Browsing by Author "Egesa, Moses"
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Item Antibody Responses to Schistosoma Mansoni Schistosomula Antigens(Parasite immunology, 2018) Egesa, Moses; Lubyayi, Lawrence; Jones, Frances M.; Tukahebwa, Edridah M.; Bagaya, Bernard S.; Dunne, David W.; Elliott, Alison M.; Wilson, Shona; Cose, StephenWhile antigens from Schistosoma schistosomula have been suggested as potential vaccine candidates, the association between antibody responses with schistosomula antigens and infection intensity at reinfection is not well known. Schistosoma mansoni-infected individuals were recruited from a schistosomiasis endemic area in Uganda (n = 372), treated with 40 mg/kg praziquantel (PZQ) and followed up at five weeks and at one year post-treatment. Pre-treatment and five weeks post-treatment immunoglobulin (Ig) E, IgG1 and IgG4 levels against recombinant schistosomula antigens rSmKK7, rSmLy6A, rSmLy6B and rSmTSP7 were measured using ELISA. Factors associated with detectable pre-treatment or post-treatment antibody response against the schistosomula antigens and the association between five-week antibody responses and one year post-treatment reinfection intensity among antibody responders were examined. Being male was associated with higher pre-treatment IgG1 to rSmKK7, rSmLy6a and AWA. Five weeks post-treatment antibody responses against schistosomula antigens were not associated with one year post-treatment reinfection intensity among antibody responders’ antibody levels against rSmKK7, rSmLy6B and rSmTSP7 dropped, but increased against rSmLy6A, AWA and SEA at five weeks post-treatment among antibody responders. S. mansoni-infected individuals exhibit detectable antibody responses to schistosomula antigens that are affected by treatment. These findings indicate that schistosomula antigens induce highly varied antibody responses and could have implications for vaccine development.Item Correspondence of Neutralizing Humoral Immunity and CD4 T Cell Responses in Long Recovered Sudan Virus Survivors(Viruses, 2016) Sobarzo, Ariel; Herbert, Andrew S.; Ochayon, David E.; Eskira, Yael; Egesa, Moses; Cose, Stephen; Lutwama, Julius Julian; Dye, John M.; Lobel, LeslieRobust humoral and cellular immunity are critical for survival in humans during an ebolavirus infection. However, the interplay between these two arms of immunity is poorly understood. To address this, we examined residual immune responses in survivors of the Sudan virus (SUDV) outbreak in Gulu, Uganda (2000–2001). Cytokine and chemokine expression levels in SUDV stimulated whole blood cultures were assessed by multiplex ELISA and flow cytometry. Antibody and corresponding neutralization titers were also determined. Flow cytometry and multiplex ELISA results demonstrated significantly higher levels of cytokine and chemokine responses in survivors with serological neutralizing activity. This correspondence was not detected in survivors with serum reactivity to SUDV but without neutralization activity. This previously undefined relationship between memory CD4 T cell responses and serological neutralizing capacity in SUDV survivors is key for understanding long lasting immunity in survivors of filovirus infections.Item Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study(BMC infectious diseases, 2015) Andia Biraro, Irene; Egesa, Moses; Kimuda, Simon; Smith, Steven G.; Toulza, Frederic; Levin, Jonathan; Joloba, Moses; Katamba, Achilles; Cose, Stephen; Hazel M., Dockrell; Elliott, Alison M.With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis. Methods: Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months’ follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months. Results: Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95 % confidence interval (CI), p-value) -1488.6 pg/ml ((−2682.5, −294.8), p = 0.01), and IL- 2 (−213.1 pg/ml (−419.2, −7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95 % CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6. Conclusions: IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.Item Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10–11, 2019(Archives of