Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness).

Toll-like receptors (TLRs) regulate dendritic cell function and activate signals that mediate the nature of the adaptive immune response. The current study examined the role of TLRs in dendritic cell activation and in regulating T cell and antibody responses to antigens from the filarial parasites Onchocerca volvulus and Brugia malayi, which cause river blindness and lymphatic filariasis, respectively. Bone-marrow-derived CD11c(+) cells from C57BL/6 and TLR4(-/-) mice produced high levels of IL-6 and RANTES, and showed elevated surface CD40 expression, whereas CD11c(+) cells from myeloid differentiation factor 88(-/-) (MyD88(-/-)), TLR2(-/-) and TLR2/4(-/-) mice were not activated. Similarly, IFN-gamma production by splenocytes from immunized TLR2(-/-) mice was significantly impaired compared with splenocytes from C57BL/6 and TLR4(-/-) mice. In contrast, there was no difference among these strains in Th2-associated responses including IL-5 production by splenocytes from immunized animals, serum IgE and IgG(1), or eosinophil infiltration into the corneal stroma. Neutrophil recruitment to the cornea and CXC chemokine production was inhibited in immunized TLR2(-/-) mice compared with C57BL/6 and TLR4(-/-) mice. Taken together, these findings demonstrate an essential role for TLR2 in filaria-induced dendritic cell activation, IFN-gamma production and neutrophil migration to the cornea, but does not affect filaria-induced Th2-associated responses.

The role of endosymbiotic Wolbachia bacteria in filarial disease.

In this review, we describe the pathogenic role of Wolbachia endosymbiotic bacteria in filarial diseases, focusing on the host innate immune responses to filarial and Wolbachia products. A description of the host pathogen recognition and early inflammatory responses including TLR4-mediated signalling, chemokine and cytokine responses and inflammatory cell recruitment is provided from human studies and from animal models of filarial disease. Finally, the impact of the discovery and characterization of Wolbachia on filarial research and treatment programmes is discussed.

Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis.

We examined 906 residents of an area of Papua New Guinea where bancroftian filariasis is endemic for genetic polymorphisms in three innate immunity genes suspected of contributing to susceptibility to infection and lymphatic pathology. Active infection was confirmed by the presence of blood-borne microfilariae and circulating filarial antigen in plasma. Disease was ascertained by physical examination for the presence of overt lymphedema (severe swelling of an arm or leg) or hydrocele. There was no association of infection status, lymphedema of an extremity, or hydrocele with chitotriosidase genotype (CHIT1). Polymorphisms of toll-like receptor-2 and toll-like receptor-4 genes (TLR4 A896G; TLR2 T2178A, G2258A) were not detected (N=200-625 individuals genotyped) except for two individuals heterozygous for a TLR2 mutation (C2029 T). These results indicate that a CHIT1 genotype associated previously with susceptibility to filariasis in residents of southern India and TLR2 and TLR4 polymorphisms do not correlate with infection status or disease phenotype in this Melanesian population.

A whole blood bactericidal assay for tuberculosis.

The bactericidal activity of orally administered antituberculosis (anti-TB) drugs was determined in a whole blood culture model of intracellular infection in which microbial killing reflects the combined effects of drug and immune mechanisms. Rifampin (Rif) was the most active compound studied and reduced the number of viable bacilli by >4 logs. Isoniazid (INH), 2 quinolones, and pyrazinamide (PZA) showed intermediate levels of activity. Ethambutol exerted only a bacteristatic effect; amoxicillin/clavulanate was inactive. The combination of INH-Rif-PZA showed strong activity against 11 drug-sensitive isolates (mean, -3.8 log) but no activity against 12 multidrug-resistant (MDR) strains. The combination of levofloxacin-PZA-ethambutol had intermediate bactericidal activity against MDR isolates (mean, -1.2 log) but failed to equal that of INH-Rif-PZA against sensitive isolates (P<.001). The whole blood BACTEC method (Becton Dickinson) may be useful for the early clinical evaluation of new anti-TB drugs and in the management of individual patients.