Leishmania major-Infected Phlebotomus duboscqi Sand Fly Bites Enhance Mast Cell Degranulation

Leishmania parasites infect mammalian hosts through the bites of sand fly vectors. The response by mast cells (MC) to the parasite and vector-derived factors, delivered by sand fly bites, has not been characterized. We analyzed MC numbers and their mediators in BALB/c mice naturally infected in the ear with Leishmania major through the bite of the sand fly vector Phlebotomus duboscqi and compared them to non-infected sand fly bites. MC were found at the bite sites of infective and non-infected sand flies throughout 48 h, showing the release of granules with intense TNF-α, histamine, and tryptase staining. At 30 min and 48 h, the MC numbers were significantly higher (p < 0.001) in infected as compared to non-infected bites or controls. Neutrophil recruitment was intense during the first 6 h in the skin of infected and non-infected sand fly bites and decreased thereafter. An influx of neutrophils also occurred in lymph nodes, where a strong TNF-α stain was observed in mononuclear cells. Our data show that MC orchestrate an early inflammatory response after infected and non-infected sand fly bites, leading to neutrophilic recruitment, which potentially provides a safe passage for the parasite within the mammalian host.

[1]  J. Andersen,et al.  A sand fly salivary protein acts as a neutrophil chemoattractant , 2021, Nature Communications.

[2]  S. Kamhawi,et al.  Sequential blood meals augment vector infectiousness by promoting Leishmania replication and triggering amplification of metacyclics via a novel retroleptomonad developmental stage , 2018, Nature Microbiology.

[3]  P. Bhattacharya,et al.  Gut Microbes Egested during Bites of Infected Sand Flies Augment Severity of Leishmaniasis via Inflammasome-Derived IL-1β. , 2018, Cell host & microbe.

[4]  C. Bogdan,et al.  Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response , 2016, Front. Microbiol..

[5]  M. Olivier,et al.  Exosome Secretion by the Parasitic Protozoan Leishmania within the Sand Fly Midgut. , 2015, Cell reports.

[6]  S. Kamhawi,et al.  What's behind a sand fly bite? The profound effect of sand fly saliva on host hemostasis, inflammation and immunity. , 2014, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[7]  S. Kamhawi,et al.  Characterization of the Early Inflammatory Infiltrate at the Feeding Site of Infected Sand Flies in Mice Protected from Vector-Transmitted Leishmania major by Exposure to Uninfected Bites , 2014, PLoS neglected tropical diseases.

[8]  E. Brzezińska‐Błaszczyk,et al.  IgE by Itself Affects Mature Rat Mast Cell Preformed and De Novo-Synthesized Mediator Release and Amplifies Mast Cell Migratory Response , 2013, PloS one.

[9]  R. Dey,et al.  A new model of progressive visceral leishmaniasis in hamsters by natural transmission via bites of vector sand flies. , 2013, The Journal of infectious diseases.

[10]  D. Khismatullin,et al.  Synergistic Effect of Histamine and TNF-α on Monocyte Adhesion to Vascular Endothelial Cells , 2013, Inflammation.

[11]  E. Stebut,et al.  Dendritic cells in Leishmania major infections: mechanisms of parasite uptake, cell activation and evidence for physiological relevance , 2012, Medical Microbiology and Immunology.

[12]  M. Rogers The Role of Leishmania Proteophosphoglycans in Sand Fly Transmission and Infection of the Mammalian Host , 2012, Front. Microbio..

[13]  G. Sridharan,et al.  Toluidine blue: A review of its chemistry and clinical utility , 2012, Journal of oral and maxillofacial pathology : JOMFP.

[14]  V. Dixit,et al.  Signaling in innate immunity and inflammation. , 2012, Cold Spring Harbor perspectives in biology.

[15]  E. von Stebut,et al.  Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function , 2011, European journal of immunology.

[16]  M. Barral-Netto,et al.  Lesion size correlates with Leishmania antigen-stimulated TNF-levels in human cutaneous leishmaniasis. , 2011, The American journal of tropical medicine and hygiene.

[17]  F. Luscinskas,et al.  Regulation of Endothelial Cell Adhesion Molecule Expression by Mast Cells, Macrophages, and Neutrophils , 2011, PloS one.

