Abe T et al. (1993) Parasite Immunol "Different susceptibility to the IL-3 induced-protective effects between Strongyloides ratti and Nippostrongylus brasiliensis in C57BL/6 mice."

Sugaya H, Yoshimura K, Abe T

[Parasite Immunol, 1993]

Repetitive administration of recombinant IL-3 induced protection against Strongyloides ratti but not against Nippostrongylus brasiliensis in C57BL/6 mice. Numbers of S. ratti were negligible from day 4 to day 6 post-infection in mice injected with IL-3, whereas N. brasiliensis burdens were almost equal from day 4 to day 6 between mice injected with IL-3 or with medium. Mice treated with IL-3 and then concurrently infected with S. ratti and N. brasiliensis were protected from intestinal S. ratti but not from N. brasiliensis. The numbers of intestinal mucosal mast cells were increased by the repetitive IL-3 treatment on one day after the final injection and was augmented by subsequent infection with both nematodes.

O'Connell EM et al. (2015) J Infect Dis "Targeting Filarial Abl-like Kinases: Orally Available, Food and Drug Administration-Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and Macrofilaricidal."

Nutman TB, O'Connell EM, Bennuru S, Steel C, Dolan MA

[J Infect Dis, 2015]

BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.

Abe T et al. (1988) Immunology "Worm expulsion and mucosal mast cell response induced by repetitive IL-3 administration in Strongyloides ratti-infected nude mice."

Abe T, Nawa Y

[Immunology, 1988]

After a primary infection of congenitally athymic nu/nu mice with Strongyloides ratti, worms were not expelled and the number of intestinal mucosal mast cells (MMC) remained at a low level. When S. ratti-infected nu/nu mice were treated by repetitive injections of semi-purified IL-3 from Day 5 to Day 10 post-infection (total 1.4 X 10(5) U), significant reduction of larval excretion in faeces (LPG) was observed on Day 13. The number of adult worms in the small intestine of IL-3-treated mice was significantly lower than that of untreated, infected nude mice. The higher dose of IL-3 treatment from Day 4 to Day 13 (total 5.8 X 10(5) U) caused more profound reduction of LPG as early as Day 9, although complete cessation of LPG was not observed until Day 13, the end of this series of experiments. By this higher dose of IL-3 treatment, adult worms were completely expelled from the small intestine, although a small number of residual worms, which could explain the persistent low level of LPG detected from Day 9 to Day 13, was found in the caecum. Histological examination revealed that the number of MMC, especially in the epithelium, of the small intestine of IL-3-treated mice was significantly higher than that of untreated mice.

Abe T et al. (1992) Immunology "Induction of the expulsion of Strongyloides ratti and retention of Nippostrongylus brasiliensis in athymic nude mice by repetitive administration of recombinant interleukin-3."

Nawa Y, Abe T, Yoshimura K, Sugaya H

[Immunology, 1992]

A repetitive administration of recombinant interleukin-3 (rIL-3), which can induce the expulsion of Strongyloides ratti in athymic nude mice, did not affect the expulsion of Nippostrongylus brasiliensis. Nude mice infected with N. brasiliensis were injected i.p. with a total of 6.8 x 10(5) U rIL-3 or medium twice a day from Day 5 to Day 11 post-infection. The kinetics of expulsion estimated by egg excretion in faeces up to Day 20 post-infection and adult worm burden on Day 21 was not affected by the IL-3 administration. A similar administration with a higher dose (total 10.6 x 10(5) U) of rIL-3 did not alter the adult worm burden on Day 13. The number of intestinal mucosal mast cells on Day 13 was markedly increased by the treatment, although the number of intestinal goblet cells was comparable between the treated and control mice. When nude mice were infected concurrently with N. brasiliensis and S. ratti and then injected repeatedly with rIL-3 (total 2.2 x 10(5) U) from Day 5 to Day 11, adult worms of S. ratti were expelled from the small intestine by Day 13; however adult worms of N. brasiliensis were retained. Again in the concurrent infection, the number of intestinal mucosal mast cells was significantly increased but that of intestinal goblet cells was not altered by the rIL-3 administration. These results indicate that the expulsion of S. ratti is dependent on IL-3 whereas that of N. brasiliensis is less dependent on IL-3.

King CD et al. (2018) J Proteomics "Proteomic identification of virulence-related factors in young and aging C. elegans infected with Pseudomonas aeruginosa."

Keith SA, Singh D, King CD, Govan AB, Holden K, Robinson RAS, Ghazi A

[J Proteomics, 2018]

The molecular mechanisms that distinguish immunosenescence from general age-related decline are poorly understood. We addressed this by exposing Day 1 and Day 5 adults of Caenorhabditis elegans to Pseudomonas aeruginosa strain PA01, an opportunistic pathogen. Day 5 adult C. elegans exhibited greater vulnerability to infection as compared to Day 1 C. elegans. Using TMT⁶-plex isobaric labeling and reductive dimethylation, we identified 55 proteins whose levels were altered following infection of Day 1 and Day 5 adults. Proteins whose levels changed in response to infection at both ages were strongly enriched for locomotory functions underscoring the importance of pathogen avoidance mechanisms. In Day 1 C. elegans, proteins with reproductive functions were highly enriched, whereas, Day 5 worms showed elevated levels of factors representing stress response pathways such as unfolded protein response (UPR) and metabolic functions. We also found that PA01 infection is associated with elevated protein carbonylation, an irreversible marker for oxidative stress. We explored the function of UNC-60, a cytoskeletal protein whose levels were changed by both age and infection, and found that mutants of unc-60 have reduced lifespan. Overall, our data provide novel insights into the relationship between age and immunosenescence in metazoans.

