Dr William Horsnell

United Kingdom
Scientific Field
July, 2017 - July, 2018

LE STUDIUM / Marie Skłodowska-Curie Research Fellowship 


University of Cape Town - ZA

In residence at

Experimental and Molecular Immunology and Neurogenetics (INEM) / CNRS, University of Orléans - FR

Host scientist

Dr Bernhard Ryffel


Targeting acetylcholine receptors to enhance immunity to acute viral infection

Recently studies have shown that acetylcholine (ACh), a neuro-transmitter, which regulates nerve and muscle functions, also strongly regulates the immune system. Immune cells can produce and release ACh to control local immune responses independently of the nervous system. The understanding of ACh mediated immunoregulation in disease is very limited. Here we will build on recent discoveries made by us that blocking ACh signaling can boost the ability of the immune system to control a viral infection in the lung. The infection we are studying is known as RSV and is the main cause of small children being hospitalized for breathing difficulties. Our project will show how blocking ACh can be used to develop new treatments for this and similar diseases such as influenza established in the host laboratory. This will be a major breakthrough as currently infection associated inflammation are difficult to treat.

Events organised by this fellow

Publications in relation with the research project


Matthew G. Darby
Alisha Chetty
Dunja Mrjden
Marion Rolot
Katherine Smith
Claire Mackowiak
Delphine Sedda
Donald Nyangahu
Heather Jaspan
Kai-Michael Toellner
Ari Waisman
Valerie Quesniaux
Bernhard Ryffel
Adam F. Cunningham
Benjamin G. Dewals
Frank Brombacher
William G. C. Horsnell

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection.
Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4R−/− offspring.
This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes.

Sulayman Benmerzoug
Badreddine Bounab
Stéphanie Rose
David Gosset
Franck Biet
Thierry Cochard
Aurore Xavier
Nathalie Rouxel
Louis Fauconnier
William G.C. Horsnell
Bernhard Ryffel
Dieudonnee Togbe
Valerie F.J. Quesniaux

Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.

Matthew K. O'Shea
Thomas E. Fletcher
Julius Muller
Rachel Tanner
Magali Matsumiya
J. Wendi Bailey
Steven G. Smith
Gavin Koh
William G. Horsnell
Nicholas J. Beeching
James Dunbar
Duncan Wilson
Adam F. Cunningham
Helen McShane

Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. However, few studies have focused on latent TB infection (LTBI), which predominates globally. We performed a large observational study of healthy adults migrating from Nepal to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to control virulent mycobacterial growth in vitro than from those without, which was lost following hookworm treatment. There was a significant negative relationship between mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene expression characterized the whole blood transcriptome of hookworm infection and correlated with improved mycobacterial control. These data provide a potential alternative explanation for the reduced prevalence of LTBI among individuals with hookworm infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils.

Marion Rolot
Annette M. Dougall
Alisha Chetty
Justine Javaux
Ting Chen
Xue Xiao
Bénédicte Machiels
Murray E. Selkirk
Rick M. Maizels
Cornelis Hokke
Olivier Denis
Frank Brombacher
Alain Vanderplasschen
Laurent Gillet
William G. C. Horsnell
Benjamin G. Dewals

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhances control of viral infection.

Brittany-Amber Jacobs
Alisha Chetty
William Gordon Charles Horsnell
Georgia Schäfer
Sharon Prince
Katherine Ann Smith

Persistent infection with human papillomavirus (HPV) is responsible for nearly all new cervical cancer cases worldwide. In low- and middle-income countries (LMIC), infection with helminths has been linked to increased HPV prevalence. As the incidence of cervical cancer rises in helminth endemic regions, it is critical to understand the interaction between exposure to helminths and the progression of cervical cancer. Here we make use of several cervical cancer cell lines to demonstrate that exposure to antigens from the hookworm N. brasiliensis significantly reduces cervical cancer cell migration and global expression of vimentin and N-cadherin. Importantly, N. brasiliensis antigen significantly reduced expression of cell-surface vimentin, while decreasing HPV type 16 (HPV16) pseudovirion internalization. In vivo infection with N. brasiliensis significantly reduced vimentin expression within the female genital tract, confirming the relevance of these in vitro findings. Together, these findings demonstrate that infection with the hookworm-like parasite N. brasiliensis can systemically alter genital tract mesenchymal markers in a way that may impair cervical cancer cell progression. These findings reveal a possible late-stage treatment for reducing cervical cancer progression using helminth antigens.

