differ- ent 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-in- duced 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 on March 26, 2013 by ALBERT EINSTEIN COLL OF MED 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. ryptococcus neoformans and Candida albicans are two of the ence of risk factors such as immunosuppression, use of antibacte- Cmost important human-pathogenic fungi. C. neoformans is a rial therapy, major abdominal surgery, or placement of venous soil saprophyte with a worldwide distribution, whereas C. albicans and urinary catheters, C. albicans cells can breach epithelial barri- is a commensal in the human digestive tract and skin. Despite ers and reach the bloodstream, from where they disseminate to these differences, these two microorganisms are common causes cause invasive candidiasis with a mortality of 30 to 40% (9). Mac- of severe systemic infections in the vast population of immuno- rophages are among the most important immune cells in control- compromised individuals that results from the AIDS pandemic, ling C. albicans cells in tissues and the bloodstream, both because hematologic malignancies, and therapies created by modern med- they phagocytose and kill the fungus and because they secrete icine, such as transplantation, intravenous catheters, and immu- proinflammatory cytokines (47). nosuppressive drugs. Autophagy is a mechanism by which cells recycle cytoplasmic C. neoformans is unique among the medically important fungi material and organelles. It is conserved through all Eukarya and for bearing a polysaccharide capsule, which is its major virulence has been shown to play important roles in homeostasis and patho- attribute (50). Cryptococcosis most commonly presents as a me- genesis (26). Several forms of autophagy are recognized, but only ningoencephalitis that is fatal when untreated and that kills about macroautophagy will be dealt with in this report. This process 20% of the patients, despite treatment with amphotericin B and results in the sequestration of intracellular material inside a dou- flucytosine (34). Moreover, these drugs lead to acute renal failure ble-membrane vesicle named an autophagosome. The formation in 49% to 65% of the patients (5), poignant reminders that anti- fungal therapy is far from optimal. The global burden of crypto- coccosis exceeds 1 million cases a year, of whom about 600,000 die Received 4 April 2012 Returned for modification 27 April 2012 (33). The initial infection with C. neoformans, usually subclinical, Accepted 1 June 2012 is believed to commonly occur in early childhood (11) due to Published ahead of print 18 June 2012 inhalation of desiccated yeast cells and spores. Upon deposition in Editor: G. S. Deepe, Jr. the lung, fungal particles are phagocytosed by alveolar macro- Address correspondence to Arturo Casadevall, [email protected]. phages and the yeast cells can survive within mature phagosomes. * Present address: André Moraes Nicola, Universidade Católica de Brasília, Brasília, DF, Brazil; Patrícia Albuquerque, Universidade de Brasília, Brasília, DF, Brazil; Luis R. The host response leads to the formation of granulomas contain- Martinez, Department of Biomedical Sciences, Long Island University, Brookville, ing the intracellular or extracellular yeast, which herald the state of New York, USA; Magdia De Jesus, Division of Infectious Diseases, Wadsworth latency (8, 21). Center, New York State Department of Health, Albany, New York, USA. C. albicans is a commensal in most humans but can cause a Supplemental material for this article may be found at http://iai.asm.org/. wide range of diseases, especially in hosts with impaired immunity Copyright © 2012, American Society for Microbiology. All Rights Reserved. (19). The most common ones are superficial infections of the oro- doi:10.1128/IAI.00358-12 pharyngeal, esophageal, or vaginal mucosa and skin. In the pres- September 2012 Volume 80 Number 9 Infection and Immunity p. 3065–3076 iai.asm.org 3065 Nicola et al. of these vesicles requires two ubiquitin-like conjugates, one imal Care (AAALAC) and National Institutes of Health (NIH) guidelines. formed by ATG5 (autophagy-related 5) and ATG12 and the other All experiments were approved by the Albert Einstein College of Medicine formed by LC3 (microtubule-associated protein 1 light chain 3 Institutional Animal Care and Use Committee (IACUC). alpha) and phosphatidylethanolamine (20). After their formation, ATG5 knockdown by shRNA lentiviral transduction. RNA interfer- autophagosomes fuse with lysosomes, resulting in the digestion ence was used to reduce expression of ATG5, a gene that is essential for and recycling of nutrients (26). autophagy (27). J774.16 cells were stably transduced with lentiviral vec- tors encoding five different small hairpin RNAs (shRNAs) that target In addition to its role in nutritional homeostasis, autophagy ATG5 and one scrambled shRNA without targets in the murine genome. has recently been established as a mechanism of innate immunity Transduced cells were then selected and maintained in medium supple- against viruses, bacteria, and protozoa (6). The formation of au- mented with 5 ␮g/ml puromycin. Knockdown efficiency was assessed by Downloaded from tophagosomes around pathogens found in the cytoplasm, such as immunoblotting using rabbit polyclonal antibody to murine ATG5 Sindbis virus (22)orListeria monocytogenes (39), leads to their (Santa Cruz Biotechnology), followed by detection with horseradish per- clearance by lysosomal degradation. It also allows the cell to over- oxidase and chemiluminescence (Thermo Scientific). Sample loading was come pathogen-mediated inhibition of phagosomal maturation, controlled by stripping the membranes and reprobing with mouse mono- as demonstrated by the gamma interferon (IFN-␥)-dependent, clonal antibody to ␤-actin. To obtain optimal ATG5-knockdown effi- autophagy-mediated clearance of Mycobacterium tuberculosis ciency, individual transduced cells were cloned by limiting dilution, and (12). A recent study found that autophagy is also involved in the those ones with the lowest ATG5 expression were selected. Macrophage-fungus interaction assays. (i) C. neoformans. Two dif- interaction between C. neoformans and macrophages (37). http://iai.asm.org/ Screening an RNA interference library, the autophagy genes Atg2, ferent assays were used to study the
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