Bolanowski MA et al. (1981) Mech Ageing Dev "Quantitative measures of aging in the nematode Caenorhabditis elegans. I. Population and longitudinal studies of two behavioral parameters."

Bolanowski MA, Jacobson LA, Russell RL

[Mech Ageing Dev, 1981]

As a first step in the quantitative characterization of senescence in the nematode Caenorhabditis elegans, we have studied movement wave frequency, defecation frequency, and whole-body water efflux as a function of age. Populations of C. elegans, strain N2, were cultured monoxenically on E. coli lawns at 20 degrees C. The median lifespan in such populations was approximately 12 days. Population mean movement wave frequency declined linearly with age (slope = -4.66 waves/minute per day). The decline in population mean defecation frequency (defecations per minute) was multiphasic, consisting of (1) a rapid decline (slope = -0.233 defecations/minute per day) from day 3 to day 6, (2) no apparent trend from day 6 to day 9, and (3) a gradual decline (slope = -0.089 defecations/minute per day) from 9 to day 14. Animals alive on or after day 15 were not observed to defecate. In longitudinal studies, individual animals exhibited linear declines in movement wave frequency and multiphasic declines in defecation frequency. For future population studies, the age- dependent declines in movement and defecation frequency appear sufficiently large and reproducible to a multiparametric description of senescence in C. elegans. One physiological parameter, 3H2O efflux, was found to be age-independent and to consist of two first- order rates. The half-times of the slow and fast efflux rates were approximately 15 and approximately 2.1 minutes, respectively. The two half-times and the fractions of 3H2O exhibiting the two half-times were invariant with

Ebrahimi CM et al. (2007) Genes Brain Behav "Early patterned stimulation leads to changes in adult behavior and gene expression in C. elegans."

Rankin CH, Ebrahimi CM

[Genes Brain Behav, 2007]

Across phylogeny, early experience plays a critical role in nervous system development. In these experiments, we investigated the long-term effects that specific patterns of sensory experience during development had on the biology and function of the Caenorhabditis elegans nervous system. The delivery of a specific pattern of mechanosensory stimulation in the first larval stage (L1) produced significant enhancement in the tap withdrawal behavioral response, expression patterns of an ionotropic glutamate receptor (iGluR) subunit and mRNA levels for that receptor in 3-day-old adult worms and a depression of these same three measures in 5-day-old adult worms. A critical period for the 3-day enhanced behavior and GLR distribution was observed in L1, whereas there was no critical period for the depressed effects observed in 5-day-old worms. The spaced pattern of stimulation was essential for expression of this effect: Various forms of massed training produced neither the enhancement at 3 days nor the depression at 5 days. The 5-day depressed behavioral response had many features in common with long-term memory, including sensitivity to disruption following retrieval. The different behavioral and molecular effects that early patterned mechanosensory stimulation produced in 3 and 5-day-old worms led us to hypothesize that separate cellular phenomena produced the enhanced 3-day and depressed 5-day behaviors and molecular effects.

Shintoku Y et al. (2011) Parasitology "Strongyloides ratti: transplantation of adults recovered from the small intestine at different days after infection into the colon of naive and infection-primed Wistar rats, and the effect of antioxidant treatment on large intestinal parasitism."

Shintoku Y, Kadosaka T, Itoh M, Kimura E, Takagi H, Honda S, Kondo S, Nagaoka F

[Parasitology, 2011]

Strongyloides ratti (Nagoya strain) is unique in that a portion of adults parasitizing the small intestine withstands 'worm expulsion', which starts at around day 8 post-infection (p.i.) by host immunity, and establishes in the large intestine after day 19 p.i. To investigate the mechanism, adults obtained from the small intestine at day 7 or 19 p.i. were transplanted into the colon of infection-primed immune rats. Adults obtained at day 7 p.i. were rejected quickly, whereas those obtained at day 19 p.i. could establish infection. Moreover, the body length and the number of intrauterine eggs increased in the large intestine. In a separate experiment, large intestinal parasitism was abolished by the treatment of host rats with an anti-oxidant, butylated hydroxyanisole. These results indicate that small intestinal adults between days 7 and 19 p.i. acquired the ability to parasitize the large intestine of immune rats, and that free radicals produced by the host may have played a significant role in the process.

Shen EZ et al. (2014) Nature "Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans."

Lin Y, Lin N, Su PF, Xu J, Wang X, Song CQ, Zhang WH, Zhang P, Zhan C, Liu WY, Dong MQ, Shyr Y, Shen EZ, Cheng H

[Nature, 2014]

It has been theorized for decades that mitochondria act as the biological clock of ageing, but the evidence is incomplete. Here we show a strong coupling between mitochondrial function and ageing by in vivo visualization of the mitochondrial flash (mitoflash), a frequency-coded optical readout reflecting free-radical production and energy metabolism at the single-mitochondrion level. Mitoflash activity in Caenorhabditis elegans pharyngeal muscles peaked on adult day 3 during active reproduction and on day 9 when animals started to die off. A plethora of genetic mutations and environmental factors inversely modified the lifespan and the day-3 mitoflash frequency. Even within an isogenic population, the day-3 mitoflash frequency was negatively correlated with the lifespan of individual animals. Furthermore, enhanced activity of the glyoxylate cycle contributed to the decreased day-3 mitoflash frequency and the longevity of daf-2 mutant animals. These results demonstrate that the day-3 mitoflash frequency is a powerful predictor of C.elegans lifespan across genetic, environmental and stochastic factors. They also support the notion that the rate of ageing, although adjustable in later life, has been set to a considerable degree before reproduction ceases.

Wypijewska A et al. (2012) Biochemistry "7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity."

Wypijewska A, Darzynkiewicz E, Davis RE, Jemielity J, Bojarska E, Lukaszewicz M, Stepinski J

[Biochemistry, 2012]

Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.