A history of helminth exposure protects against pneumovirus infection in an IL-4Rα-independent manner

peer reviewedHelminths have developed a reputation for being able to regulate bystander inflammatory disorders and the mechanisms for how they carry this out are beginning to be elucidated. In this study, we investigated the impact of helminth infection on immune control in a model of lethal viral pneumonia. BALB/c mice were infected with Nippostrongylus brasiliensis, and at either 6 or 35 days after N. brasiliensis infection, mice were intranasally infected with a wild-type pneumonia virus of mice (PVM, strain J3666) or a recombinant virus expressing the luciferase gene (PVM-luc) to track viral replication over time by in vivo imaging. PVM belongs to the Pneumoviridae family and is a murine model for the closely related human respiratory syncytial respiratory virus (hRSV), a respiratory virus of medical significance in neonates, geriatrics, and immunosuppressed patients. Based on daily weight changes and viral bioluminescence, we demonstrated that prior exposure to helminths protects against PVM-induced pathology compared to naïve PVM-infected mice that exhibit a deleterious phenotype. Interestingly, protection was independent of IL-4Rα signaling, as both wild-type and IL-4Rα-/- mice were equally protected after helminth exposure. N. brasiliensis-induced protection was abolished by high doses of PVM-luc, which indicated a fine threshold for protection. Further investigations are needed to determine how exposure to N. brasiliensis can control viral replication and/or regulate PVM-associated detrimental inflammation

A history of helminth exposure protects against pneumovirus infection in an IL-4Rα-independent manner

peer reviewe

Inflammatory bowel disease: A review of pre-clinical murine models of human disease

Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4+ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discusse

IL-4 induces CD22 expression to restrain the effector program of self-reactive virtual memory T cells

Parasitic helminths induce the production of interleukin (IL)-4 which causes the expansion of virtual memory CD8+ T cells (TVM), a cell subset contributing to the control of viral coinfection. However, the mechanisms regulating IL-4-dependent TVM activation and expansion during worm infection remain ill defined. We used single-cell RNA sequencing of CD8+ T cells to investigate IL-4-dependent TVM responses upon helminth infection in mice. Gene signature analysis of CD8+ T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a specific and selective surface marker of IL-4-induced TVM cells. CD22+ TVM were enriched for IFN-γ and granzyme A and retained a diverse TCR repertoire, while enriched in CDR3 sequences with features of self-reactivity. Deletion of CD22 expression in CD8+ T cells enhanced TVM responses to helminth infection, indicating that this inhibitory receptor modulates TVM responses. Thus, helminth-induced IL-4 drives the expansion and activation of self-reactive TVM in the periphery that is counter-inhibited by CD22

IL-4 induces CD22 expression to restrain the effector program of self-reactive virtual memory T cells

Abstract Parasitic helminths induce the production of interleukin (IL)-4 which causes the expansion of virtual memory CD8+ T cells (Tvm), a cell subset contributing to the control of viral coinfection. However, the mechanisms regulating IL-4-dependent Tvm activation and expansion during worm infection remain ill defined. We used single-cell RNA sequencing of CD8+ T cells to investigate IL-4-dependent Tvm responses upon helminth infection in mice. Gene signature analysis of CD8+ T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a specific and selective surface marker of IL-4-induced Tvm cells. CD22+ Tvm were enriched for IFN-γ and granzyme A and retained a diverse TCR repertoire, while enriched in CDR3 sequences with features of self-reactivity. Deletion of CD22 expression in CD8+ T cells enhanced Tvm responses to helminth infection, indicating that this inhibitory receptor modulates Tvm responses. Thus, helminth-induced IL-4 drives the expansion and activation of self-reactive Tvm in the periphery that is counter-inhibited by CD22

Determining the impact of Heligmosomoides polygyrus infection on the development of colitis

The ability of helminths to regulate inflammatory disorders and the mechanisms by which they carry this out are of great scientific interest. Currently, established literature emphasises the protective role of helminth infection in mouse models of inflammatory bowel disease (IBD). Utilising two well-established murine models of human disease, the oxazolone and dextran sulfate sodium (DSS) models, I found that induction of murine IBD is highly sensitive to diet change and mouse gender. Using the gastrointestinal helminth Heligmosomoides polygyrus (H.polygyrus), I demonstrate that helminth infection exacerbates IBD in both the oxazolone and DSS models of colitis. Underlying helminth infection results in increased inflammation locally in the colon and systemically in the spleen in both models of IBD, as measured by histology and flow cytometry. Exacerbation of DSS colitis is dependent on the dose of H.polygyrus but is independent of the phase of H.polygyrus infection, with both acute and chronic infections resulting in the same phenotype. Helminth exacerbated DSS colitis is characterised by significant bacterial translocation to the spleen, which is concluded to be due to loss of intestinal epithelial integrity. Helminth infection also resulted in a microbial shift of translocating bacteria following DSS administration, as evidenced by gram staining and bacterial sequencing. Administration of an 8- strain probiotic during acute helminth infection ameliorated helminth exacerbation of DSS colitis, restored epithelial integrity and abrogated splenomegaly. This work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive disease. These studies reveal restoration of the microbiota through probiotics or helminth eradication as potential therapies for the treatment of gastrointestinal inflammatory disorders

