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Achim Hoerauf

Publications and source records attributed to Achim Hoerauf.

At least 19 recordsLinked to original sources
PubMed2006

A niche for Wolbachia.

Wolbachia are endosymbionts of arthropods and filarial nematodes. Arthropods infected with these endobacteria display altered reproductive phenotypes, including cytoplasmic incompatibility and sex-ratio distortion. In nematodes, the endobacteria are essential for embryogenesis and worm survival. Wolbachia are transmitted vertically from mother to progeny, and Frydman et al. recently showed that, after transfer to uninfected Drosophila, Wolbachia rapidly accumulate in the somatic stem cell niche. From this location, the endobacteria might enter the developing oocytes and infect the progeny.

Animals↗
PubMed2006

Cloning, expression and functional activity of deoxyhypusine synthase from Plasmodium vivax.

BACKGROUND: Plasmodium vivax is the most widespread human malaria parasite. However, genetic information about its pathogenesis is limited at present, due to the lack of a reproducible in vitro cultivation method. Sequencing of the Plasmodium vivax genome suggested the presence of a homolog of deoxyhypusine synthase (DHS) from P. falciparum, the key regulatory enzyme in the first committed step of hypusine biosynthesis. DHS is involved in cell proliferation, and thus a valuable drug target for the human malaria parasite P. falciparum. A comparison of the enzymatic properties of the DHS enzymes between the benign and severe Plasmodium species should contribute to our understanding of the differences in pathogenicity and phylogeny of both malaria parasites. RESULTS: We describe the cloning of a 1368 bp putative deoxyhypusine synthase gene (dhs) sequence from genomic DNA of P. vivax PEST strain Salvador I (Accession number AJ549098) after touchdown PCR. The corresponding protein was expressed and functionally characterized as deoxyhypusine synthase by determination of its specific activity and cross-reactivity to human DHS on a Western blot. The putative DHS protein from P. vivax displays a FASTA score of 75 relative to DHS from rodent malaria parasite, P. yoelii, and 74 relative to that from the human parasite, P. falciparum strain 3D7. The ORF encoding 456 amino acids was expressed under control of IPTG-inducible T7 promoter, and expressed as a protein of approximately 50 kDa (theoretically 52.7 kDa) in E. coli BL21 DE3 cells. The N-terminal histidine-tagged protein was purified by Nickel-chelate affinity chromatography under denaturing conditions. DHS with a theoretical pI of 6.0 was present in both eluate fractions. The specific enzymatic activity of DHS was determined as 1268 U/mg protein. The inhibitor, N-guanyl-1, 7-diaminoheptane (GC7), suppressed specific activity by 36-fold. Western blot analysis performed with a polyclonal anti-human DHS antibody revealed cross-reactivity to DHS from P. vivax, despite an amino acid identity of 44% between the proteins. CONCLUSION: We identify a novel DHS protein in the more benign malaria parasite,P. vivax, on the basis of specific enzymatic activity, cross-reactivity with a polyclonal antibody against human DHS, and amino acid identity with DHS homologs from the rodent malaria parasite, P. yoelii, and human P. falciparum strains.

Amino Acid Sequence↗
PubMed2006

Differential display of genes expressed in the filarial nematode Litomosoides sigmodontis reveals a putative phosphate permease up-regulated after depletion of Wolbachia endobacteria.