Public Health, 2021) Alabi, Ayodele; Mengome, Christine Ndong; Egesa, Moses; Driciru, Emmanuella; Wammes, Linda J.; Adegnika, Ayola Akim; Agnandji, Selidji TodagbeHookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting.Item Ethical and Practical Considerations Arising from Community Consultation on Implementing a Controlled Human Infection Studies using Schistosoma Mansoni in Uganda(Global Bioethics, 2022) Egesa, Moses; Ssali, Agnes; Tumwesige, Edward; Kizza, Moses; Driciru, Emmanuella; Luboga, Fiona; Roestenberg, Meta; Seeley, Janet; Elliott, Alison M.Issues related to controlled human infection studies using Schistosoma mansoni (CHI-S) were explored to ensure the ethical and voluntary participation of potential CHI-S volunteers in an endemic setting in Uganda. We invited volunteers from a fishing community and a tertiary education community to guide the development of informed consent procedures. Consultative group discussions were held to modify educational materials on schistosomiasis, vaccines and the CHI-S model and similar discussions were held with a test group. With both groups, a mock consent process was conducted. Fourteen in-depth key informant interviews and three group discussions were held to explore perceptions towards participating in a CHI-S. Most of the participants had not heard of the CHI-S. Willingness to take part depended on understanding the study procedures and the consenting process. Close social networks were key in deciding to take part. The worry of adverse effects was cited as a possible hindrance to taking part. Volunteer time compensation was unclear for a CHI-S. Potential volunteers in these communities are willing to take part in a CHI-S. Community engagement is needed to build trust and time must be taken to share study procedures and ensure understanding of key messages.Item Ethical and Practical Considerations arising from Community Consultation on Implementing Controlled Human Infection Studies using Schistosoma Mansoni in Uganda(Global Bioethics, 2022) Egesa, Moses; Ssali, Agnes; Tumwesige, Edward; Kizza, Moses; Driciru, Emmanuella; Luboga, Fiona; Roestenberg, Meta; Seeley, Janet; Elliott, Alison M.Issues related to controlled human infection studies using Schistosoma mansoni (CHI-S) were explored to ensure the ethical and voluntary participation of potential CHI-S volunteers in an endemic setting in Uganda. We invited volunteers from a fishing community and a tertiary education community to guide the development of informed consent procedures. Consultative group discussions were held to modify educational materials on schistosomiasis, vaccines and the CHI-S model and similar discussions were held with a test group. With both groups, a mock consent process was conducted. Fourteen in-depth key informant interviews and three group discussions were held to explore perceptions towards participating in a CHI-S. Most of the participants had not heard of the CHI-S. Willingness to take part depended on understanding the study procedures and the consenting process. Close social networks were key in deciding to take part. The worry of adverse effects was cited as a possible hindrance to taking part. Volunteer time compensation was unclear for a CHI-S. Potential volunteers in these communities are willing to take part in a CHI-S. Community engagement is needed to build trust and time must be taken to share study procedures and ensure understanding of key messages.Item Ethical and Scientific Considerations on the Establishment of a Controlled Human Infection Model for Schistosomiasis in Uganda: report of a stakeholders’ meeting held in Entebbe, Uganda.