Maternal Helminth Infection Is Associated With Higher Infant Immunoglobulin A Titers to Antigen in Orally Administered Vaccines.

BACKGROUND: Many studies have documented lower vaccine efficacy among children in low-income countries, compared with their counterparts in high-income countries. This disparity is especially apparent with respect to oral vaccines such as rotavirus and oral polio vaccines. One potential contributing factor is the presence of maternal antenatal helminth infections, which can modulate the infant's developing immune system. METHODS: Using a multiplex immunoassay, we tested plasma immunoglobulin A (IgA) or immunoglobulin G (IgG) levels specific for antigens in 9 routinely administered childhood vaccines among 1639 children aged approximately 13 months enrolled in the ECUAVIDA (Ecuador Life) birth cohort study in Ecuador. We compared vaccine responses in 712 children of mothers who tested positive for helminth infections in the last trimester of pregnancy to responses in 927 children of mothers without helminth infection. RESULTS: Plasma IgA levels specific for antigens in rotavirus vaccine and oral polio vaccine containing poliovirus serotypes 1 and 3 were all significantly higher in children of helminth-infected mothers, compared with children of uninfected mothers. Plasma IgG levels specific for diphtheria, tetanus, pertussis, measles, rubella, and Haemophilus influenzae type b vaccine antigens were comparable between the 2 groups. CONCLUSIONS: Antenatal maternal helminth infections were not associated with reduced antibody responses to infant vaccines, but rather with modestly increased IgA responses to oral vaccines.

Pleural cavity type 2 innate lymphoid cells precede Th2 expansion in murine Litomosoides sigmodontis infection.

Recently, a family of innate cells has been identified that respond to IL-25 and IL-33 in murine intestinal helminths. Termed Type 2 innate lymphoid cells (ILC2s) they facilitate the development of Th2 responses responsible for helminth clearance. We evaluated these cells in a tissue-invasive helminth model. Using Litomosides sigmodontis (a strong Th2 polarizing filarial infection) we observed a robust Th2 response in the pleural cavity, where adult worms reside, marked by increased levels of IL-5 and IL-13 in infected mice. In parallel, ILC2s were expanded in the pleural cavity early in the infection, peaking during the pre-patent period. L. sigmodontis also elicits a strong systemic Th2 response, which includes significantly increased levels of IgG1, IgE and IL-5 in the plasma of infected mice. Although ILC2s were expanded locally, they were not expanded in the spleen, blood, or mediastinal lymph nodes in response to L. sigmodontis infection, suggesting that ILC2s function primarily at the site of infection. The increase in ILC2s in the pleural cavity and the expansion in Th2 responses indicates a probable role for these cells in initiating and maintaining the Th2 response and highlights the importance of these cells in helminth infections and their role in Th2 immunity.

Human CD117 (cKit)+ innate lymphoid cells have a discrete transcriptional profile at homeostasis and are expanded during filarial infection.

Since innate lymphoid cells (ILCs) have been found to play a role in the immune response to helminth parasites in rodents, we sought to determine their role in human helminth infection. By developing multicolor flow cytometry-based methods to identify and enumerate circulating ILCs and their subsets, we were able to identify a subset of cKit+ ILCs defined as Lineage (Lin)-/CD45+/cKit+/CD127+ that were significantly expanded in the filarial-infected individuals (p=0.0473) as were those cKit+ ILCs that produced IL-13. Additionally, the frequency of these cKit+ ILCs correlated with the frequency of IL-17 producing CD4+ T cells (Th17 cells; p=0.025). To investigate the function of cKit+ ILCs, sorted, highly purified human ILCs were subjected to transcriptional profiling by RNAseq and compared to appropriate control cells. These cKit+ ILCs expressed TLRs, a broad range of cytokines/cytokine receptors and MHC Class II molecules suggesting that these ILCs sense pathogens independent of other cell types. Functional analysis revealed expanded cKit+ ILC-specific transcription and ILC-specific microRNA precursors.

Quiescent innate response to infective filariae by human Langerhans cells suggests a strategy of immune evasion.

Filarial infection is initiated by mosquito-derived third-stage larvae (L3) deposited on the skin that transit through the epidermis, which contains Langerhans cells (LC) and keratinocytes (KC), among other cells. This earliest interaction between L3 and the LC likely conditions the priming of the immune system to the parasite. To determine the nature of this interaction, human LC (langerin(+) E-cadherin(+) CD1a(+)) were generated in vitro and exposed to live L3. LC exposed to live L3 for 48 h showed no alterations in the cell surface markers CD14, CD86, CD83, CD207, E-cadherin, CD80, CD40, and HLA-DR or in mRNA expression of inflammation-associated genes, such as those for interleukin 18 (IL-18), IL-18BP, and caspase 1. In contrast to L3, live tachyzoites of Toxoplasma gondii, an intracellular parasite, induced production of CXCL9, IP-10, and IL-6 in LC. Furthermore, preexposure of LC to L3 did not alter Toll-like receptor 3 (TLR3)- or TLR4-mediated expression of the proinflammatory cytokines IL-1ß, gamma interferon (IFN-γ), IL-6, or IL-10. Interestingly, cocultures of KC and LC produced significantly more IL-18, IL-1α, and IL-8 than did cultures of LC alone, although exposure of the cocultures to live L3 did not result in altered cytokine production. Microarray examination of ex vivo LC from skin blisters that were exposed to live L3 also showed few significant changes in gene expression compared with unexposed blisters, further underscoring the relatively muted response of LC to L3. Our data suggest that failure by LC to initiate an inflammatory response to the invasive stage of filarial parasites may be a strategy for immune evasion by the filarial parasite.

