Neurocysticercosis (NCC) is a common neurological disease in developing countries and the United States caused by the larva stages of the parasite Taenia solium. The pathogenesis and clinical manifestations vary with the location of the parasite within the brain and accompanying host immune response. Our long term goal has been to characterize and understand the host immune response and the pathology associated with NCC to establish better therapeutic interventions. Apart from analyses of brain specimens from NCC patients, we have developed a mouse model of NCC by intra-cranial infection with the related cestode, Mesocestoides corti. We have shown that the parasite releases glycans with distinct sugar specificities that are taken up by host cells in the CNS environment in both human and murine NCC. Of particular relevance, two C-type lectin receptors (CLRs) are highly up-regulated after parasite infection: mannose receptor (MRC1) and macrophage galactose C-type lectin (MGL1) which recognize sugars from parasite and host origin respectively. We hypothesize that recognition of parasite- released glycans via MRC1 leads to protective CNS responses. This is based on the observation that Mrc1-/- mice survive significantly longer and exhibit reduced CNS pathology that correlates with increased infiltration a novel population of myeloid cells with a suppressor phenotype. In contrast, Mgl1-/- mice show decreased survival and up-regulation of inflammatory cytokines. We further hypothesize that CLRs differentially modulate myeloid plasticity thus regulating the degree of inflammation vs. suppression in murine NCC. To test this, we will identify the effects of MRC1 and MGL1 in myeloid cell function during the early and late stages of murine NCC (Aim 1), and determine the mechanisms by which MRC1 modulate effector antigen specific T cell immune responses (Aim 2). Our proposed studies will provide the first detailed assessment of CLR expression and function in CNS parasite infections and present novel therapeutic strategies.

Public Health Relevance

Neurocysticercosis is the most frequent parasitic disease affecting the central nervous system (CNS), and the clinical symptoms can be devastating and lifelong. The severity of the symptoms is associated with the intensity of the immunological response and involves innate immune receptors called C-type lectins, understudied molecules in the CNS. C-type lectins can induce immune suppression so understanding their function will likely result in new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078501-03
Application #
8662823
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$456,601
Indirect Cost
$145,989
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Bemiller, Shane M; Maphis, Nicole M; Formica, Shane V et al. (2018) Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy. J Neuroinflammation 15:278
Wilson, Kyle D; Ochoa, Lorenzo F; Solomon, Olivia D et al. (2018) Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria. J Neuroinflammation 15:173
Mendiola, Andrew S; Cardona, Astrid E (2018) The IL-1? phenomena in neuroinflammatory diseases. J Neural Transm (Vienna) 125:781-795
Mishra, Pramod K; Li, Qun; Munoz, Luis E et al. (2016) Reduced Leukocyte Infiltration in Absence of Eosinophils Correlates with Decreased Tissue Damage and Disease Susceptibility in ?dblGATA Mice during Murine Neurocysticercosis. PLoS Negl Trop Dis 10:e0004787
Garcia, Jenny A; Cardona, Sandra M; Cardona, Astrid E (2014) Isolation and analysis of mouse microglial cells. Curr Protoc Immunol 104:Unit 14.35.
Mishra, Pramod Kumar; Morris, Elizabeth G; Garcia, Jenny A et al. (2013) Increased accumulation of regulatory granulocytic myeloid cells in mannose receptor C type 1-deficient mice correlates with protection in a mouse model of neurocysticercosis. Infect Immun 81:1052-63
Mishra, Pramod Kumar; Teale, Judy M (2013) Changes in gene expression of pial vessels of the blood brain barrier during murine neurocysticercosis. PLoS Negl Trop Dis 7:e2099
Cardona, Sandra M; Garcia, Jenny A; Cardona, Astrid E (2013) The fine balance of chemokines during disease: trafficking, inflammation, and homeostasis. Methods Mol Biol 1013:1-16