title: Increased disease severity of parasite-infected TLR2-/- mice is correlated with decreased central nervous system inflammation and reduced numbers of cells with alternatively activated macrophage phenotypes in a murine model of neurocysticercosis.
abstract: In a murine model for neurocysticercosis (NCC), intracranial inoculation of the helminth parasite Mesocestoides corti induces multiple Toll-like receptors (TLRs), among which TLR2 is upregulated first and to a relatively high extent. Here, we report that TLR2(-/-) mice displayed significantly increased susceptibility to parasite infection accompanied by increased numbers of parasites in the brain parenchyma compared to infection in wild-type (WT) mice. This coincided with an increased display of microglial nodule formations and greater neuropathology than in the WT. Parasite-infected TLR2(-/-) brains exhibited a scarcity of lymphocytic cuffing and displayed reduced numbers of infiltrating leukocytes. Fluorescence-activated cell sorter (FACS) analyses revealed significantly lower numbers of CD11b(+) myeloid cells, γδ T cells, αβ T cells, and B cells in the brains of parasite-infected TLR2(-/-) mice. This correlated with significantly reduced levels of inflammatory mediators, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), CCL2, CCL3, and interleukin-6 (IL-6) in the central nervous system (CNS) of TLR2(-/-) mice. As TLR2 has been implicated in immune regulation of helminth infections and as alternatively activated macrophages (AAMs) are thought to play a profound regulatory role in such infections, induction of AAMs in infected TLR2(-/-) mice was compared with that in WT mice. Parasite-infected WT brains showed larger numbers of macrophages/microglia (CD11b(+) cells) expressing AAM-associated molecules such as YM1, Fizz1 (found in inflammatory zone-1 antigen), and arginase 1 than TLR2(-/-) brains, consistent with a protective role of AAMs during infection. Importantly, these results demonstrate that TLR2-associated responses modulate the disease severity of murine NCC.
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-1644,USA.
authors.forename: Uma Mahesh
authors.initials: UM
authors.lastname: Gundra
authors.forename: Bibhuti B
authors.initials: BB
authors.lastname: Mishra
authors.forename: Kondi
authors.initials: K
authors.lastname: Wong
authors.forename: Judy M
authors.initials: JM
authors.lastname: Teale
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001402:B-Lymphocytes; D001921:Brain / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D039481:CD11b Antigen / Q000032:analysis; D002590:Cestode Infections / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008645:Mesocestoides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D020019:Neurocysticercosis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D013601:T-Lymphocytes; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; D051195:Toll-Like Receptor 2; C544448:Arg1 protein, mouse; D001119:Arginase