Achievements

Research Achievements of the Lab

 

pic1Fungal infections are under recognized causes of human disease with huge economical and health impact [1, 2].  In particular, Aspergillus fumigatus, an airborne ubiquitous saprophytic fungus (mold), is a major cause of asthma, allergy and chronic inflammation of the lung in immunocompetent adults [1-4]. In immunocompromised patients, A. fumigatus is the most important cause of invasive fungal pneumonia worldwide [1, 2] Opportunistic molds are also implicated in recent fatal outbreaks of fungal meningitis associated with the use of contaminated steroid injections [5]. Collectively, invasive mold infections (IMI) are major causes of death in an expanding population of immunocompromised patients with mortality rates that exceed 90% upon disease dissemination [1, 2]. Better understanding of immunopathogenesis of IMI is required to improve patient’s outcome.

Professional phagocytes, mainly alveolar macrophages (AMs) and neutrophils, phagocytose hundreds of inhaled conidia on a daily basis and prevent fungal germination, inflammation and invasive growth [2]. Physiologically, conidia are efficiently eliminated inside acidified phagolysosomes of AMs via incompletely understood mechanisms.

img2Our research in centered on the discovery of novel molecular pathways regulating biogenesis of fungal phagosomes. We have recently identified the important role of a new specialized autophagy pathway termed LC3 associated phagocytosis (LAP) [6], in immunity against Aspergillus fumigatus and identified the signaling requirements for activation of LAP [7]. Specifically, we found that LAP is selectively activated during intracellular swelling of A. fumigatus conidia (spores) via a Dectin-1/Syk Kinase/NADPH oxidase signaling pathway. The physiological role of LAP in Aspergillus immunity was also revealed by the discovery that LAP is compromised in patients with genetic defects in NADPH oxidase activity and following administration of corticosteroids, two uniquely predisposed patient populations for development of invasive aspergillosis.

In a follow up study we discovered that cell wall melanin selectively targets LAP to promote fungal pathogenicity via excluding the p22phox NADPH oxidase subunit from the phagosome membrane. Of interest, melanin-induced LAP blockade was a principal virulence mechanism because the avirulent melanin deficient A. fumigatus mutant regained full virulence in transgenic mice with conditional inactivation of Atg5 in myeloid cells [8].

Collectively, our findings led to a new model of Aspergillus pathogenicity by demonstrating that two fundamental events for elimination of fungal conidia that occur concomitantly during intracellular swelling (i) exposure of PAMPs and (ii) removal of melanin are required for phagosome maturation and fungal killing. Importantly, LAP blockade is a general property of melanin pigments, a finding with broad implication in pathogenesis of human diseases beyond fungal infections.

 

 

Selected References

  1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012 Dec 19;4(165):165rv13.
  2. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011 Apr;11(4):275-88.
  3. Knutsen AP, Bush RK, Demain JG, Denning DW, Dixit A, Fairs A, Greenberger PA, Kariuki B, Kita H, Kurup VP, Moss RB, Niven RM, Pashley CH, Slavin RG, Vijay HM, Wardlaw AJ. Fungi and allergic lower respiratory tract diseases. J Allergy Clin Immunol. 2012 Feb;129(2):280-91; quiz 292-3. doi: 10.1016/j.jaci.2011.12.970.
  4. Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013 May;51(4):361-70
  5. Smith RM, Schaefer MK, Kainer MA, Wise M, Finks J, Duwve J, Fontaine E, Chu A,Carothers B, Reilly A, Fiedler J, Wiese AD, Feaster C, Gibson L, Griese S,Purfield A, Cleveland AA, Benedict K, Harris JR, Brandt ME, Blau D, Jernigan J,Weber JT, Park BJ; Multistate Fungal Infection Outbreak Response Team. Fungal infections associated with contaminated methylprednisolone injections. N Engl JMed. 2013 Oct 24;369(17):1598-609.
  6. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007 Dec 20;450(7173):1253-7
  7. Kyrmizi I, Gresnigt MS, Akoumianaki T, Samonis G, Sidiropoulos P, Boumpas D, Netea MG, van de Veerdonk FL, Kontoyiannis DP, Chamilos G. Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling. J Immunol. 2013 Aug 1;191(3):1287-99.
  8. Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt MS, Samonis G, Drakos E, Boumpas D, Muszkieta L, Prevost MC, Kontoyiannis DP, Chavakis T, Netea MG, van de Veerdonk FL, Brakhage AA, El-Benna J, Beauvais A, Latge JP, Chamilos G. Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity. Cell Host Microbe. 2016 Jan 13;19(1):79-90.