(AAS open research, 2018) Elliott, Alison M.; Wajja, Anne; Opio, Christopher; Angumya, Francis; Adriko, Moses; Egesa, Moses; Mfutso-Bengo, Joseph; Kapulu, Melissa; Lutalo, Tom; Nazziwa, Winfred Badanga; Muwumuza, Asuman; Kaleebu, Pontiano; Kabatereine, Narcis; Tukahebwa, EdridahControlled human infection (CHI) models are gaining recognition as an approach to accelerating vaccine development, for use in both non-endemic and endemic populations: they can facilitate identification of the most promising candidate vaccines for further trials and advance understanding of protective immunity. Helminths present a continuing health burden in sub-Saharan Africa. Vaccine development for these complex organisms is particularly challenging, partly because protective responses are akin to mechanisms of allergy. A CHI model for Schistosoma mansoni (CHI-S) has been developed at Leiden University Medical Centre, the Netherlands. However, responses to schistosome infections, and candidate vaccines, are likely to be different among people from endemic settings compared to schistosome-naïve Dutch volunteers. Furthermore, among volunteers from endemic regions who have acquired immune responses through prior exposure, schistosome challenge can be used to define responses associated with clinical protection, and thus to guide vaccine development. To explore the possibility of establishing the CHI-S in Uganda, a Stakeholders’ Meeting was held in Entebbe in 2017. Regulators, community members, researchers and policy-makers discussed implementation challenges and recommended preparatory steps: risk assessment; development of infrastructure and technical capacity to produce the infectious challenge material in Uganda; community engagement from Parliamentary to grass-roots level; pilot studies to establish approaches to assuring fully informed consent and true voluntariness, and strategies for selection of volunteers who can avoid natural infection during the 12-week CHI-S; the building of regulatory capacity; and the development of study protocols and a product dossier in close consultation with ethical and regulatory partners. It was recommended that, on completion, the protocol and product dossier be reviewed for approval in a joint meeting combining ethical, regulatory and environment management authorities. Most importantly, representatives of schistosomiasis-affected communities emphasised the urgent need for an effective vaccine and urged the research community not to delay in the development process.Item Gene Expression Changes in Mammalian Hosts during Schistosomiasis(Open Research Africa, 2021) Namulondo, Joyce; Mulindwa, Julius; Nyangiri, Oscar A.; Egesa, Moses; Noyes, Harry; Matovu, EnockSchistosomiasis affects over 250 million people worldwide with an estimated mortality of more than 200,000 deaths per year in sub-Saharan Africa. Efforts to control schistosomiasis in the affected areas have mainly relied on mass administration of praziquantel, which kills adult but not immature worms of all Schistosoma species. Mammalian hosts respond differently to Schistosoma infection with some being more susceptible than others, which is associated with risk factors such as sociodemographic, epidemiological, immunological and/or genetic. Host genetic factors play a major role in influencing molecular processes in response to schistosomiasis as shown in gene expression studies. These studies highlight gene profiles expressed at different time points of infection using model animals. Immune function related genes; cytokines (Th1 and Th17) are upregulated earlier in infection and Th2 upregulated later indicating a mixed Th1/Th2 response. However, Th1 response has been shown to be sustained in S. japonicum infection. Immune mediators such as matrix metalloproteinases (Mmps) and tissue inhibitors of matrix metalloproteinases (Timps) are expressed later in the infection and these are linked to wound healing and fibrosis. Downregulation of metabolic associated genes is recorded in later stages of infection. Most mammalian host gene expression studies have been done using rodent models, with fewer in larger hosts such as bovines and humans. The majority of these studies have focused on S. japonicum infections and less on S. haematobium and S. mansoni infections (the two species that cause most global infections). The few human schistosomiasis gene expression studies so far have focused on S. japonicum and S. haematobium infections and none on S. mansoni, as far as we are aware. This highlights a paucity of gene expression data in humans, specifically with S. mansoni infection. This data is important to understand the disease pathology, identify