Mutualist symbiotic Wolbachia endobacteria are found in most filarial nematodes. Wolbachia are essential for embryogenesis and for larval development into adults, and thus represent a new target for anti-filarial drug development. Tetracycline antibiotics deplete Wolbachia in animal model filaria Litomosoides sigmodontis and Brugia pahangi, as well as in the human parasites Brugia malayi, Onchocerca volvulus and Wuchereria bancrofti. Very little is known about the molecular details of the symbiotic interaction between Wolbachia and filarial nematodes. Nematode genes that respond to anti-Wolbachia antibiotic treatment may play important roles in the symbiosis. Differential display PCR was used to detect several candidate genes that are up-regulated after 3, 6, 15, 30 and 36 days of tetracycline treatment. One of these genes, Ls-ppe-1, was similar to a family of phosphate permeases, and had putative orthologues in O. volvulus and B. malayi. Ls-ppe-1 steady-state mRNA levels were elevated by day 3-6 of treatment, and remained elevated through to 70 days post-treatment. In Caenorhabditis elegans, the knockdown of a homologous phosphate permease results in embryonic lethality, with the production of degenerating embryos, a phenotype also seen in filarial nematodes after depletion of Wolbachia with tetracycline. The potential role of Ls-ppe-1 in the nematode-bacterial symbiosis is discussed.

Adaptation, Physiological↗
PubMed2006

Piperidones with activity against Plasmodium falciparum.

The increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. We have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (DHS) and eukaryotic initiation factor 5A (eIF-5A) in the malaria parasites. eIF-5A is activated by the formation of the unusual amino acid hypusine. This process occurs in two steps. DHS transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eIF-5A precursor protein to form deoxyhypusine. In a second step, deoxyhypusine hydroxylase (DHH), completes hypusine biosynthesis. We used DHH inhibitors, being effective in mammalian cells, to study an antiplasmodicidal effect in Plasmodium falciparum. Experiments with the antifungal drug ciclopiroxolamine, an alpha-hydroxypyridone, and the plant amino acid L: -mimosine, a 4-pyridone, resulted in an antiplasmodial effect in vitro. Using mimosine as a lead structure, alkyl 4-oxo-piperidine 3-carboxylates were found to have the most efficient antiplasmodial effects in vitro and in vivo.

Animals↗
PubMed2006

A randomized, double-blind clinical trial of a 3-week course of doxycycline plus albendazole and ivermectin for the treatment of Wuchereria bancrofti infection.

BACKGROUND: Eight- and 6-week courses of doxycycline are superior to standard treatment of bancroftian filariasis. Standard treatment (albendazole plus ivermectin) is associated with adverse reactions. We assessed whether a shorter (i.e, 3-week) course of doxycycline with standard treatment would show superior efficacy to standard treatment alone and reduce the incidence of adverse reactions. METHODS: A total of 44 adults from Ghana were recruited in January 2003: 20 received doxycycline (200 mg/day) for 3 weeks, and 24 received matching placebo. Participants received albendazole (400 mg) and ivermectin (150 microg/kg) at month 4, and adverse reactions were assessed 48 h later. Treatment efficacy was evaluated at months 4, 12, and 24. RESULTS: The microfilariae level was significantly reduced after receipt of doxycycline treatment at months 4 (P = .017), 12 (P = .001), and 24 (P = .005). The microfilariae level was only significantly reduced at month 12 in the placebo group (P = .041). At all follow-up points, the microfilariae level was significantly lower in the doxycycline group. Adverse reactions to standard antifilarial treatment were similar in frequency between the doxycycline group (in 7 of 11 subjects) and the placebo group (in 13 of 17 subjects). Moderate reactions only occurred in the placebo group (in 3 of 17 subjects). Severity of adverse reaction was associated with microfilaremia (P = .037), Wolbachia bacteria in plasma (P = .048), and proinflammatory cytokines in plasma (P = .019). Adult parasite viability was not significantly different between doxycycline and placebo groups at months 12 or 24. CONCLUSIONS: Treatment with doxycycline for 3 weeks is more effective in inducing a long-term amicrofilaremia than is standard treatment alone, but it is ineffective at inducing curative effects. Inflammatory reactions to antifilarial treatment are associated with levels of microfilariae and Wolbachia endosymbionts released into plasma.

Adolescent↗
PubMed2006

RNAi mediated silencing of actin expression in adult Litomosoides sigmodontis is specific, persistent and results in a phenotype.