[18]  M. Tsai,et al.  Mast cells in allergy and infection: Versatile effector and regulatory cells in innate and adaptive immunity , 2010, European journal of immunology.

[19]  S. Abraham,et al.  Mast cell-orchestrated immunity to pathogens , 2010, Nature Reviews Immunology.

[20]  M. Monteiro,et al.  Mast cell degranulation contributes to susceptibility to Leishmania major , 2009, Parasite immunology.

[21]  G. V. van Dooren,et al.  Dynamics of neutrophil migration in lymph nodes during infection. , 2008, Immunity.

[22]  M. Fay,et al.  In Vivo Imaging Reveals an Essential Role for Neutrophils in Leishmaniasis Transmitted by Sand Flies , 2008, Science.

[23]  L. Gutiérrez-Kobeh,et al.  Mast cells are activated by Leishmania mexicana LPG and regulate the disease outcome depending on the genetic background of the host , 2008, Parasite immunology.

[24]  B. S. Schneider,et al.  Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease , 2008, The Journal of experimental medicine.

[25]  G. Caughey Mast cell tryptases and chymases in inflammation and host defense , 2007, Immunological reviews.

[26]  M. Maurer,et al.  Skin mast cells control T cell‐dependent host defense in Leishmania major infections , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  Gunnar Nilsson,et al.  Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion. , 2006, The Journal of clinical investigation.

[28]  L. Fiette,et al.  Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes. , 2005, Blood.

[29]  P. Brey,et al.  Anopheles Mosquito Bites Activate Cutaneous Mast Cells Leading to a Local Inflammatory Response and Lymph Node Hyperplasia1 , 2005, The Journal of Immunology.

[30]  J. Marshall,et al.  Mast cells in innate immunity. , 2004, The Journal of allergy and clinical immunology.

[31]  F. Ribeiro-Gomes,et al.  Macrophage Interactions with Neutrophils Regulate Leishmania major Infection1 , 2004, The Journal of Immunology.

[32]  M. Rogers,et al.  The role of promastigote secretory gel in the origin and transmission of the infective stage of Leishmania mexicana by the sandfly Lutzomyia longipalpis , 2002, Parasitology.

[33]  J. Bonnefoy,et al.  Histamine Induces CD86 Expression and Chemokine Production by Human Immature Dendritic Cells , 2001, The Journal of Immunology.

[34]  Y. Belkaid,et al.  An Immunomodulatory Function for Neutrophils During the Induction of a CD4+ Th2 Response in BALB/c Mice Infected with Leishmania major1 , 2000, The Journal of Immunology.

[35]  S. Holgate,et al.  The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. , 1998, Journal of immunology.

[36]  P. Debré,et al.  Evidence for direct interaction between mast cells and Leishmania parasites , 1997, Parasite immunology.

[37]  R. Tanaka,et al.  Inhaled tryptase causes bronchoconstriction in sheep via histamine release. , 1996, American journal of respiratory and critical care medicine.

[38]  S. Coutinho,et al.  Tumor necrosis factor-alpha in human american tegumentary leishmaniasis. , 1996, Memorias do Instituto Oswaldo Cruz.

[39]  J. Cairns,et al.  Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. , 1996, Journal of immunology.

[40]  J. Butterfield,et al.  Role of tryptase in immediate cutaneous responses in allergic sheep. , 1995, Journal of applied physiology.

[41]  M. Röllinghoff,et al.  Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigen‐specific T cells , 1993, European journal of immunology.

[42]  K. Amin The role of mast cells in allergic inflammation. , 2012, Respiratory medicine.

[43]  C. Shelburne,et al.  The mast cell in innate and adaptive immunity. , 2011, Advances in experimental medicine and biology.

[44]  M. Tsai,et al.  Mast cells as "tunable" effector and immunoregulatory cells: recent advances. , 2005, Annual review of immunology.

[45]  G. Milon,et al.  Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1alpha /beta released from neutrophils recruited by mast cell-derived TNFalpha. , 2003, Blood.

[46]  J. Convit,et al.  Serum levels of tumor necrosis factor in patients with American cutaneous leishmaniasis. , 1993, Biological research.