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More than 2 billion people live on less than 2 US dollars per day. People in these conditions often have inadequate access to basic sanitation, safe water, and medical services. These individuals, households and communities may be at high risk for a wide range of preventable and treatable infectious diseases. The aims of this study were to: 1) describe the prevalence of endemic helminth, protozoal, bacterial and viral infections of people in a small-holder farming community in western Kenya; 2) explore the spatial distribution of infection risk; 3) quantify associations between social and environmental conditions and individual- and household-level infection; 4) identify shared risk factors operating on multiple pathogens. All data were collected between July 2010 and July 2012 as part of a cross-sectional survey of 416 households and 2113 people. This sample was considered representative of a population of 1.4 million people living in an area of western Kenya characterised by high levels of poverty. Sampled individuals were tested for exposure to, or infection with, 21 infectious agents using a range of faecal, blood and serological tests. Extensive questionnaire-based data were also collected. Individual- and household-level risk factors for infection with prevalent pathogens were explored using multilevel logistic regression, with a particular focus on examining the impact of socioeconomic position (SEP). Hierarchical zero-inflated binomial (ZIB) regression was used to derive an estimate of household pathogen ‘species richness’ with correction for imperfect detection. This modelling framework allowed assessment of the relationship between household-level infection with each parasite and a range of social and environmental conditions and, uniquely for a single study setting, the average response of the ‘group’ of parasites to these conditions. This study found very high levels of parasitism in the community, particularly with hookworm (36.3% (95% CI 32.8 – 39.9)), Entamoeba histolytica/dispar (30.1% (27.5 – 32.8)), Plasmodium falciparum (29.4% (26.8 – 32.0)), and Taenia spp. (19.7% (16.7 – 22.7)). Some degree of within-household clustering was found for all pathogens, and this was particularly large for the helminth species and HIV. Most pathogens also showed spatial heterogeneity in infection risk, with evidence of spatial clustering in household-level infection, most notably for HIV, Schistosoma mansoni, P. falciparum and the soiltransmitted helminths. A socioeconomic gradient was identified, even in this predominantly poor community. Increasing socioeconomic position (SEP) resulted in significantly reduced risk of individual infection for E. histolytica/dispar, P. falciparum, and hookworm. By contrast, individuals living in the richest households were at significantly elevated risk of infection with Mycobacterium spp. Individuals living in the poorest households were least likely to report the recent use of medical treatments. The average pathogen species richness (out of 21 species) per household was 4.7 (range: 0 to 13). Following correction for detection error, the predicted average helminth species count (out of 6 species) was 3 (range: 0.94 to 5.96). While socioeconomic position had little effect on the probability that a household was infected with any of the helminth species of interest, domestic (within-household) transmission appeared to be greatest in the poorest households for hookworm, S. mansoni, Ascaris lumbricoides and Strongyloides stercoralis. Household size had a consistent effect on probably of household infection with each helminth species, so that the largest households were also the most pathogen diverse. Household-level helminth species richness was identified as a significant positive predictor of individual risk of HIV infection, raising potentially important questions about helminth-HIV interactions in the study area. This study integrates approaches from epidemiology and ecology to explore infectious disease risk and its determinants at a range of social and geographic scales in a small-holder farming community in western Kenya. Considering risk at both the individual and household level within the same community can contribute to better understanding of the factors that influence disease transmission in both domestic and public domains.

With the current trends in integrated management of childhood diseases in developing countries, it is important to resolve the controversies of coinfections between helminths and malaria, and properly evaluate the epidemiology of diarrhegenic parasites with molecular study, which sometimes cause overlapping infections. Again, the major challenge facing the global success of mass deworming initiative aimed at controlling helminths is lack of sustainability due to limited donor funds. We therefore decided to evaluate the effectiveness of a school based deworming program using only the school teachers without spending money on training and logistics. Demographic information, height and weight were measured and stool samples were collected from pupils in a semi-rural area of Nigeria during the initial visit by the study team. Malaria cases were recorded over a 3 month malaria transmission period prior to stool sampling. Four hundred and seventy six (33%) of the study population was infected with one Soil transmitted helminth (STH) or the other, especially with Askaris lumbricoides (26.0%) and Hookworm (8.4%). We found a negative association between malaria and STH in this community. Helminth infection rate of 18.3% was observed in children with malaria compared to 34.4% in controls. We also found a high carriage rate of Giardia (37.2%), low Cryptosporidium (1%) and no E. histolytica infection contrary to previous studies that were based on traditional diagnostic techniques. There was 7.9% reduction in the number children with low weight-for-age in the helminth infected children at 6 months after mass deworming, the number of uninfected children with low weight-for-age also reduced by 3.2%. There was also a reduction in the number of children with more than 25% absenteeism among both helminth infected (13.9%) as well as uninfected (7.2%). The association between malaria and STH in our study calls for the need for integrated approach to health problem in Africa instead of the common vertical campaigns. Results from our molecular study also shows the need to strengthen collaborations between researchers from developed and developing countries to be able to map out the true epidemiology of these parasites and hopefully produce novel, inexpensive diagnostics that circumvent the need for advance technological infrastructure

