Leishmania donovani-induced expression of suppressor of cytokine signaling 3 in human macrophages: a novel mechanism for intracellular parasite suppression of activation.

Leishmania donovani protozoan parasites, the causative agent of visceral leishmaniasis, establish an infection partly by interfering with cytokine signaling in the host macrophages. Therefore, we investigated the expression of the suppressor of cytokine signaling (SOCS) genes in human macrophages infected with L. donovani. The expression of SOCS3 mRNA was induced transiently after exposure to live or heat-killed parasites, but not purified lipophosphoglycan, while that of other SOCS genes remained unchanged. SOCS3 gene expression was not dependent on phagocytosis or on cytokines released by L. donovani-infected macrophages, such as interleukin-1beta or tumor necrosis factor alpha. In addition, Leishmania used a different signaling pathway(s) than bacterial lipopolysaccharide to induce SOCS3 mRNA, as indicated by the kinetics of induction and sensitivity to polymyxin B inhibition. Finally, phosphorylation of the STAT1 transcription factor was significantly reduced in L. donovani-infected macrophages and required de novo transcription. The induction of SOCS3 provides a potent inhibitory mechanism by which intracellular microorganisms may suppress macrophage activation and interfere with the host immune response.

CpG oligodeoxynucleotides as vaccine adjuvants in primates.

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants in mice, boosting the humoral and cellular response to coadministered Ags. CpG ODN that stimulate human PBMC are only weakly active in mice. Thus, alternative animal models are needed to monitor the activity and safety of "human" CpG ODN in vivo. This work demonstrates that rhesus macaques recognize and respond to the same CpG motifs that trigger human immune cells. Coadministering CpG ODN with heat-killed Leishmania vaccine provided significantly increased protection of macaques against cutaneous Leishmania infection. These findings indicate that rhesus macaques provide a useful model for studying the in vivo activity of human CpG motifs, and that ODN expressing these motifs act as strong immune adjuvants.

Age-prevalence and household clustering of Strongyloides stercoralis infection in Jamaica

The epidemiology of Strongyloides stercoralis was studied in families of clinical (reference) cases and their neighbours at endemic foci in Jamaica. Thirteen foci were studied based on the place of residence of a reference case. For each household of a reference case, the 4 most proximal neighbourhood households (spatial controls) were included in the study. Out of 312 persons contacted 244 were followed up using questionaires, stool examimation and serology. Prevalence of infection based on based on stool examination was 3.5 percent and on ELISA 24.2 percent. Prevalence increased with age but was not related to gender. Reference cases were significantly older than the general study population. The prevalence of infection based on both serology and stool examination was significantly higher in referecne than in neighbouring households (the reference cases, themselves, were not included in the analysis). Furthermore, prevalence of infection was highest among persons who shared a bedroom with a reference case and decreased significantly with increasing spatial separation. This is indicative of close contact transmission which has not been previously shown for a geohelminth, but which is common among microparasites.(AU)

Age-prevalence profile and household clustering of cases of strongyloides infection at endemic foci at Jamaica - abstract

Strongyloides sterocalis infections were examined in families of clinical cases and also in those of their most proximal neighbours. Thirteen clinical cases in Kingston, Jamaica led to the identification of thirteen endemic foci. In addition to the clinical cases, 299 persons were contacted using questionnaires, stool examination and serology. Two hundred and thirty-one persons were fully compliant. The stool prevalence of S.sterocalis was 3.5 percent, while that based on ELISA was 24.2 percent (not including the 13 clinical cases). Both estimates of infection prevalence were significantly higher in the households of the clinical cases compared with the neighbours. The clinical cases were significantly older than the general study population. Furthermore, prevalence was highest among persons who shared a bedroom with a clinical case and decreased with spatial separation. These data strongly suggest that human strongyloides is a close-contact infection. This is likely to be facilitated by the direct phase of the parasite's life cycle and has significant implications for control of infections in endemic areas (AU)_

Immunoepidemiologic studies of Strongyloides stercoralis and human T lymphoropic virus type I infection in Jamaica

Epidemilogic investigations of Strongyloides stercoralis and human T lymphotropic virus type I (HTLV-I) infections were conducted. Of 312 persons contacted, 209 (67 percent) provided blood and stool samples. Prevalences of S. stercoralis and HTLV-I antibodies were 26.8 percent and 8.1 percent (n = 198), respectively, and S. stercoralis larvae were detected in 4 percent. HTLV-I antibodies were significantly more common in persons positive for S. stercoralis larvae (10 [58.8 percent] of 17) compared with seropositive larvae-negative (4 [8.9 percent] of 45) or seronegative persons (9 [6.2 percent] of145) (P< .002). IgE levels increased with age in S. stercoralis-seropositive persons who were HTLV-I negative (P, .))2). However, there was an age-related depression of serum IgE in HTLV-I-positive persons (P < .003) that was sufficient to annul the IgE level-raising effect of S stercoralis seropositivity. The data provide evidence that HTLV-I infection is associated with increased frequency of larvae in the stool of S. stercoralis-infected persons and suggest that the mechanism may involve suppression of the IgE response (AU)