In this report, the actin gene from the rodent filaria Litomosoides sigmodontis was successfully knocked down by RNA interference (RNAi). By establishing controls for measuring off-target RNAi effects we showed that lower concentrations of double stranded RNA (dsRNA) are more effective than those previously reported. While all tested concentrations reduced Ls-act transcription, the concentration that consistently reduced Ls-act expression to <10% of the controls was 3.5 microM, a 10-fold lower concentration than that used previously for Brugia malayi. The knockdown of Ls-act was specific as Ls-hsp60 and Ls-gst2 showed no reduction in transcription. Soaking of nematodes with dsRNA coding for the Caenorhabditis elegans yolk receptor (Ce-rme-2), which has no orthologues in filaria, did not affect Ls-act transcription, further demonstrating that the reduction in Ls-act was specific and not due to toxicity of dsRNA or off-target effects. After transferring the nematodes to dsRNA-free medium, the inhibition of Ls-act persisted for at least 72 h, the length of the observation time. Additionally, two phenotypes were seen with Ls-act RNAi. First, adults observed 48 and 72 h after the start of the experiment showed paralysis, as demonstrated by being stretched out and having slower movements. Second, the release of microfilariae was significantly inhibited after soaking with dsRNA. Thus, the use of lower dsRNA concentrations and proper controls for off-target effects make RNAi a viable method to study the function of filarial genes.

Actins↗
PubMed2006

Assessment of microfilarial loads in the skin of onchocerciasis patients after treatment with different regimens of doxycycline plus ivermectin.

BACKGROUND: Infection with the filarial nematode Onchocerca volvulus can lead to severe dermatitis, visual impairment, and ultimately blindness. Since the currently used drug, ivermectin does not have macrofilaricidal or strong permanent sterilising effects on the adult worm, more effective drugs are needed to complement the use of ivermectin alone. Wolbachia endosymbiotic bacteria in filariae have emerged as a new target for treatment with antibiotics which can lead to long -term sterilization of the adult female filariae. METHODS: In the Central Region of Ghana, 60 patients were recruited, allocated into four groups and treated with 200 mg doxycycline per day for 2 weeks, 4 weeks, 6 weeks respectively. Untreated patients served as controls. Some of the treated patients and the untreated controls were given 150 microg/kg ivermectin 8 months after the start of doxycycline treatment. RESULTS: A follow up study 18 months post treatment showed that when using doxycycline alone there was a significant reduction of microfilarial (mf) loads in patients treated for either 4 or 6 weeks. However, there was no significant difference between the untreated controls and those given the 2 weeks regimen. Although no significant difference was demonstrated between the 4 and 6 weeks regimens, there was a trend observed, in that, microfilarial reduction appeared to have been greater following the 6 weeks regimen. Twelve months after ivermectin (i.e. 20 months after doxycycline) treatment, 8 out of 11 ivermectin-alone treated patients were mf-positive. In contrast, 1 out of the 7 patients treated for 4 weeks with doxycycline and none of the 4 patients treated for 6 weeks doxycycline (who were available for re-examination) were mf-positive after the combined treatment of doxycycline plus ivermectin treatment. CONCLUSION: Treatment of onchocerciasis with doxycycline for 4 weeks is effective. Nonetheless, mf reduction appeared to be greater in the 6 weeks regimen. It is recommended that until further studies are carried out i.e. 4 weeks treatment with doxycycline is proven equivalent to the 6 weeks, selected groups of onchocerciasis patients should be treated for 6 weeks with doxycycline. As discussed earlier, this treatment should be accompanied by two doses of ivermectin.

Journal Article↗
PubMed2006

Newbouldiaquinone A: A naphthoquinone-anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from Newbouldia laevis.