Parasitic worms affect virus coinfection: a mechanistic overview.

peer reviewedHelminths are parasitic worms that coevolve with their host, usually resulting in long-term persistence through modulating host immunity. The multifarious mechanisms altering the immune system induced by helminths have significant implications on the control of coinfecting pathogens such as viruses. Here, we explore the recent literature to highlight the main immune alterations and mechanisms that affect the control of viral coinfection. Insights from these mechanisms are valuable in the understanding of clinical observations in helminth-prevalent areas and in the design of new therapeutic and vaccination strategies to control viral diseases

Helminths and Colitis: Friends or Foes?

The mechanisms by which gastrointestinal helminths can modulate inflammatory disorders are of great scientific interest for the development of novel therapeutics to treat disease. Currently, the established literature emphasizes the protective role of helminth infection in murine models of inflammatory bowel disease (IBD). Using the gastrointestinal helminth Heligmosomoides polygyrus (H.polygyrus), we demonstrate that helminth infection exacerbates IBD in 2 different models - induced with oxazolone or dextran sulfate sodium (DSS). Helminth exacerbation of DSS colitis is dependent on host gender, host specific pathogen free (SPF) status and the dose of H.polygyrus infective larvae but is independent of the phase of H.polygyrus infection. Helminth exacerbation of disease is associated with increased inflammation in the colon as well as increased systemic inflammation, including splenomegaly and neutrophilia. This heightened systemic inflammation is characterised by significant bacterial translocation to the spleen, significant shifts in bacterial composition and a loss in intestinal epithelial integrity, following helminth infection. Administration of probiotics during helminth infection reduces helminth exacerbation of DSS colitis, restores epithelial integrity, significantly reduces bacterial translocation to the spleen and ameliorates splenomegaly. Our work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive disease. These studies reveal restoration of the microbiota through probiotics as a potential therapy for the treatment of gastrointestinal inflammatory disorders

Probiotic administration ameliorates helminth exacerbation of colitis

INTRODUCTION: Historically, Inflammatory Bowel Disease (IBD) was thought of as a disease of high-income countries (HIC) such as the USA, where 1-3 million people are estimated to suffer from IBD. However, as lowmiddle income countries (LMIC) become more westernized they are exposed to a number of risk factors for IBD, including diet change and smoking. Importantly, these LMIC regions also have a high burden of infectious diseases, including gastrointestinal parasite helminths that may impact on disease. Helminth infection is reported to both exacerbate and alleviate IBD, however one consensus on how helminths modify disease is lacking. METHODS: This study makes use of a well-defined model of murine colitis (IBD) and a natural parasite of mice Heligmosomoides polygyrus (H.polygyrus) to test how helminth infection alters the incidence of IBD. BALB/c mice were infected with 200 H.polygyrus L3 larvae for either 7 or 28 days. Dextran Sulfate Sodium (DSS) colitis was induced through the administration of the DSS chemical in drinking water for 7 days, after which the mice were put back on normal drinking water for 3 days. The probiotic VSL#3 was administered in drinking water ad libitum during helminth infection. RESULTS: We demonstrate that helminth infection exacerbates DSS colitis . Infection with H.polygyrus is associated with increased colon inflammation as well as increased systemic inflammation, including splenomegaly and neutrophilia. This heightened systemic inflammation is characterised by significant bacterial translocation to the spleen, significant shifts in bacterial composition and a loss in intestinal epithelial integrity. Exacerbation of DSS colitis is dependent on host gender, host specific pathogen free (SPF) status and the dose of H.polygyrus infective larvae but is independent of the phase of H.polygyrus infection. The administration of probiotics during helminth infection restored epithelial integrity, significantly reduced bacterial translocation to the spleen, ameliorated splenomegaly and reduced helminth exacerbation of DSS colitis. CONCLUSION: Our work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive exacerbation. These studies reveal restoration of the microbiota through probiotics as a potential therapy for the treatment of gastrointestinal inflammatory disorders