HTLV-1 infection - a risk factor for severe strongyloidiasis? - abstract

Epidemiological associations of Strongyloides stercoralis and Human T-Lymphotropic Virus Type-1 (HTLV-1) were investigated at eleven (11) foci endemic for strongyloidiasis in Jamaica. Each focus was identified on the basis of residency of a parasitologically-proved case of strongyloidiasis who presented at the University Hospital. Three hundred and twelve (312) persons were contacted, and blood and stool samples were collected for HTLV-1 and S. stercoralis serology and S. stercoralis coproculture, respectively. Overall compliance was 66.6 per cent. The prevalence of S. stercoralis in the pooled foci was 8.2 per cent including and 4.0 per cent excluding the hospital presenters, and for HTLV-1 it was 11.1 per cent and 8.1 per cent. Seroprevalence of S. stercoralis infection was 30 per cent and 26.8 per cent with and without the clinical cases, respectively. The prevalence of each infection was correlated with the age of the host (Spearman Rank Correlation, p<0.001). HTLV-1 was clustered in S. stercoralis larval shedders (58.8 per cent, n=17) compared with non-shedders (8.9 per cent, n=45) (Fisher's exact test, p<0.001), but particularly so among clinical cases 7 of whom (n=9) had HTLV-1 antibodies. The association was explained on the basis of age-related total serum IgE levels in HTLV-1/S. stercoralis infection cases. Individuals uninfected by S. stercoralis displayed a tendency for decreased IgE levels with age. This especially so in HTLV-1 carriers (ANCOVA: age * HTLV-1 interaction term t = 3.176, p<0.002). In marked contrast, S. stercoralis seropositive individuals had significantly elevated IgE titres in older persons compared with seronegative controls (ANCOVA: age * S. stercoralis interaction term t = 3.733, p<0.001). In persons seropositive for both HTLV-1 and S. stercoralis, however, the elevation of IgE levels previously observed in S. stercoralis positive individuals was completely subsumed by the negative influence of HTLV-1. It is suggested that impairment of host immunity by HTLV-1, and/or S. stercoralis in the presence of HTLV-1, exacerbates strongyloidiasis resulting in increased frequency of both larval shedding and parasite disease. Effect of S. stercoralis (S) and HTLV-1 (H) infection status on the host age/serum IgE association. This figure is designed to illustrate general trends; ungrouped data were used in statistical analyses (AU)

Interaction between HTLV-1 and Strongyloides stercoralis infection resulting in lowered IgE titres in Jamaica - abstract

In Japan, a positive association exists between the presence of serum antibodies to HTLV-1 and S. stercoralis. Also, it has been shown in Jamaica that coincidental HTLV-I infection may influence the outcome of treatment of S. stercoralis, or even underlie development of severe strongyloidiasis in some persons. However, the relationship between HTLV-I and S. stercoralis remains unclear. This paper highlights a hitherto unreported association between the occurrence of serum antibodies to HTLV-I, to S. stercoralis, and total serum IgE and strongyloidiasis in a Jamaican community. Blood and stool samples were collected from 67 persons from 6 geographical locations in Kingston. Sera were analysed for antibodies to S. stercoralis and HTLV-I, while stool samples were subjected to charcoal coproculture. As in Japan, individuals serologically positive for S. stercoralis tended to be infected more often with HTLV-I (33 per cent) than seronegative individuals (15 per cent), but the difference was not significant (two-tailed Fisher's exact test; P = 0.15). However, parasitologically-proved strongyloidiasis and HTLV-I seroconversion were strongly associated; while occurrence of HTLV-I was 67 per cent in individuals whose stool contained S. stercoralis larvae, it was only 15 per cent in their parasitologically negative counterparts (two-tailed Fisher's exact test; P = 0.01). Analyses strongly suggest that serological status for S. stercoralis HTLV-I affect IgE titres interaction term, F = 3.54; P = 0.06). IgE titres were lower in HTLV-I seropositive than seronegative individuals in both groups with and without S. stercoralis antibodies (HTLV-I main effect, F = 11.13; P = 0.002), but more strongly so in the former group (Table). S. stercoralis infection appeared to elevate reagin levels in some individuals in the HTLV-I negative group (n=13) (one-way ANOVA, F = 2.09; P - 0.15). In contrast, however, serum IgE titres were depressed in the group (n-5) with HTLV-I and concomitant S. stercoralis infection to levels perhaps even lower than those seen in HTLV-I individuals who did not have S. stercoralis (one-way ANOVA, F = 2.39; p = 0.15). Thus, it appears that HTLV-I and S. stercoralis operate synergistically to effect a significant reduction in IgE serum antibodies in infected individuals. If expressed at the level of the intestinal mucosa, this may permit increased rates of autoinfection of the parasite and result in correspondingly greater worm loads and patient morbidity. Lower levels of IgE antibodies against S. stercoralis are known to be associated with disseminated disease (AU)