Babu S et al. (1998) J Immunol "Host NK cells are required for the growth of the human filarial parasite Brugia malayi in mice."

Shultz LD, Rajan TV, Porte P, Klei TR, Babu S

[J Immunol, 1998]

Human lymphatic filariasis, which afflicts an estimated 120 million people worldwide, is caused by the large nematode parasites Wuchereria bancrofti and Brugia malayi. Filarial nematodes require both an arthropod vector and a mammalian host to complete their life cycle. Within the definitive (mammalian) host, the lymphatic filarial parasites reside in the lymph nodes and lymphatics, a seemingly hostile environment for infectious agents, since the location exposes them to the immune defenses of the host. We present data here that suggest that the growth of B. malayi in the mammalian host is dependent on host NK cell function. Comparisons of worm survival and development in different strains of mice with varying levels of NK cell activity reveal that NOD/LtSz-scid/scid and NOD/LtSz-scid/scid B2m(null) mice (with diminished to absent NK cell activity respectively), are nonpermissive to worm growth, while C.B-17-scid/scid mice with normal NK cell activity are highly permissive. Depletion of NK cells in the permissive C57BL/6J-scid/scid mice renders them nonpermissive to B. malayi growth, whereas stimulation of NK cells in NOD/LtSz-scid/scid mice makes them permissive. Tg epsilon26 mice, which lack NK and T cells, are nonpermissive, but, when reconstituted with NK cells by adoptive transfer of bone marrow cells from C57BL16J-scid/scid mice, are rendered permissive. This requirement for NK cell activity may explain the site specificity of these parasites. Furthermore, these data suggest that the interaction of the host immune system with the filarial parasite is double edged, with both host protective and parasite growth-promoting activities emanating from the former.

Harfe BD et al. (1994) Worm Breeder's Gazette "ceh-24, a New NK Class Homeodomain Gene."

Okkema PG, Fire A, Harfe BD

[Worm Breeder's Gazette, 1994]

ceh-24, a new NK class homeodomain gene Brian Harfe 1, 2, Pete Okkema 1, and Andy Fire 1 1 Carnegie Institution of Washington, Department of Embryology, 2 Biology Graduate Program, The Johns Hopkins University The NK class of homeodomain proteins are a set of regulatory factors with a broad evolutionary distribution and a variety of expression patterns. Analysis of pharyngeal myosin regulation led to the identification of a member of this family, ceh-22, which appears to mediate aspects of pharyngeal gene expression (Okkema and Fire, Development 120, 2175). To determine the extent of the NK homeodomain family in C. elegans we have used a degenerate primer based PCR strategy. Among several candidates from the initial PCR, we have so far characterized one gene, denoted ceh-24. The CEH-24 homeodomain falls into the NK class, but is closer to diverse members of the NK family seen in other species than to CEH-22. In addition to the homeodomain, CEH-24 contains an acid activation domain C-terminal to the homeodomain. ceh-24 maps (thanks to Alan Coulson) to chromosome V just left of him-5.

Barua P et al. (2011) Southeast Asian J Trop Med Public Health "A rare case of ocular onchocerciasis in India."

Bhuyan S, Alam ST, Hazarika NK, Barua P, Barua N, Sharma A

[Southeast Asian J Trop Med Public Health, 2011]

Onchocerca volvulus is a spirurid nematode that mainly affects the rural poor of Sub-Saharan Africa, Yemen and parts of Central and South Africa. River blindness, caused by Onchocerca volvulus, is considered to be the second commonest infectious cause of blindness worldwide. We report a rare case of ocular onchocerciasis where a live adult worm was extracted from the eye of a patient from a nonendemic region. The worm was identified as Onchocerca volvulus based on morphological features. The patient was treated with Ivermectin (0.2 mg/kg). At six months follow-up she had complete remission of symptoms.

Harfe BD et al. (1995) International C. elegans Meeting "ceh-24, A NEW NK CLASS HOMEODOMAIN GENE"

Okkema PG, Fire A, Harfe BD

[International C. elegans Meeting, 1995]