Godfrey A. Dzhivhuho
Samantha A. Rehrl
Hlumani Ndlovu
William G. C. Horsnell
Frank Brombacher
Anna-Lise Williamson
Gerald K. Chege

Future HIV vaccines are expected to induce effective Th1 cell-mediated and Env-specific antibody responses that are necessary to offer protective immunity to HIV infection. However, HIV infections are highly prevalent in helminth endemic areas. Helminth infections induce polarised Th2 responses that may impair HIV vaccine-generated Th1 responses. In this study, we tested if Schistosoma mansoni (Sm) infection altered immune responses to SAAVI candidate HIV vaccines (DNA and MVA) and an HIV-1 gp140 Env protein vaccine (gp140) and whether parasite elimination by chemotherapy or the presence of Sm eggs (SmE) in the absence of active infection influenced the immunogenicity of these vaccines. In addition, we evaluated helminth-associated pathology in DNA and MVA vaccination groups. Mice were chronically infected with Sm and vaccinated with DNA+MVA in a prime+boost combination or MVA+gp140 in concurrent combination regimens. Some Sm-infected mice were treated with praziquantel (PZQ) prior to vaccinations. Other mice were inoculated with SmE before receiving vaccinations. Unvaccinated mice without Sm infection or SmE inoculation served as controls. HIV responses were evaluated in the blood and spleen while Smassociated pathology was evaluated in the livers. Sm-infected mice had significantly lower magnitudes of HIV-specific cellular responses after vaccination with DNA+MVA or MVA

Erin Logan
Angelique Kany Kany Luabeya
Humphrey Mulenga
Dunja Mrdjen
Cynthia Ontong
Adam F. Cunningham
Michele Tameris
Helen McShane
Thomas J. Scriba
William G. C. Horsnell
Mark Hatherill

Background: It is unclear whether antibodies can prevent Mycobacterium tuberculosis (Mtb) infection. In this study, we examined the relationship between total plasma IgG levels, IgG elicited by childhood vaccines and soil-transmitted helminths, and Mtb infection prevalence, defined by positive QuantiFERON (QFT) test.

Methods: We studied 100 Mtb uninfected infants, aged 4–6 months. Ten infants (10%) converted to positive QFT test (QFT+) within 2 years of follow-up for Mtb infection. Antibody responses in plasma samples acquired at baseline and tuberculosis investigation were analyzed by enzyme-linked immunosorbent assay and ImmunoCAP® assay.

Results: QFT− infants displayed a significant increase in total IgG titers when re-tested, compared to IgG titers at baseline, which was not observed in QFT+ infants. Bacille Calmette-Guérin (BCG) vaccine-specific IgG2 and live-attenuated measles vaccine-specific IgG were raised in QFT− infants, and infants who acquired an Mtb infection did not appear to launch a BCG-specific IgG2 response. IgG titers against the endemic helminth Ascaris lumbricoides increased from baseline to QFT re-testing in all infants.

Conclusion: These data show raised IgG associates with a QFT-status. Importantly, this effect was also associated with a trend showing raised IgG titers to BCG and measles vaccine. Our data suggest a possible protective association between raised antibody titers and acquisition of Mtb infection, potentially mediated by exposure to antigens both related and unrelated to Mtb.

Donald D. Nyangahu
Katie S. Lennard
Bryan P. Brown
Matthew G. Darby
Jerome M. Wendoh
Enock Havyarimana
Peter Smith
James Butcher
Alain Stintzi
Nicola Mulder
William Horsnell
Heather B. Jaspan

Early life microbiota is an important determinant of immune and metabolic development and may have lasting consequences. The maternal gut microbiota during pregnancy or breastfeeding is important for defining infant gut microbiota. We hypothesized that maternal gut microbiota during pregnancy and breastfeeding is a critical determinant of infant immunity. To test this, pregnant BALB/c dams were fed vancomycin for 5 days prior to delivery (gestation; Mg), 14 days postpartum during nursing (Mn), or during gestation and nursing (Mgn), or no vancomycin (Mc). We analyzed adaptive immunity and gut microbiota in dams and pups at various times after delivery.

In addition to direct alterations to maternal gut microbial composition, pup gut microbiota displayed lower α-diversity and distinct community clusters according to timing of maternal vancomycin. Vancomycin was undetectable in maternal and offspring sera, therefore the observed changes in the microbiota of stomach contents (as a proxy for breastmilk) and pup gut signify an indirect mechanism through which maternal intestinal microbiota influences extra-intestinal and neonatal commensal colonization. These effects on microbiota influenced both maternal and offspring immunity. Maternal immunity was altered, as demonstrated by significantly higher levels of both total IgG and IgM in Mgn and Mn breastmilk when compared to Mc. In pups, lymphocyte numbers in the spleens of Pg and Pn were significantly increased compared to Pc. This increase in cellularity was in part attributable to elevated numbers of both CD4+ T cells and B cells, most notable Follicular B cells.