Thesis (M.Sc.). / Written for the Institute of Parasitology. Title from title page of PDF (viewed 2009/08/07). Includes bibliographical references.

With the current trends in integrated management of childhood diseases in developing countries, it is important to resolve the controversies of coinfections between helminths and malaria, and properly evaluate the epidemiology of diarrhegenic parasites with molecular study, which sometimes cause overlapping infections. Again, the major challenge facing the global success of mass deworming initiative aimed at controlling helminths is lack of sustainability due to limited donor funds. We therefore decided to evaluate the effectiveness of a school based deworming program using only the school teachers without spending money on training and logistics. Demographic information, height and weight were measured and stool samples were collected from pupils in a semi-rural area of Nigeria during the initial visit by the study team. Malaria cases were recorded over a 3 month malaria transmission period prior to stool sampling. Four hundred and seventy six (33%) of the study population was infected with one Soil transmitted helminth (STH) or the other, especially with Askaris lumbricoides (26.0%) and Hookworm (8.4%). We found a negative association between malaria and STH in this community. Helminth infection rate of 18.3% was observed in children with malaria compared to 34.4% in controls. We also found a high carriage rate of Giardia (37.2%), low Cryptosporidium (1%) and no E. histolytica infection contrary to previous studies that were based on traditional diagnostic techniques. There was 7.9% reduction in the number children with low weight-for-age in the helminth infected children at 6 months after mass deworming, the number of uninfected children with low weight-for-age also reduced by 3.2%. There was also a reduction in the number of children with more than 25% absenteeism among both helminth infected (13.9%) as well as uninfected (7.2%). The association between malaria and STH in our study calls for the need for integrated approach to health problem in Africa instead of the common vertical campaigns. Results from our molecular study also shows the need to strengthen collaborations between researchers from developed and developing countries to be able to map out the true epidemiology of these parasites and hopefully produce novel, inexpensive diagnostics that circumvent the need for advance technological infrastructure

Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring chronic infections. This immune suppression forms a major barrier to the acquisition of protective Th2 immunity, both in regard to natural infections and potential vaccinations. At the same time, immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and epidemiological links between helminth infections and the amelioration of allergy and autoimmunity diseases indicate that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions. Foxp3+ regulatory T cells (Treg) play central downregulatory roles in controlling reactivity to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during infection. Helminths induce dominant Foxp3+ Treg responses that play key roles in inhibiting protective immunity and alleviating immunopathology, and that can protect against allergic inflammation. Thus, Foxp3+ Tregs are a fundamental mechanism of immune regulation during helminth infections, and an understanding of the mechanisms governing the induction of Foxp3+ Treg responses is of principal importance for the design of both prophylactic helminth treatments and therapies for allergies and autoimmunity. However, the nature of the T cell co-stimulatory signals driving Treg generation during helminth infection is largely unclear. Recent evidence suggests that the inducible costimulator (ICOS) contributes to Treg control of autoimmune inflammation. Further, ICOS expression is upregulated by Foxp3+ Treg during infection with the filarial nematode Litomosoides sigmodontis suggesting ICOS is important for Treg during helminth infection. Therefore, we investigated the role of ICOS in helminth-induced Treg responses. Similar to L. sigmodontis infection, Foxp3+ Treg increased ICOS expression in response to infection with the intestinal nematode Heligmosomoides polygyrus and with the blood trematode Schistosoma mansoni. Functionally, ICOS was required for the optimal expansion of lymphoid Treg numbers during early stage H. polygyrus infection and following the onset of the acute egg phase of S. mansoni infection suggesting common pathways for Treg induction by diverse helminth species. Whilst helminth induced proliferation and activation of Foxp3+ Treg was ICOS independent, ICOS was essential for Treg survival in settings of homeostasis and helminth infection. In contrast to the lymph node, Treg responses in the intestinal lamina propria (LP) of ICOS-/- mice were increased due to expanded natural Treg. Following H. polygyrus infection Foxp3+ Helios- CD4+ T cells preferentially expanded in wild-type (WT) mice but not in ICOS deficient mice suggesting ICOS is required for the expansion of adaptive Treg at the site of intestinal nematode infection. Functionally, ICOS supports Treg, but not effector T cells (Teff), H. polygyrus induced IL- 10 production suggesting ICOS differentially regulates Treg and Teff. At the H. polygyrus infection site, ICOS acted to downregulate CD4+ T cell Th2 cytokine production. Conversely, in the reactive lymph node ICOS signalling promoted Th2 immune responses, possibly by maintaining the pool of IL-4 secreting type 2 follicular helper T cells. Thus, ICOS has different effects on Th2 immunity depending on tissue location. Because Th2 immunity governs expulsion of H. polygyrus parasites, the differences in Th2 responses between lymph node and infection site could explain why ICOS deficiency did not impact worm burden. Protective immunity to long-lived helminth infection can be quenched in the initial days of infection by the action of Treg. Whether Treg expand and suppress protective immunity during S. mansoni larvae lung transit has not been investigated. We found that in contrast to H. polygyrus and L. sigmodontis infection, early S. mansoni infection did not induce a Treg response suggesting other mechanisms are employed for immune subversion. During the acute egg-phase of S. mansoni infection, Foxp3+ Treg protect the host from damaging egg-induced hepatic immunopathology. Despite reduced Foxp3+ Treg responses, ICOS deficiency did not impact egg-induced immunopathology. Thus, ICOS co-stimulation contributes to early expansion and the continued maintenance of Treg during helminth infection, both in the local lymph node and at the infection site. ICOS is required for Treg function during helminth infection by promoting IL-10 production, whilst its contribution to Th2 effector immunity is tissue specific. In addition, ICOS is dispensable for protective immunity and pathology during helminth infection. As ICOS controls both positive and negative immune responses and can have opposing roles depending on tissue location, an understanding of the consequences of these contradictory effects will be important when considering targeting ICOS therapeutically.

Intestinal dwelling parasites live in close association with the complex microbiota that inhabit our intestinal tracts. The intestinal helminth, Trichuris muris, depends on these bacteria for egg hatching and successful establishment of infection within the epithelium of the caecum and colon. Infection causes significant alterations to the host intestinal microbiota, including a decrease in bacterial diversity and shifts in proportions of certain bacterial groups. This is accompanied by a decrease in Foxp3+ regulatory T cells and changes to the metabolic potential of the host microbiota, consequently impacting host health. However, the factor(s) driving these changes and the existence and role of its own intestinal microbiota is unknown. Infection of C57BL/6 and immunodeficient SCID mice with a high dose (~ 200 embryonated eggs) and a low dose (~ 20 embryonated eggs) of T. muris was used to determine the impact of worm burden and the adaptive immune system on the host intestinal microbiota, in comparison to naïve controls. Microbiota analysis was performed by 16S rRNA gene denaturing gradient gel electrophoresis (DGGE) and Illumina sequencing. This revealed that infection-induced microbiota changes were dose dependent and high level infection caused an increase in the Bacteroidaceae and Enterobacteriaceae families, independently of the host adaptive immune system. Development of a surface sterilisation protocol enabled the internal T. muris microbiota to be analysed by 16S rRNA gene DGGE and fluorescence in situ hybridisation (FISH). The resulting data indicated that T. muris requires its own diverse intestinal microbiota that is derived from, but distinct to, that of its host. A core microbiota is selected and maintained by the parasite regardless of the surrounding host microbiota. The parasite microbiota is important for its fitness, shown in vitro using an antibiotic motility assay and in vivo using germ free (GF) mice. Furthermore, infection with T. muris causes a significant reduction in caecal butyrate concentrations and consequently a decrease in the expression of butyrate transporters in caecal tissue. Interestingly, the T. muris microbiota is able to produce the short-chain fatty acid (SCFA) butyrate, which the parasite is unable to make itself yet secretes into its local environment. Together these strategies promote the long term survival of T. muris within the intestinal niche, adding a new level of complexity to the interaction between the pathogen, the host and their respective microbiotas that underpins successful chronic nematode infection.