We are interested in the mechanisms establishing muscle diversity in C. elegans. The NK class of homeodomain proteins are a set of regulatory factors with a broad evolutionary distribution and a variety of expression patterns in both muscle and nonmuscle tissue. Analysis of pharyngeal myosin regulation led to the identification of a member of this family, ceh-22, which appears to mediate aspects of pharyngeal gene expression (see abstract by P. Okkema et al.). To determine the extent of the NK homeodomain family in C. elegans we have used a degenerate primer based PCR strategy. Among several candidates from the initial PCR, we have so far characterized one gene, denoted ceh-24. The CEH-24 homeodomain falls into the NK class, but is closer to diverse members of the NK family seen in other species than to CEH-22. In addition to the homeodomain, CEH-24 contains an acid activation domain C-terminal to the homeodomain. ceh-24 maps (thanks to Alan Coulson) to chromosome V just left of him-5. We are in the process of determining the ceh-24 expression pattern using several approaches (in situs, antibodies, and lacZ fusions). lacZ reporter constructs have been the first to yield results; these have been quite intriguing. We started with a large construct with the first 3 exons of ceh-24 and approximately 8 kb upstream. In hermaphrodites, beta-galactosidase is detected in the eight vulva muscle cells, muscle m8 of the pharynx, and 6-8 unidentified non-pharyngeal cells in the head (presumptive neurons). In males, the same staining pattern is seen in the head and pharynx. Instead of vulval muscle, we see a set of male tail cells that may be lineally equivalent to vulval muscle. Preliminary deletion analysis of upstream sequences suggests that distinct elements contribute to m8 and vulval activity of the promoter.

Sinchita Roy Chowdhuri et al. (2004) Mid-west Worm Meeting "The C. elegans T-box gene tbx-2 is required for pharyngeal development"

Sinchita Roy Chowdhuri, Peter G Okkema, Yen Huynh

[Mid-west Worm Meeting, 2004]

T-domain transcription factors are crucial developmental regulators in all animals. In the vertebrate heart, T-domain factors interact genetically and physically with NK-2 homeodomain factors to promote cardiomyocyte differentiation. C. elegans contains 20 T-box genes, many of which have not been functionally characterized. We have focused on tbx-2 , a member of the Tbx2 subfamily that includes factors involved in vertebrate heart development. Loss of C. elegans tbx-2 function, either by RNAi or in deletion mutants, results in feeding defects, L1 arrest and abnormal pharyngeal morphology, although most markers of pharyngeal differentiation are expressed. These phenotypes are similar to those of animals defective in the pharyngeal muscle specific NK-2 homeobox gene ceh-22 , and we hypothesize tbx-2 functions with ceh-22 in pharyngeal muscle development. A ceh-22::gfp reporter is expressed in tbx-2 mutants, although the number of ceh-22::gfp expressing cells is reduced. We are currently examining the tbx-2 expression pattern to understand its role in pharyngeal development and to determine if it is co-expressed with ceh-22 . In addition we are currently examining possible genetic and physical interactions between tbx-2 and ceh-22 .

Broitman-Maduro G et al. (2009) Development "The NK-2 class homeodomain factor CEH-51 and the T-box factor TBX-35 have overlapping function in C. elegans mesoderm development."

Sternberg PW, Broitman-Maduro G, Maduro MF, Hung WW, Owraghi M, Kuntz S

[Development, 2009]

The C. elegans MS blastomere, born at the 7-cell stage of embryogenesis, generates primarily mesodermal cell types, including pharynx cells, body muscles and coelomocytes. A presumptive null mutation in the T-box factor gene tbx-35, a target of the MED-1 and MED-2 divergent GATA factors, was previously found to result in a profound decrease in the production of MS-derived tissues, although the tbx-35(-) embryonic arrest phenotype was variable. We report here that the NK-2 class homeobox gene ceh-51 is a direct target of TBX-35 and at least one other factor, and that CEH-51 and TBX-35 share functions. Embryos homozygous for a ceh-51 null mutation arrest as larvae with pharynx and muscle defects, although these tissues appear to be specified correctly. Loss of tbx-35 and ceh-51 together results in a synergistic phenotype resembling loss of med-1 and med-2. Overexpression of ceh-51 causes embryonic arrest and generation of ectopic body muscle and coelomocytes. Our data show that TBX-35 and CEH-51 have overlapping function in MS lineage development. As T-box regulators and NK-2 homeodomain factors are both important for heart development in Drosophila and vertebrates, our results suggest that these regulators function in a similar manner in C. elegans to specify a major precursor of mesoderm.

Babu S et al. (1999) Exp Parasitol "T cells facilitate Brugia malayi development in TCRalpha(null) mice."

Shultz LD, Babu S, Rajan TV

[Exp Parasitol, 1999]

The host-parasite interactions of Brugia malayi in mice are complex and multifactorial. In order to study the role of T cells in early B. malayi development, we infected TCRalpha(null) mice, which retain a population of CD4+ TCRbeta+ cells and TCRbeta(null) mice, which lack all TCRalphabeta(+) T cells. TCRalpha(null) mice were permissive to L4 larval and adult worm development but TCRbeta(null) mice were not. Depletion of the CD4(+) T cells in the former abrogated the permissive phenotype. It appears that the CD4(+) TCRbeta(+) T cells that have been described in TCRalpha(null) mice may facilitate early B. malayi development. These data are similar to our earlier demonstration of the role of NK cells in facilitating worm growth in SCID mice.