Our results indicate that perturbations to maternal gut microbiota dictate neonatal adaptive immunity.

lan S. Schwartz
Barbra Lerm
J. Claire Hoving
Chris Kenyon
William G. Horsnell
W. Joan Basson
Patricia Otieno-Odhiambo
Nelesh P. Govender
Robert Colebunders
Alfred Botha

We detected Emergomyces africanus, a thermally dimorphic fungus that causes an HIV-associated systemic mycosis, by PCR in 18 (30%) of 60 soil samples from a wide range of habitats in South Africa. Direct and indirect culture techniques were unsuccessful. Experimental intraperitoneal inoculation of conidia induced murine disease.

N. O. Jõgi
C. Svanes
S. P. Siiak
E. Logan
J. W. Holloway
J. Igland
A. Johannessen
M. Levin
F. G. Real
V. Schlunssen
W. G. C. Horsnell
R. J. Bertelsen

Background: Animal and human studies indicate that definitive host helminth infections may confer protection from allergies. However, zoonotic helminths, such as Toxocara species (spp.), have been associated with increased allergies.

Objective: We describe the prevalence of Toxocara spp. and Ascaris spp. seropositivity and associations with allergic diseases and sensitization, in 2 generations in Bergen, Norway.

Methods: Serum levels of total IgG4, anti-Toxocara spp. IgG4 and Ascaris spp. IgG4 were established by ELISA in 2 cohorts: parents born 1945-1972 (n = 171) and their offspring born 1969-2003 (n = 264). Allergic outcomes and covariates were recorded through interviews and clinical examinations including serum IgEs and skin prick tests.

Results: Anti-Ascaris spp. IgG4 was detected in 29.2% of parents and 10.3% of offspring, and anti-Toxocara spp. IgG4 in 17.5% and 8.0% of parents and offspring, respectively. Among offspring, anti-Toxocara spp. IgG4 was associated with pet keeping before age 15 (OR = 6.15; 95% CI = 1.37-27.5) and increasing BMI (1.16 [1.06-1.25] per kg/m2). Toxocara spp. seropositivity was associated with wheeze (2.97[1.45- 7.76]), hayfever (4.03[1.63-9.95]), eczema (2.89[1.08-7.76]) and cat sensitization (5.65[1.92-16.6]) among offspring, but was not associated with allergic outcomes among parents. Adjustment for childhood or current pet keeping did not
alter associations with allergies. Parental Toxocara spp. seropositivity was associated with increased offspring allergies following a sex-specific pattern.

Conclusions & Clinical Relevance: Zoonotic helminth exposure in Norway was less frequent in offspring than parents; however, Toxocara spp. seropositivity was associated with increased risk of allergic manifestations in the offspring generation, but not among parents. Changes in response to helminth exposure may provide insights into the increase in allergy incidence in affluent countries.

Amanda Ardain
William G. C. Horsnell
Racquel Domingo-Gonzalez
Shibali Das
Samuel Kazer
Nicole Howard
Alveera Singh
Mushtaq Ahmed
Shepherd Nhamoyebonde
Javier Rangel-Moreno
Paul Ogongo
Lan Lu
Duran Ramsuran
Maria de la Luz Garcia-Hernandez
Tyler K. Ulland
Matthew Darby
Eugene Park
Farina Karim
Laura Melocchi
Rajhmun Madansein
Kaylesh Jay Dullabh
Micah Dunlap
Nancy Marin-Agudelo
Takashi Ebihara
Thumbi Ndung’u
Deepak Kaushal
Alexander Pym
Jay Kolls
Adrie Steyn
Joaquín Zúñiga
Wayne Yokoyama
Alex Shalek
Henrik Kløverpris
Marco Colonna
Alasdair Leslie
Shabaana Khader

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)–C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

Final reports

William G. C. Horsnell
Murray E. Selkirk
Luke B. Roberts
Corinna Schnoeller
Matthew Darby
Claire Mackowiak
Delphine Sedda
Valerie Quesniaux
Bernhard Ryffel
Rachel Vaux
Rita Berkachy
Kleoniki Gounaris
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Group 2 innate lymphoid cell (ILC2s) responses drive type 2 immunity against helminths and are initiated by host alarmin release. Here we show that in addition to signature type 2 cytokines ILC2 also synthesise and release acetylcholine (ACh).  ILC2 ACh synthesis (defined by choline acetyltransferase (ChAT) expression) following Nb or Alternaria challenge revealed pronounced ACh synthesis in ILC2 when compared to other immune cell populations. In vivo alarmin cytokine challenges selectively induced this ILC2 ACh responses. Nippostrongylus brasiliensis infection of RORCreChATLoxP mice (which have a targeted disruption of the ILC2 ACh response) resulted in higher intestinal helminth burdens than in control mice.  This impaired control of infection associated with reduced ILC2 and CD4 IL-13 production. Adoptive transfer of  RORCreChATLoxP ILC2s into RAG2-/-IL-2rg-/- resulted in subsequent infection having a higher intestinal burden than in ChATloxp recipeints. These data identify ILC2-derived ACh as a novel axis required for optimal type 2 immunity.