title: A Novel Model of Asymptomatic Plasmodium Parasitemia That Recapitulates Elements of the Human Immune Response to Chronic Infection.
abstract: In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection.
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Mary F
authors: http://orcid.org/0000-0003-3630-181X
authors: MF
authors: Fontana
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Alyssa
authors: A
authors: Baccarella
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Joshua F
authors: JF
authors: Craft
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.|The Burnet Institute, Center for Biomedical Research, Melbourne, Australia.
authors: Michelle J
authors: MJ
authors: Boyle
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Tara I
authors: TI
authors: McIntyre
authors: Department of Pathology, Division of Neuropathology, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Matthew D
authors: MD
authors: Wood
authors: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, 94158, United States of America.
authors: Kurt S
authors: KS
authors: Thorn
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Chioma
authors: C
authors: Anidi
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Aqieda
authors: A
authors: Bayat
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Me Ree
authors: MR
authors: Chung
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Rebecca
authors: R
authors: Hamburger
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Chris Y
authors: CY
authors: Kim
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Emily
authors: E
authors: Pearman
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Jennifer
authors: J
authors: Pham
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Jia J
authors: JJ
authors: Tang
authors: EPIRUS Biopharmaceuticals, Utrecht, Netherlands BV.
authors: Louis
authors: L
authors: Boon
authors: School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors: Moses R
authors: MR
authors: Kamya
authors: Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Grant
authors: G
authors: Dorsey
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.|Division of Pediatric Infectious Diseases and Global Health, Department of Pediatrics, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Margaret E
authors: ME
authors: Feeney
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
authors: Charles C
authors: CC
authors: Kim
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000469:parasitology*; D016788:Plasmodium chabaudi / Q000302:isolation & purification*