Paramita Ray et al. (2004) Mid-west Worm Meeting "ceh-28 is required for feeding in C. elegans"

Peter G Okkema, Paramita Ray

[Mid-west Worm Meeting, 2004]

NK-2 family homeobox genes are important developmental regulators in many organisms. The C. elegans genome contains 4 members of this gene family ( ceh-22, ceh-24, ceh-27 and ceh-28 ). ceh-22 is expressed in the pharyngeal muscles where it regulates gene expression with the pan-pharyngeal factor PHA-4, and we are determining if additional NK-2 family members function similarly in other pharyngeal cell types. Brian Harfe and Andy Fire have previously shown a ceh-28::gfp transcriptional fusion is expressed exclusively in the M4 pharyngeal neuron. We have similarly found a ceh-28::gfp translational fusion containing 3.7 kb of 5' flanking DNA is expressed in M4. Expression initiates during embryogenesis in two cells, and we speculate these cells are M4 and its sister cell, which dies during normal development. We are currently verifying the expression pattern of the endogenous ceh-28 gene using anti-CEH-28 antibodies. M4 is a motor neuron essential for pharyngeal isthmus peristalsis and feeding. To functionally characterize ceh-28 , we have isolated a deletion mutant ceh-28(cu11) . This deletion removes much of the ceh-28 homeobox and is likely a null allele. Homozygous ceh-28(cu11) strains can be maintained, although these mutants appear starved and exhibit slow growth and partially penetrant larval lethality. Similar phenotypes were observed in ceh-28(RNAi) animals. All ceh-28 mutant worms have a stuffed pharynx phenotype similar to animals in which M4 has been killed by laser ablation (Avery and Horvitz, 1987), suggesting M4 is defective. We are currently examining M4 differentiation, morphology and function in ceh-28(cu11) mutants to understand the role of ceh-28 in pharyngeal development.

Harfe BD et al. (1998) Genes Dev "Analysis of a Caenorhabditis elegans Twist homolog identifies conserved and divergent aspects of mesodermal patterning."

Liu J, Harfe BD, Kenyon CJ, Vaz Gomes A, Fire A, Krause MW

[Genes Dev, 1998]

Mesodermal development is a multistep process in which cells become increasingly specialized to form specific tissue types. In Drosophila and mammals, proper segregation and patterning of the mesoderm involves the bHLH factor Twist. We investigated the activity of a Twist-related factor, CeTwist, during Caenorhabditis elegans mesoderm development. Embryonic mesoderm in C. elegans derives from a number of distinct founder cells that are specified during the early lineages; in contrast, a single blast cell (M) is responsible for all nongonadal mesoderm formation during postembryonic development. Using immunofluorescence and reporter fusions, we determined the activity pattern of the gene encoding CeTwist. No activity was observed during specification of mesodermal lineages in the early embryo; instead, the gene was active within the M lineage and in a number of mesodermal cells with nonstriated muscle fates. A role for CeTwist in postembryonic mesodermal cell fate specification was indicated by ectopic expression and genetic interference assays. These experiments showed that CeTwist was responsible for activating two target genes normally expressed in specific subsets of nonstriated muscles derived from the M lineage. In vitro and in vivo assays suggested that CeTwist cooperates with the C. elegans E/Daughterless homolog in directly activating these targets. The two target genes that we have studied, ceh-24 and egl-15, encode an NK-2 class homeodomain and an FGF receptor (FGFR) homolog, respectively. Twist activates FGFR and NK-homeodomain target genes during mesodermal patterning of Drosophila and similar target interactions have been proposed to modulate mesenchymal growth during closure of the vertebrate skull. These results suggest the possibility that a conserved pathway may be used for diverse functions in mesodermal specification.

Banyai L et al. (1998) Biochim Biophys Acta "Amoebapore homologs of Caenorhabditis elegans."

Banyai L, Patthy L

[Biochim Biophys Acta, 1998]

It is shown that the Caenorhabditis elegans genome contains several distantly related members of the gene family of saposin-like proteins. The putative products of genes T07C4.4, T08A9.7A, T08A9.7B, T08A9.8, T08A9.9, T08A9.10 are similar to the amoebapores of Entamoeba histolytica, granulysin of cytotoxic T lymphocytes and a putative amoebapore-related protein of the liver fluke Fasciola hepatica inasmuch as they consist of only a single saposin-like domain and a secretory signal peptide. The saposin-like domain of protein T07C4.4, which is most closely related to NK-lysin and granulysin, has been expressed in Escherichia coli and the recombinant protein was shown to have a circular dichroism spectrum consistent with the helix bundle structure characteristic of saposin-like domains. Recombinant T07C4.4 protein was found to have antibacterial activity, suggesting that these amoebapore homologs may play a role in antibacterial mechanisms of C. elegans.