Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri

Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb , were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri . Genetic deletion of IL-25 (IL-25 −/− ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 −/− mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 −/− mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.

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Role of stat6 in hypercontractility of murine small intestinal smooth muscle induced by nematode infection

Gastroenterology ◽

10.1016/s0016-5085(01)82654-8 ◽

2001 ◽

Vol 120 (5) ◽

pp. A534-A534

Author(s):

A ZHAO ◽

D MULLOY ◽

J URBANJR ◽

W GAUSE ◽

T SHEADONOHUE

Keyword(s):

Smooth Muscle ◽

Nematode Infection ◽

Intestinal Smooth Muscle ◽

Small Intestinal

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Role of stat6 in hypercontractility of murine small intestinal smooth muscle induced by nematode infection

Gastroenterology ◽

10.1016/s0016-5085(08)82654-6 ◽

2001 ◽

Vol 120 (5) ◽

pp. A534 ◽

Cited By ~ 2

Author(s):

Aiping Zhao ◽

Daniel P. Mulloy ◽

Joseph F. Urban ◽

William C. Gause ◽

Terez Shea-Donohue

Keyword(s):

Smooth Muscle ◽

Nematode Infection ◽

Intestinal Smooth Muscle ◽

Small Intestinal

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Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion

eLife ◽

10.7554/elife.38269 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 11

Author(s):

Katherine A Smith ◽

Stephan Löser ◽

Fumi Varyani ◽

Yvonne Harcus ◽

Henry J McSorley ◽

...

Keyword(s):

Chronic Infection ◽

Lymphoid Cells ◽

Helminth Parasites ◽

Wild Type ◽

Heligmosomoides Polygyrus ◽

Innate Effector ◽

Interleukin 25 ◽

Deficient Mice

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14–17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

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The effect of nematode infection upon intestinal smooth muscle function

Parasite Immunology ◽

10.1046/j.1365-3024.1998.00155.x ◽

1998 ◽

Vol 20 (5) ◽

pp. 249-253 ◽

Cited By ~ 19

Author(s):

VALLANCE ◽

COLLINS

Keyword(s):

Smooth Muscle ◽

Muscle Function ◽

Nematode Infection ◽

Intestinal Smooth Muscle ◽

Smooth Muscle Function

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Antibody Response Specific to the Capsular Polysaccharide Is Impaired in Streptococcus suis Serotype 2-Infected Animals

Infection and Immunity ◽

10.1128/iai.02427-14 ◽

2014 ◽

Vol 83 (1) ◽

pp. 441-453 ◽

Cited By ~ 22

Author(s):

Cynthia Calzas ◽

Paul Lemire ◽

Gael Auray ◽

Volker Gerdts ◽

Marcelo Gottschalk ◽

...

Keyword(s):

Capsular Polysaccharide ◽

Phenotypic Diversity ◽

Streptococcus Suis ◽

Content Type ◽

Memory Response ◽

Specific Memory ◽

Versus Protein ◽

Toll Like Receptor 2 ◽

Encapsulated Bacteria

Streptococcus suisserotype 2 is an extracellular encapsulated bacterium that causes severe septicemia and meningitis in swine and humans. Albeit crucial in the fight against encapsulated bacteria, the nature of the capsular polysaccharide (CPS)-specific antibody (Ab) response duringS. suistype 2 infection is unknown. We compared for the first time the features of CPS-specific versus protein-specific Ab responses during experimental infections with live virulentS. suistype 2 in mice. The primary protein-specific Ab response was dominated by both type 1 and 2 IgG subclasses, whereas IgM titers were more modest. The secondary protein-specific Ab response showed all of the features of a memory response with faster kinetics and boosted the titers of all Ig isotypes. In contrast, the primary CPS-specific Ab response was either inexistent or had titers only slightly higher than those in noninfected animals and was essentially composed of IgM. A poor CPS-specific memory response was observed, with only a moderate boost in IgM titers and no IgG. Both protein- and CPS-specific Ab responses were Toll-like receptor 2 independent. By usingS. suistype 2 strains of European or North American origin, the poor CPS-specific Ab response was demonstrated to be independent of the genotypic/phenotypic diversity of the strain within serotype 2. Finally, the CPS-specific Ab response was also impaired and lacked isotype switching inS. suis-infected pigs, the natural host of the bacterium. The better resistance of preinfected animals to reinfection with the same strain ofS. suistype 2 might thus more likely be related to the development of a protein rather than CPS Ab response.

