title: Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection.
abstract: The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogenCryptococcus neoformans, remains unknown. Using a mouse model ofC. neoformansinfection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO-/-mice was accompanied by impaired recruitment of Ly6Chighmonocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO-/-mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis duringC. neoformansinfection. Lastly, we found that MARCO was involved inC. neoformansphagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions betweenC. neoformansand lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Jintao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Adam
authors.identifier: 0000-0002-9799-3170
authors.initials: A
authors.lastname: Flaczyk
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Lori M
authors.initials: LM
authors.lastname: Neal
authors.affiliation: Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Zhenzong
authors.identifier: 0000-0003-3975-4996
authors.initials: Z
authors.lastname: Fa
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Eastman
authors.affiliation: Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Antoni N
authors.initials: AN
authors.lastname: Malachowski
authors.affiliation: Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Daphne
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Bethany B
authors.identifier: 0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Jeffrey L
authors.identifier: 0000-0001-5191-4847
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; olszewsm@umich.edu.|Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and.
authors.forename: Michal A
authors.identifier: 0000-0001-7474-0843
authors.initials: MA
authors.lastname: Olszewski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054410:Chemokine CCL7 / Q000378:metabolism; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D054410:Chemokine CCL7; C490460:MARCO protein, human; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D007371:Interferon-gamma