The study of the chemical constituents of the roots of Newbouldia laevis (Bignoniaceae) has resulted in the isolation and characterization of a naphthoquinone-anthraquinone coupled pigment named newbouldiaquinone A (1) together with 14 known compounds: apigenin, chrysoeriol, newbouldiaquinone, lapachol, 2-methylanthraquinone, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, oleanolic acid, canthic acid, 2-(4-hydroxyphenyl)ethyl triacontanoate, newbouldiamide, 5,7-dihydroxydehydroiso-alpha-lapachone, beta-sitosterol, and beta-sitosterol glucopyranoside. The structure elucidation of the isolated compounds was established based on spectroscopic studies, notably of the 2D NMR spectra. The antimalarial activity of compound (1) against Plasmodium falciparum in vitro shows moderate chemo suppression of parasitic growth. Its antimicrobial activity against a wide range of microorganisms was 13- and 24-fold more active against Candida gabrata and Enterobacter aerogens than the reference antibiotics nystatin and gentamycin.

Animals↗
PubMed2006

Induction of chronic colitis in IL-10 deficient mice requires IL-4.

Th 1 cells activated by IL-12 and secreting IFN-gamma have been described as the main mediators for onset and maintenance of chronic colitis in IL-10 deficient mice. It was therefore surprising that mice deficient for IL-4 in addition to IL-10 showed intestinal pathology very rarely, whereas IL-10 KO mice developed rectal prolapse in most cases. To investigate the underlying mechanisms, we studied changes of ongoing inflammatory processes in mice deficient for IL-4, IL-10 or both cytokines. Levels of IFN-gamma, IL-12p40 and MHCII mRNA were elevated to a much higher degree in colonic tissue of IL-10 KO compared to IL-4/10 KO at the onset of colitis. Furthermore, the influx of eosinophils, a marker for Th2 responses, was investigated. Only IL-10 deficient mice displayed a significant increase of eosinophils in the lamina propria of the colon and rectum. In contrast, IL-4/10 deficient mice had eosinophil levels comparable to wildtype controls and IL-4 KO. Together these results indicate an important role of IL-4 for the onset of colitis in IL-10 KO mice by promoting a Th1 response and induction of a deleterious Th2 effector response.

Animals↗
PubMed2006

Lack of eosinophil peroxidase or major basic protein impairs defense against murine filarial infection.

Eosinophils are a hallmark of allergic diseases and helminth infection, yet direct evidence for killing of helminth parasites by their toxic granule products exists only in vitro. We investigated the in vivo roles of the eosinophil granule proteins eosinophil peroxidase (EPO) and major basic protein 1 (MBP) during infection with the rodent filaria Litomosoides sigmodontis. Mice deficient for either EPO or MBP on the 129/SvJ background developed significantly higher worm burdens than wild-type mice. Furthermore, the data indicate that EPO or MBP is involved in modulating the immune response leading to altered cytokine production during infection. Thus, in the absence of MBP, mice showed increased interleukin-10 (IL-10) production after stimulation of macrophages from the thoracic cavity where the worms reside. In addition to elevated IL-10 levels, EPO(-/-) mice displayed strongly increased amounts of the Th2 cytokine IL-5 by CD4 T cells as well as a significantly higher eosinophilia. Interestingly, a reduced ability to produce IL-4 in the knockout strains could even be seen in noninfected mice, arguing for different innate propensities to react with a Th2 response in the absence of either EPO or MBP. In conclusion, both of the eosinophil granule products MBP and EPO are part of the defense mechanism against filarial parasites. These data suggest a hitherto unknown interaction between eosinophil granule proteins, defense against filarial nematodes, and cytokine responses of macrophages and CD4 T cells.

Animals↗
PubMed2006

Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis.

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150-200 microg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

Adult↗
PubMed2006

New strategies to combat filariasis.