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W1696 Type-2 Il4 Receptor(IL-4r) Plays a Pivotal Role in Regulating the Hypercontractile Smooth Muscle Response to Nematode Infection

Gastroenterology ◽

10.1016/s0016-5085(09)63319-9 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-719

Author(s):

Rex Sun ◽

Aiping Zhao ◽

Jennifer A. Stiltz ◽

Kathleen B. Madden ◽

Joseph F. Urban ◽

...

Keyword(s):

Smooth Muscle ◽

Nematode Infection ◽

Pivotal Role ◽

Muscle Response

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Susceptibility to Ticks and Lyme Disease Spirochetes Is Not Affected in Mice Coinfected with Nematodes

Infection and Immunity ◽

10.1128/iai.01309-15 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1274-1286 ◽

Cited By ~ 5

Author(s):

Denny Maaz ◽

Sebastian Rausch ◽

Dania Richter ◽

Jürgen Krücken ◽

Anja A. Kühl ◽

...

Keyword(s):

Lyme Disease ◽

Tick Feeding ◽

Heligmosomoides Polygyrus ◽

Wild Mice ◽

Content Type ◽

Th2 Immune Response ◽

Th2 Responses ◽

Parasitological Survey ◽

Reservoir Hosts

Small rodents serve as reservoir hosts for tick-borne pathogens, such as the spirochetes causing Lyme disease. Whether natural coinfections with other macroparasites alter the success of tick feeding, antitick immunity, and the host's reservoir competence for tick-borne pathogens remains to be determined. In a parasitological survey of wild mice in Berlin, Germany, approximately 40% ofIxodes ricinus-infested animals simultaneously harbored a nematode of the genusHeligmosomoides. We therefore aimed to analyze the immunological impact of the nematode/tick coinfection as well as its effect on the tick-borne pathogenBorrelia afzelii. Hosts experimentally coinfected withHeligmosomoides polygyrusand larval/nymphalI. ricinusticks developed substantially stronger systemic type 2 T helper cell (Th2) responses, on the basis of the levels of GATA-3 and interleukin-13 expression, than mice infected with a single pathogen. During repeated larval infestations, however, anti-tick Th2 reactivity and an observed partial immunity to tick feeding were unaffected by concurrent nematode infections. Importantly, the strong systemic Th2 immune response in coinfected mice did not affect susceptibility to tick-borneB. afzelii. An observed trend for decreased local and systemic Th1 reactivity againstB. afzeliiin coinfected mice did not result in a higher spirochete burden, nor did it facilitate bacterial dissemination or induce signs of immunopathology. Hence, this study indicates that strong systemic Th2 responses in nematode/tick-coinfected house mice do not affect the success of tick feeding and the control of the causative agent of Lyme disease.

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The vascular smooth muscle cell: a therapeutic target in Type 2 diabetes?