biomarkers, diagnostics and possible drug targets.Item The Genetics of Human Schistosomiasis Infection Intensity and Liver Disease: A Review(Frontiers in Immunology, 2021) Mewamba, Estelle M.; Nyangiri, Oscar A.; Egesa, Moses; Matovu, Enock; Simo, GustaveSchistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans. S. mansoni and S. haematobium infection intensity have been showed to be controlled by a major quantitative trait locus SM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and the SM2 quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies: IL17B and IL12B in SM1, IL17A and IL17F in 6p21-q2, IL6R in 1p21-q23 and IL22RA2 in SM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.Item Impact of Co-Infections and BCG Immunisation on Immune Responses among Household Contacts of Tuberculosis Patients in a Ugandan Cohort(PLoS ONE, 2014) Biraro, Irene A.; Egesa, Moses; Toulza, Frederic; Levin, Jonathan; Cose, Stephen; Joloba, Moses; Smith, Steven; Dockrell, Hazel M.; Katamba, Achilles; Elliott, Alison M.Tuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic. Methods: Adults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11- plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models. Results: We enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBIpositive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNc 0.20 (0.09–0.42), ,0.0001; IL-2 0.34 (0.20–0.59), ,0.0001; and TNFa 0.36 (0.16–0.79), 0.01. Conclusions: We found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.Item The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette–Gue´rin immunization(Philosophical Transactions of the Royal Society B: Biological Sciences, 2015) Mawa, Patrice A.; Nkurunungi, Gyaviira; Egesa, Moses; Webb, Emily L.; Smith, Steven G.; Kizindo, Robert; Akello, Mirriam; Lule, Swaib A.; Muwanga, Moses; Dockrell, Hazel M.; Cose, Stephen; Elliott, Alison M.Bacille Calmette–Gue´rin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n ¼ 53) and cellular (n ¼ 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml21 [3300–11 050] in cord blood) and sixweeks (0.00 ng ml21 [0–288]). Frequencies of PPD-specific IFN-g-expressing CD4þT cells increased at one week and declined between one and six weeks ( p ¼ 0.031). Frequencies of IL-2- and TNF-a-expressing PPD-specific CD4þT cells increased between one and six weeks ( p ¼ 0.019, p ¼ 0.009, respectively). At one week, the frequency of PPD-specific CD4þT cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses ( p ¼ 0.002) and after adjusting for confounders (mean difference, 95% CI 20.041% (20.082, 20.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCGimmunization. These findings are being explored further in a larger study.Item Infection with HIV-1 subtype D among Acutely Infected Ugandans is Associated with Higher Median Concentration of Cytokines Compared to Subtype(IJID Regions, 2022) Kapaata, Anne; Balinda, Sheila N.; Kikaire, Bernard; Egesa, Moses; Lubyayi, Lawrence; Macharia, Gladys N.; Kamali, Anatoli; Gilmour, Jill; Bagaya, Bernard; Salazar-Gonzalez, Jesus F.; Kaleebu, PontianoThe observation that HIV-1 subtype D progresses faster to disease than subtype A prompted us to examine cytokine levels early after infection within the predominant viral subtypes that circulate in Uganda and address the following research questions: (1) Do cytokine levels vary between subtypes A1 and D? (2) Do cytokine profiles correlate with disease outcomes? To address these questions, HIV-1 subtypes were determined by population sequencing of the HIV-1 pol gene and 37 plasma cytokine concentrations were evaluated using V-Plex kits on Meso Scale Discovery platform in 65 recent sero-converters. HIV-1 subtype D (pol) infections exhibited significantly higher median plasma concentrations of IL-5, IL-16, IL-1α, IL-7, IL-17A, CCL11 (Eotaxin-1), CXCL10 (IP-10), CCL13 (MCP-4) and VEGF-D compared to subtype A1 (pol) infections. We also found that IL-12/23p40 and IL-1α were associated with faster CD4+T cell count decline, while bFGF was associated with maintenance of CD4+ counts above 350 cells/microliter. Our results suggest that increased production of cytokines in early HIV infection may trigger a disruption of the immune environment and contribute to pathogenic mechanisms underlying the accelerated disease progression seen in individuals infected with HIV-1 subtype D in Uganda.Item Marburg Virus Survivor Immune Responses are Th1 Skewed with Limited Neutralizing Antibody Responses(Journal of Experimental Medicine, 2017) Stonier, Spencer W.; Herbert, Andrew S.; James, Rebekah M.; Egesa, Moses; Cose, Stephen; Lutwama, Julius Julian; Dye, John M.Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunityItem Mycobacterium Tuberculosis Infection Boosts B Cell 2 Responses to Unrelated Pathogens(bioRxiv, 2019) Kimuda, Simon G.; Andia-Biraro, Irene; Sebina, Ismail; Egesa, Moses; Nalwoga, Angela; Bagaya, Bernard S.; Elliott, Alison M.; Cose, StephenAntigens from Mycobacterium tuberculosis (M.tb), have been shown to stimulate human B cell responses to unrelated recall antigens in vitro. However, it is not known whether natural M.tb infection or whether vaccination with the related species, Mycobacterium bovis BCG, has a similar effect. This study investigated the effects of M.tb infection and BCG vaccination on B cell responses to heterologous pathogen recall antigens. Antibodies against several bacterial and viral pathogens were quantified by ELISA in 68 uninfected controls, 62 individuals with latent TB infection (LTBI) and 107 active pulmonary TB (APTB) cases, and 24 recently BCG-vaccinated adolescents and naive controls. Antibody avidity was investigated using surface plasmon resonance and B cell ELISPOT assays were used to measure plasmablast and memory B cell responses (MBC) in APTB cases and healthy donor controls. APTB was associated with higher levels of antibodies to tetanus toxoid (TT), diphtheria toxoid, respiratory syncytial virus, measles virus and Kaposi’s sarcoma herpesvirus, compared to uninfected controls. Vaccination with BCG did not alter levels of antibodies against heterologous pathogens. TT-specific antibody avidity was increased in APTB and the ratio of TT-specific plasmablasts to MBCs in the APTB cases was 7:1. M.tb infection boosts serological memory to heterologous pathogens in human subjects and this process may be driven by polyclonal activation of memory B cells.Item Mycobacterium Tuberculosis Infection is Associated with Increased B Cell Responses to Unrelated Pathogens(Scientific reports, 2020) Kimuda, Simon G.; Andia‑Biraro, Irene; Sebina, Ismail; Egesa, Moses; Nalwoga, Angela; Smith, Steven G.; Bagaya, Bernard S.; Levin, Jonathan; Elliott, Alison M.; Cose, StephenAntigens from Mycobacterium tuberculosis (M.tb), have been shown to stimulate human B cell responses to unrelated recall antigens in vitro. However, it is not known whether natural M.tb infection or whether vaccination with, Mycobacterium bovis BCG, has a similar efect. This study investigated the efects of M.tb infection and BCG vaccination on B cell responses to heterologous pathogen recall antigens. Antibodies against several bacterial and viral pathogens were quantifed by ELISA in 68 uninfected controls, 62 individuals with latent TB infection (LTBI) and 107 active pulmonary TB (APTB) cases, and 24 recently BCG-vaccinated adolescents and naive controls. Antibody avidity was investigated using surface plasmon resonance and B cell ELISPOTs were used to measure plasmablast and memory B cell responses (MBC) in APTB cases and healthy donor controls. APTB was associated with higher levels of antibodies to respiratory syncytial virus and measles virus, compared to uninfected controls. BCG vaccination did not alter levels of antibodies against heterologous pathogens. Tetanus toxoid (TT)-specifc antibody avidity was increased in APTB cases in comparison to uninfected individuals and the ratio of TT-specifc plasmablasts to MBCs in the APTB cases was 7:1. M.tb infection is associated with increased antibody responses to heterologous pathogens in human subjects.Item Rethinking Schistosomiasis Vaccine Development(Trends in parasitology, 2017) Egesa, Moses; Hoffmann, Karl F.; Yazdanbakhsh, Maria; Cose, StephenThere is currently no vaccine against schistosomiasis. With few Schistosoma vaccine