Two of the major filarial infections, lymphatic filariasis (LF) and onchocerciasis, affect 150 million people, while 1 billion living in endemic areas are at risk of infection. Public health programs to control these infections have successfully existed for years and have evolved from activities driven by the WHO into global programs with public-private partnerships. Currently, these programs use yearly mass application of drugs that mainly kill the larval stages (the microfilariae), with the aim of preventing uptake by the transmitting insect vectors and thus, to block transmission and reduce the infections to such levels that in 15-30 years from now, they will no longer pose a public health problem. While the programs have been very successful in general, there are drawbacks such as coverage being too low within the population, reappearance of infection by migration of infected people into controlled areas, targeting of a stage (the microfilaria) that does not induce pathology in LF and thus lowers compliance, and the potential development of drug resistance, first indications of which have been clearly observed in onchocerciasis. In addition, even without drawbacks, program scopes are not the eradication of filarial infections, which is, however, an ultimate goal of control activities. There is therefore an unequivocal call for the development of higher efficient, complementary chemotherapeutical approaches that lead to a long-lasting reduction of the pathology-inducing worm stages; that is, microfilariae in onchocerciasis and adult worms in LF, or to a macrofilaricidal effect. The recent discovery that depletion of Wolbachia endosymbionts by tetracycline antibiotics leads to long-lasting sterility of adult female worms in onchocerciasis and a macrofilaricidal effect in LF fulfils these requirements. Successful regimens have already been published and agreed upon for use by expert panels. While these regimens are still too long for mass application, the antiwolbachial chemotherapy can currently be applied in the form of a suitable doxycycline regimen for 6 weeks for the treatment of individuals, and exploited in the future for the development of new drugs suitable for mass application. In addition, first data suggest that Wolbachia may also be major mediators of lymphangiogenesis and that their depletion is associated with reduction of lymph vessel-specific vascular endothelial growth factors and reduced lymph vessel size.

Animals↗
PubMed2005

T regulatory-1 cells induce IgG4 production by B cells: role of IL-10.

The study was aimed to find out whether T cells with a regulatory profile could regulate the secretion of IgG4. Using tetanus Ag we found that PBMC of healthy human donors responded to exogenous IL-10 by down-regulating IgG1 and increasing IgG4 secretion. IgE was not affected. To investigate the direct effect of IL-10-producing T cells on B cells, we generated T cell clones (TCC) with two different cytokine profiles: first, IL-10high, IL-2low, IL-4low TCC, and second, IL-10low, IL-2high, IL-4high. The T cell-dependent Ab secretion was measured by coculturing purified CD19+ B cells and the TCC. Interestingly, we found that IgG4 production in the coculture correlated with the TCC production of IL-10 (r2 = 0.352, p = 0.0001), but not with IL-2, IL-4, nor IFN-gamma. IgE showed only a trend with regard to IL-4. Further, there was decreased Ab secretion in the absence of T-B cell contact. IL-10 also induced IgG4 when added to a Th1 TCC-B cell coculture system. The present study thus shows that in T-B cell coculture, IL-10, if induced by the TCC or added to the system, down-regulates the immune response by inducing IgG4 secretion. This establishes a direct implication of IL-10 in humoral hyporesponsiveness, particularly in compartments where the T-B cell interplay determines the subsequent immune response. The correlation between IgG4 and IL-10 (r2 = 0.352) indicates that IL-10 is an important but not the only factor for IgG4 induction.

Antigens↗
PubMed2005

Frequent detection of worm movements in onchocercal nodules by ultrasonography.

BACKGROUND: Ultrasonography (USG) is known to be a suitable tool for diagnosis in lymphatic filariasis as the adult filarial nematode Wuchereria bancrofti in scrotal lymphatic vessels of infected men can be detected by the characteristic pattern of movement, the Filaria Dance Sign. In onchocerciasis, moving adult worms have not yet been demonstrated by USG. In addition the verification of drug effects on living adult Onchocerca volvulus filariae in trials is hampered by the lack of tools for longitudinal observation of alterations induced by potentially macrofilaricidal drugs in vivo. The present study was carried out to determine the frequency of detection of moving adult filariae of O. volvulus by USG. METHODS: In an endemic region for onchocerciasis in Ghana, 61 patients infected with onchocerciasis were recruited by palpation and onchocercomas examined by USG using an ultrasound system equipped with a 7.5 - 10 MHz linear transducer. Onchocercomas were recorded on videotape and evaluated with regard to location, number and size, as well as to movements of adult filariae. RESULTS: In the 61 patients 303 onchocercomas were found by palpation and 401 onchocercomas were detected by USG. In 18 out of 61 patients (29.5%), altogether 22 nodules with moving adult O. volvulus filariae were detected and are presented in animated ultrasound images as mp-4 videos. CONCLUSION: Ultrasonographical examinations of onchocercomas where living adult filariae can be displayed may serve as a new tool for the longitudinal observation in vivo of patients with onchocerciasis undergoing treatment and as an adjunct to histological evaluation.

