Abstract
Infection with the obligate intracellular protozoan Leishmania is thought to be initiated by direct parasitization of macrophages, but the early events following transmission to the skin by vector sand flies have been difficult to examine directly. Using dynamic intravital microscopy and flow cytometry, we observed a rapid and sustained neutrophilic infiltrate at localized sand fly bite sites. Invading neutrophils efficiently captured Leishmania major (L.m.) parasites early after sand fly transmission or needle inoculation, but phagocytosed L.m. remained viable and infected neutrophils efficiently initiated infection. Furthermore, neutrophil depletion reduced, rather than enhanced, the ability of parasites to establish productive infections. Thus, L.m. appears to have evolved to both evade and exploit the innate host response to sand fly bite in order to establish and promote disease.
MeSH Terms
Animals
Apoptosis
Cell Movement
Flow Cytometry
Host-Parasite Interactions
Insect Bites and Stings
Insect Vectors/parasitology
Leishmania major/immunology,physiology
Leishmaniasis, Cutaneous/immunology,parasitology,transmission
Macrophages/parasitology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy
Neutrophil Infiltration
Neutrophils/immunology,parasitology,physiology
Phagocytosis
Phlebotomus/parasitology
Skin/immunology,parasitology
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Peters Nathan C
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Egen Jackson G
Secundino Nagila
Debrabant Alain
Kimblin Nicola
Kamhawi Shaden
Lawyer Phillip
Fay Michael P
Germain Ronald N
Sacks David
References (26)
26 references, click to expand
-
A natural model of Leishmania major infection reveals a prolonged "silent" phase of parasite amplification in the skin before the onset of lesion formation and immunity.
J Immunol. 2000 Jul 15;165(2):969-77
PMID: 10878373
-
Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies.
Science. 2000 Nov 17;290(5495):1351-4
PMID: 11082061
-
The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically?
Immunology. 2004 Sep;113(1):1-14
PMID: 15312130
-
How human neutrophils kill and degrade microbes: an integrated view.
Immunol Rev. 2007 Oct;219:88-102
PMID: 17850484
-
Modulation of dendritic cell function by Leishmania parasites.
J Immunol. 2008 Apr 1;180(7):4355-60
PMID: 18354154
-
Delayed-type hypersensitivity to Phlebotomus papatasi sand fly bite: An adaptive response induced by the fly?
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6704-9
PMID: 10841567
-
Clearance of apoptotic and necrotic cells and its immunological consequences.
Apoptosis. 2006 Oct;11(10):1709-26
PMID: 16951923
-
How neutrophils kill microbes.
Annu Rev Immunol. 2005;23:197-223
PMID: 15771570
-
Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators.
J Infect Dis. 2002 Mar 1;185(5):673-81
PMID: 11865425
-
An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB/c mice infected with Leishmania major.
J Immunol. 2000 Sep 1;165(5):2628-36
PMID: 10946291
-
Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene.
J Leukoc Biol. 2004 Apr;75(4):612-23
PMID: 14726498
-
Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes.
Int J Parasitol. 2004 Aug;34(9):991-6
PMID: 15313126
-
Neutrophils, apoptosis and phagocytic clearance: an innate sequence of cellular responses regulating intramacrophagic parasite infections.
Parasitology. 2006;132 Suppl:S61-8
PMID: 17018166
-
T-cell engagement of dendritic cells rapidly rearranges MHC class II transport.
Nature. 2002 Aug 29;418(6901):983-8
PMID: 12198548
-
Innate response to focal necrotic injury inside the blood-brain barrier.
J Immunol. 2006 Oct 15;177(8):5269-77
PMID: 17015712
-
Inflammatory cells during wound repair: the good, the bad and the ugly.
Trends Cell Biol. 2005 Nov;15(11):599-607
PMID: 16202600
-
Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection.
J Leukoc Biol. 2007 Aug;82(2):288-99
PMID: 17449725
-
Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major.
J Immunol. 2002 Jul 15;169(2):898-905
PMID: 12097394
-
Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages.
Blood. 2000 Jul 15;96(2):719-26
PMID: 10887140
-
Apoptosis driven infection.
Autoimmunity. 2007 Jun;40(4):349-52
PMID: 17516227
-
Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies.
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10125-30
PMID: 18626016
-
Quantitative imaging of Plasmodium transmission from mosquito to mammal.
Nat Med. 2006 Feb;12(2):220-4
PMID: 16429144
-
Immune privilege in sites of chronic infection: Leishmania and regulatory T cells.
Immunol Rev. 2006 Oct;213:159-79
PMID: 16972903
-
The involvement of neutrophils in the resistance to Leishmania major infection in susceptible but not in resistant mice.
Parasitol Int. 2005 Jun;54(2):109-18
PMID: 15866472
-
Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages.
J Immunol. 2004 Dec 1;173(11):6521-5
PMID: 15557140
-
Saliva from Lutzomyia longipalpis induces CC chemokine ligand 2/monocyte chemoattractant protein-1 expression and macrophage recruitment.
J Immunol. 2005 Dec 15;175(12):8346-53
PMID: 16339576