Multiplex bead assay for serum samples from children in Haiti enrolled in a drug study for the treatment of lymphatic filariasis.

A multiplex bead assay (MBA) was used to analyze serum samples collected longitudinally from children enrolled in a drug trial for treatment of filariasis in Leogane, Haiti. Recombinant antigens Bm14 and Bm33 from Brugia malayi, third polar tube protein (PTP3) from Encephalitozoon cuniculi, and merozoite surface protein-1(19) (MSP-1(19)) from Plasmodium falciparum were coupled to carboxylated polystyrene microspheres. IgG responses to PTP3 and MSP-1(19) were not affected by albendazole (ALB), diethylcarbamazine (DEC), or combination of diethylcarbamazine and albendazole (DEC/ALB). However, IgG and IgG4 responses to Bm14 and Bm33 were significantly decreased (P < 0.001) by DEC and DEC/ALB treatment. Antibody responses to Bm14 and Bm33 decreased after DEC treatment (but not placebo) among children who were negative for microfilaremia and antigenemia at baseline, suggesting that these children harbored early stages of infection. The MBA is an excellent serologic technique for multiple antigens that offers substantial advantages over single-antigen based enzyme-linked immunosorbent assay in mass drug administration studies for monitoring changes in antibody levels.

Structural and immunologic cross-reactivity among filarial and mite tropomyosin: implications for the hygiene hypothesis.

BACKGROUND: The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy. Other data suggest parasitic infections may induce allergic responsiveness. OBJECTIVE: To assess the structural and immunologic relationships between the known Dermatophagoides pteronyssinus (Der p 10) tropomyosin allergen and filarial tropomyosin of Onchocerca volvulus (OvTrop). METHODS: The molecular, structural, and immunologic relationships between OvTrop and Der p 10 were compared. Levels of OvTrop-specific and Der p 10-specific IgE, IgG, and IgG4 in sera of filaria-infected and filarial-uninfected D pteronyssinus-atopic individuals were compared, as were the responses in nonhuman primates infected with the filarial parasite Loa loa. Cross-reactivity was compared by antigen-mediated depletion assays and functionality by passive basophil sensitization. RESULTS: Filarial and mite tropomyosins were very similar, with 72% identity at the amino acid level, and overlapping predicted 3-dimensional structures. The prevalence of IgE and IgG to Der p 10 was increased in filaria-infected individuals compared with uninfected subjects. There was a strong correlation between serum levels of Ov- and Der p 10-tropomyosin-specific IgE, IgG, and IgG4 (P < .0001; r > 0.79). Preincubation of sera from anti-Der p 10-positive subjects with OvTrop completely depleted IgE, IgG, and IgG4 anti-Der p 10. Basophils sensitized with sera from individuals allergic to Der p 10 released histamine similarly when triggered with OvTrop or Der p 10. Primates experimentally infected with L loa developed IgE that cross-reacted with Der p 10. CONCLUSION: Filarial infection induces strong cross-reactive antitropomyosin antibody responses that may affect sensitization and regulation of allergic reactivity.

A community-based study of factors associated with continuing transmission of lymphatic filariasis in Leogane, Haiti.

Seven rounds of mass drug administration (MDA) have been administered in Leogane, Haiti, an area hyperendemic for lymphatic filariasis (LF). Sentinel site surveys showed that the prevalence of microfilaremia was reduced to <1% from levels as high as 15.5%, suggesting that transmission had been reduced. A separate 30-cluster survey of 2- to 4-year-old children was conducted to determine if MDA interrupted transmission. Antigen and antifilarial antibody prevalence were 14.3% and 19.7%, respectively. Follow-up surveys were done in 6 villages, including those selected for the cluster survey, to assess risk factors related to continued LF transmission and to pinpoint hotspots of transmission. One hundred houses were mapped in each village using GPS-enabled PDAs, and then 30 houses and 10 alternates were chosen for testing. All individuals in selected houses were asked to participate in a short survey about participation in MDA, history of residence in Leogane and general knowledge of LF. Survey teams returned to the houses at night to collect blood for antigen testing, microfilaremia and Bm14 antibody testing and collected mosquitoes from these communities in parallel. Antigen prevalence was highly variable among the 6 villages, with the highest being 38.2% (Dampus) and the lowest being 2.9% (Corail Lemaire); overall antigen prevalence was 18.5%. Initial cluster surveys of 2- to 4-year-old children were not related to community antigen prevalence. Nearest neighbor analysis found evidence of clustering of infection suggesting that LF infection was focal in distribution. Antigen prevalence among individuals who were systematically noncompliant with the MDAs, i.e. they had never participated, was significantly higher than among compliant individuals (p<0.05). A logistic regression model found that of the factors examined for association with infection, only noncompliance was significantly associated with infection. Thus, continuing transmission of LF seems to be linked to rates of systematic noncompliance.