Journal Article↗
PubMed2005

Wolbachia bacterial endosymbionts of filarial nematodes.

Filarial nematodes are important helminth parasites of the tropics and a leading cause of global disability. They include species responsible for onchocerciasis, lymphatic filariasis and dirofilariasis. A unique feature of these nematodes is their dependency upon a symbiotic intracellular bacterium, Wolbachia, which is essential for normal development and fertility. Advances in our understanding of the symbiosis of Wolbachia bacteria with filarial nematodes have made rapid progress in recent years. Here we summarise our current understanding of the evolution of the symbiotic association together with insights into the functional basis of the interaction derived from genomic analysis. Also we discuss the contribution of Wolbachia to inflammatory-mediated pathogenesis and adverse reactions to anti-filarial drugs and describe the outcome of recent field trials using antibiotics as a promising new tool for the treatment of filarial infection and disease.

Animals↗
PubMed2004

Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal.

Heat shock proteins (Hsp) are ubiquitous intracellular proteins that can be released in various forms of cellular stress. Some Hsp, such as Hsp60, have been shown to stimulate directly T cell-mediated immune responses in vitro. Here, it is demonstrated that Hsp60 is released from the kidneys and excreted into the urine of mice with nephrotoxic nephritis (NTN), a model of rapidly progressive glomerulonephritis. For examining the functional relevance of Hsp60 release, this protein was injected into mice with subnephritogenic NTN, in which only transient proteinuria and minimal organ damage occur that do not progress to terminal kidney failure. Injection of Hsp60 strikingly aggravated disease, as evidenced by global glomerular necrosis, tubulointerstitial damage, and complete anuria after 10 to 12 d. This effect was mediated neither by endotoxin contaminations of Hsp60 nor by autologous antibodies. It was strictly T cell dependent but not associated with a systemic Th1/Th2 shift. Thus, Hsp60 is an endogenous mediator stimulating immune effector mechanisms that contribute to the progression of NTN. These findings demonstrate in vivo that Hsp60 fulfills criteria of immunologic danger signals and suggest that such signals may be involved in immune-mediated kidney disease.

Animals↗
PubMed2004

Increased early local immune responses and altered worm development in high-dose infections of mice susceptible to the filaria Litomosoides sigmodontis.

The relationship between the number of larvae inoculated and filarial infection outcome is an important fundamental and epidemiological issue. Our study was carried out with BALB/c mice infected with the filaria Litomosoides sigmodontis. For the first time, an immunological analysis of infection with various doses was studied in parallel with parasitological data. Mice were inoculated with 200, 60 or 25 infective larvae (third stage larvae, L3), and monitored over 80 days. At 60 h post-inoculation the immune response was stronger in the 200 L3 group than the 25 L3 group. Cells from lymph nodes draining the site of inoculation proliferated intensely and produced large amounts of IL-5 and IL-4. In the pleural cavity, leukocyte populations accumulated earlier and in larger quantities. IgG1, IL-4 and IL-10 serum concentrations were transiently higher. During the first 10 days the worm recovery rates were identical in all groups, but decreased thereafter in the 200 L3 group. In this group, the development of the worms was altered, with reduced lengths, diminished intra-uterine production of microfilariae and abnormalities of male copulatory organs. Whereas mice inoculated with 25 L3 became microfilaraemic, only one third reached patency in the 200 L3 group. However, detrimental effects of high numbers of worms are not seen in studies using different inoculation protocols. This suggests that the very early events determine subsequent immune response and infection outcome rather than competitive interactions between the worms.

Animals↗