candidates in clinical trials, unexplored antigens from the vulnerable schistosomulum should be considered as possible vaccine candidates. In addition, we suggest developing synthetic vesicles as a new delivery vehicle and adjuvant for immunoprophylactic schistosomula vaccine candidates.Item Risk Assessment for the Implementation of Controlled Human Schistosoma Mansoni Infection Trials in Uganda(AAS open research, 2019) Koopman, Jan Pieter; Egesa, Moses; Wajja, Anne; Adriko, Moses; Nassuuna, Jacent; Nkurunungi, Gyaviira; Driciru, Emmanuella; Cose, Stephen; Kaleebu, Pontiano; Kabatereine, Narcis; Tukahebwa, Edridah; Elliott, Alison M.Schistosomiasis is a parasitic infection highly prevalent in sub-Saharan Africa, and a significant cause of morbidity; it is a priority for vaccine development. A controlled human infection model for Schistosoma mansoni (CHI-S) with potential to accelerate vaccine development has been developed among naïve volunteers in the Netherlands. Because responses both to infections and candidate vaccines are likely to differ between endemic and non-endemic settings, we propose to establish a CHI-S in Uganda where Schistosoma mansoni is endemic. As part of a “road-map” to this goal, we have undertaken a risk assessment. We identified risks related to importing of laboratory vector snails and schistosome strains from the Netherlands to Uganda; exposure to natural infection in endemic settings concurrently with CHI-S studies, and unfamiliarity of the community with the nature, risks and rationale for CHI. Mitigating strategies are proposed. With careful implementation of the latter, we believe that CHI-S can be implemented safely in Uganda. Our reflections are presented here to promote feedback and discussion.Item Schistosoma Mansoni schistosomula Antigens Induce Th1/ Pro-inflammatory Cytokine Responses(Parasite immunology, 2018) Egesa, Moses; Lubyayi, Lawrence; Tukahebwa, Edridah M.; Bagaya, Bernard S.; Wilson, Shona; Yazdanbakhsh, Maria; Labuda, Lucja A.; Cose, StephenLarvae of Schistosoma (schistosomula) are highly susceptible to host immune responses and are attractive prophylactic vaccine targets, although cellular immune responses against schistosomula antigens in endemic human populations are not well characterized. We collected blood and stool from 54 Schistosoma mansoni-infected Ugandans, isolated peripheral blood mononuclear cells and stimulated them for 24 hours with schistosome adult worm and soluble egg antigens (AWA and SEA), along with schistosomula recombinant proteins rSmKK7, Lymphocyte Antigen 6 isoforms (rSmLy6A and rSmLy6B), tetraspanin isoforms (rSmTSP6 and rSmTSP7). Cytokines, chemokines and growth factors were measured in the culture supernatants using a multiplex luminex assay, and infection intensity was determined before and at 1 year after praziquantel (PZQ) treatment using the Kato-Katz method. Cellular responses were grouped and the relationship between groups of correlated cellular responses and infection intensity before and after PZQ treatment was investigated. AWA and SEA induced mainly Th2 responses. In contrast, rSmLy6B, rSmTSP6 and rSmTSP7 induced Th1/pro-inflammatory responses. While recombinant antigens rSmKK7 and rSmLy6A did not induce a Th1/pro-inflammatory response, they had an association with pre-treatment infection intensity after adjusting for age and sex. Testing more schistosomula antigens using this approach could provide immune-epidemiology identifiers necessary for prioritizing next generation schistosomiasis vaccine candidates.Item Transcriptome analysis of peripheral blood of Schistosoma Mansoni Infected Children from the Albert Nile Region in Uganda Reveals Genes Implicated in Fibrosis Pathology.