Clinical Science ◽

10.1042/cs20120413 ◽

2013 ◽

Vol 125 (4) ◽

pp. 167-182 ◽

Cited By ~ 49

Author(s):

Karen E. Porter ◽

Kirsten Riches

Keyword(s):

Type 2 Diabetes ◽

Smooth Muscle ◽

Cardiovascular Risk ◽

Molecular Mechanisms ◽

Critical Role ◽

Experimental Studies ◽

Metabolic Memory ◽

Diabetic Patients ◽

Metabolic Disturbances

The rising epidemic of T2DM (Type 2 diabetes mellitus) worldwide is of significant concern. The inherently silent nature of the disease in its early stages precludes early detection; hence cardiovascular disease is often established by the time diabetes is diagnosed. This increased cardiovascular risk leads to significant morbidity and mortality in these individuals. Progressive development of complications as a result of previous exposure to metabolic disturbances appears to leave a long-lasting impression on cells of the vasculature that is not easily reversed and is termed ‘metabolic memory’. SMCs (smooth muscle cells) of blood vessel walls, through their inherent ability to switch between a contractile quiescent phenotype and an active secretory state, maintain vascular homoeostasis in health and development. This plasticity also confers SMCs with the essential capacity to adapt and remodel in pathological states. Emerging clinical and experimental studies propose that SMCs in diabetes may be functionally impaired and thus contribute to the increased incidence of macrovascular complications. Although this idea has general support, the underlying molecular mechanisms are currently unknown and hence are the subject of intense research. The aim of the present review is to explore and evaluate the current literature relating to the problem of vascular disease in T2DM and to discuss the critical role of SMCs in vascular remodelling. Possibilities for therapeutic strategies specifically at the level of T2DM SMCs, including recent novel advances in the areas of microRNAs and epigenetics, will be evaluated. Since restoring glucose control in diabetic patients has limited effect in ameliorating their cardiovascular risk, discovering alternative strategies that restrict or reverse disease progression is vital. Current research in this area will be discussed.

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Interleukin-13 Receptor α1-Dependent Responses in the Intestine Are Critical to Parasite Clearance

Infection and Immunity ◽

10.1128/iai.00990-15 ◽

2016 ◽

Vol 84 (4) ◽

pp. 1032-1044 ◽

Cited By ~ 13

Author(s):

Rex Sun ◽

Joseph F. Urban ◽

Luigi Notari ◽

Tim Vanuytsel ◽

Kathleen B. Madden ◽

...

Keyword(s):

Smooth Muscle ◽

Muscle Function ◽

Gastrointestinal Nematode ◽

Interleukin 4 ◽

Functional Responses ◽

Mucosal Permeability ◽

Alternatively Activated Macrophages ◽

Content Type ◽

Smooth Muscle Function

Nematode infection upregulates interleukin-4 (IL-4) and IL-13 and induces STAT6-dependent changes in gut function that promote worm clearance. IL-4 and IL-13 activate the type 2 IL-4 receptor (IL-4R), which contains the IL-13Rα1 and IL-4Rα chains. We used mice deficient in IL-13Rα1 (IL-13Rα1−/−) to examine the contribution of IL-13 acting at the type 2 IL-4R to immune and functional responses to primary (Hb1) and secondary (Hb2) infections with the gastrointestinal nematode parasiteHeligmosomoides bakeri. There were differences between strains in the IL-4 and IL-13 expression responses to Hb1 but not Hb2 infection. Following Hb2 infection, deficient mice had impaired worm expulsion and higher worm fecundity despite normal production of Th2-derived cytokines. The upregulation of IL-25 and IL-13Rα2 in Hb1- and Hb2-infected wild-type (WT) mice was absent in IL-13Rα1−/−mice. Goblet cell numbers and resistin-like molecule beta (RELM-β) expression were attenuated significantly in IL-13Rα1−/−mice following Hb2 infections. IL-13Rα1 contributes to the development of alternatively activated macrophages, but the type 1 IL-4R is also important. Hb1 infection had no effects on smooth muscle function or epithelial permeability in either strain, while the enhanced mucosal permeability and changes in smooth muscle function and morphology observed in response to Hb2 infection in WT mice were absent in IL-13Rα1−/−mice. Notably, the contribution of claudin-2, which has been linked to IL-13, does not mediate the increased mucosal permeability following Hb2 infection. These results show that activation of IL-13Rα1 is critical for key aspects of the immune and functional responses to Hb2 infection that facilitate expulsion.

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