(bioRxiv, 2023) Namulondo, Joyce; Nyangiri, Oscar Asanya; Kimuda, Magambo Phillip; Nambala, Peter; Nassuuna, Jacent; Egesa, Moses; Nerima, Barbara; Biryomumaisho, Savino; Nabukenya, Immaculate; Drago, Kato; Tweyongyere, Robert; Matovu, Enock; Mulindwa, Julius; Mugasa, Claire MackOver 290 million people are infected by schistosomes worldwide. Schistosomiasis control efforts focus on mass drug treatment with praziquantel (PZQ), a drug that kills the adult worm of all Schistosoma species. Nonetheless, re-infections have continued to be detected in endemic areas with individuals living in the same area presenting with varying infection intensities. Our objective was to characterize the transcriptome profiles in peripheral blood of children between 10 - 15 years with varying intensities of Schistosoma mansoni infection living along the Albert Nile in Uganda. RNA extracted from peripheral blood collected from 44 S. mansoni infected (34 high and 10 low by circulating anodic antigen [CAA] level) and 20 uninfected children was sequenced using Illumina NovaSeq S4 and the reads aligned to the GRCh38 human genome. Differential gene expression analysis was done using DESeq2 and enriched pathways in differentially expressed genes (DEGs) were identified using REACTOME. Principal component analysis revealed clustering of gene expression by gender when S. mansoni infected children were compared with uninfected children. In addition, we identified 14 DEGs between S. mansoni infected and uninfected individuals, 56 DEGs between children with high infection intensity and uninfected individuals, 33 DEGs between those with high infection intensity and low infection intensity and no DEGs between those with low infection and uninfected individuals. We also observed upregulation and downregulation of some DEGs that are associated with fibrosis and its regulation. These data suggest expression of fibrosis associated genes as well as genes that regulate fibrosis in S. mansoni infection. The relatively few significant DEGS observed in children with schistosomiasis suggests that chronic S. mansoni infection is a stealth infection that does not stimulate a strong immune response.Item Type 2 Diabetes Mellitus and Latent Tuberculosis Infection Moderately Influence Innate Lymphoid Cell Immune Responses in Uganda(Frontiers in immunology, 2021) Ssekamatte, Phillip; Nakibuule, Marjorie; Nabatanzi, Rose; Egesa, Moses; Musubika, Carol; Bbuye, Mudarshiru; Hepworth, Matthew R.; Biraro, Irene AndiaType 2 diabetes mellitus (T2DM) is a major risk factor for the acquisition of latent tuberculosis (TB) infection (LTBI) and development of active tuberculosis (ATB), although the immunological basis for this susceptibility remains poorly characterised. Innate lymphoid cells (ILCs) immune responses to TB infection in T2DM comorbidity is anticipated to be reduced. We compared ILC responses (frequency and cytokine production) among adult patients with LTBI and T2DM to patients (13) with LTBI only (14), T2DM only (10) and healthy controls (11). Using flow cytometry, ILC phenotypes were categorised based on (Lin−CD127+CD161+) markers into three types: ILC1 (Lin−CD127+CD161+CRTH2-CD117−); ILC2 (Lin−CD127+CD161+CRTH2+) and ILC3 (Lin−CD127+CD161+CRTH2−NKp44+/−CD117+). ILC responses were determined using cytokine production by measuring percentage expression of interferon-gamma (IFN-γ) for ILC1, interleukin (IL)-13 for ILC2, and IL-22 for ILC3. Glycaemic control among T2DM patients was measured using glycated haemoglobin (HbA1c) levels. Data were analysed using FlowJo version 10.7.1, and GraphPad Prism version 8.3. Compared to healthy controls, patients with LTBI and T2DM had reduced frequencies of ILC2 and ILC3 respectively (median (IQR): 0.01 (0.005-0.04) and 0.002 (IQR; 0.002-0.007) and not ILC1 (0.04 (0.02-0.09) as expected. They also had increased production of IFN-γ [median (IQR): 17.1 (5.6-24.9)], but decreased production of IL-13 [19.6 (12.3-35.1)]. We however found that patients with T2DM had lower ILC cytokine responses in general but more marked for IL-22 production (median (IQR): IFN-γ 9.3 (4.8-22.6); IL-13 22.2 (14.7-39.7); IL-22 0.7 (IQR; 0.1-2.1) p-value 0.02), which highlights the immune suppression status of T2DM. We also found that poor glycaemic control altered ILC immune responses. This study demonstrates that LTBI and T2DM, and T2DM were associated with slight alterations of ILC immune responses. Poor T2DM control also slightly altered these ILC immune responses. Further studies are required to assess if these responses recover after treatment of either TB or T2DM.