Clinical bleeding diathesis, laboratory haemostatic aberrations and survival in dogs infected with Angiostrongylus vasorum: 180 cases (2005-2019).

OBJECTIVES: Bleeding diathesis is a complication in dogs infected with Angiostrongylus vasorum. This retrospective study investigated clinical and laboratory haemostatic differences in A. vasorum-positive dogs with and without signs of bleeding and impact of bleeding on survival. MATERIALS AND METHODS: Demographics, type of clinical bleeding, haematocrit and a range of haemostatic tests, including thromboelastography and derived velocity curves were retrospectively registered from A. vasorum-positive dogs. All parameters were compared between dogs with and without signs of bleeding using univariable analyses. Binomial and multinomial regression models were applied to examine specific indicators in the bleeding dogs. P-values were false discovery rate adjusted, and adjusted P<0.05 was considered significant. RESULTS: One hundred and eighty dogs entered the study, including 65 dogs (36.1%) presenting with bleeding diathesis. Different types of cutaneous and mucosal bleeding were the most common clinical findings. Twenty dogs presented with neurological signs associated with intracranial and intra-spinal bleeding. One hundred and thirty-seven dogs had haematological and/or haemostatic laboratory analyses performed. Haematocrit, platelet count, thromboelastographic angle, maximum amplitude, global clot strength, maximum rate of thrombin generation and total thrombin generation were decreased, while prothrombin time was prolonged in bleeding dogs. Survival rate of bleeding dogs was lower at hospital discharge (76.9%) and 1 month after diagnosis (66.0%) than in dogs without signs of bleeding (94.8% and 90.1% at discharge and at 1 month, respectively). CLINICAL SIGNIFICANCE: Several haemostatic aberrations were detected in A. vasorum-positive dogs with bleeding diathesis. Bleeding was identified as an important negative prognostic indicator in A. vasorum-positive dogs.

Neuroangiostrongyliasis: Global Spread of an Emerging Tropical Disease.

Neuroangiostrongyliasis (NAS) is an emerging parasitic disease caused by the neurotropic nematode Angiostrongylus cantonensis. Since it was first discovered, in rats in southern China in the 1930s, this tropical to subtropical parasite has spread to much of Southeast Asia, the Pacific Islands (including Hawaii), Australia, Japan, South America, the southeastern United States, the Caribbean, Africa, the Canary Islands, and the Balearic Islands. The parasite completes its natural life cycle in snails and slugs (intermediate hosts), and rats (definitive hosts). Humans become accidental hosts after ingesting infective third-stage larvae contained within uncooked or undercooked intermediate or paratenic hosts, an event that sometimes results in NAS, also known as rat lungworm disease. Although A. cantonensis larvae cannot complete their life cycle in humans, their migration into the brain and spinal cord combined with a powerful inflammatory reaction often leads to eosinophilic meningitis and can, in rare instances, lead to coma, paralysis, and death or, in other cases, chronic, disabling neurologic sequelae. Symptoms of NAS are diverse, which often makes it difficult to diagnose. Treatment may include administration of analgesics, corticosteroids, anthelminthics, and repeat lumbar punctures to reduce intracranial pressure. Unfortunately, few medical providers, even in endemic areas, are familiar with A. cantonensis or its epidemiology, diagnosis, and treatment. As the parasite continues to spread and NAS affects more people, medical practitioners, as well as the general public, must become more aware of this emerging zoonosis and the potentially devastating harm it can cause.

A Rare Etiology for Ascending Paralysis in an Infant.

An 11-month-old male infant with ascending paralysis had an unremarkable initial cerebrospinal fluid (CSF) analysis and imaging. Progressive neurological symptoms resulted in repeated CSF sampling, microscopy, and plasma microbial cell-free DNA next-generation sequencing analysis, that in combination with epidemiology, confirmed the diagnosis.

Eosinophilic meningitis due to A. Cantonensis revealed at autopsy.

Parasitic infection of the central nervous system could be fatal, and its incidence is rising due to increasing worldwide travel. Amongst the various nematodes, Angiostrongylus contonensis is the commonest and causes eosinophilic meningitis. It is a zoonotic disease produced due to the ingestion of raw or undercooked snails or slugs. Most cases of angiostrongyliasis are mild and self-limiting, but death can occur in severe cases lacking timely and proper treatment. Very few autopsy cases of A. cantonensis are reported. We present the case of a 32-year-old mentally challenged orphan male with eosinophilic meningitis at autopsy.

First Case of Subretinal Ocular Angiostrongyliasis Associated with Retinal Detachment in the United States.

Angiostrongylus cantonensis, commonly known as the rat lungworm, is mostly found in Asia, the Pacific Basin, and the Caribbean, but is also endemic in Hawai'i, especially on the Island of Hawai'i. Ocular angiostrongyliasis is an uncommon but previously reported complication associated with permanent vision loss. This is the first reported case of ocular angiostrongyliasis involving the retina or posterior segment of the eye in the US. A 24-year-old male from Chicago visited the Island of Hawai'i, where he worked on a farm and ate a vegetarian diet. When he returned to Chicago, he became sick and was hospitalized for eosinophilic meningitis. One month later, he developed a retinal detachment which required surgical repair involving a pars plana vitrectomy. During the reattachment of the retina during surgery, a live motile was identified nematode in the subretinal space. An endolaser probe immobilized and killed the nematode, and it was subsequently extracted through the sclerotomy. Thermal scars around all retinal holes including the retinotomy site were made to stabilize the retina, and perfluoropropane gas was injected to achieve temporary tamponade. Thereafter, the patient's cerebrospinal fluid returned positive for angiostrongylus cantonensis antibodies. During extended follow-up, the patient eventually lost all vision in the affected eye due to recurrent retinal detachment. This case of ocular angiostrongyliasis demonstrates the importance of obtaining travel history from endemic areas, knowing the risk of developing eosinophilic meningitis, and understanding the risk of permanent vision loss in cases involving the retina.

Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity.

"Taste-like" tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell-ILC2 cell-intestinal epithelial cell circuit that drives the clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion, and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis-infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (HEK293) cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.

An unusual cause of visual loss: Subfoveal, motile angiostrongyliasis.

This is a short report describing the clinical presentation, investigations, treatment and outcome of a patient living in the Jamaican countryside who was diagnosed with a live, motile subfoveal helminth identified as Angiostrongylus cantonensis on optical coherence tomography at the University Hospital of the West Indies Eye Clinic. This is the second documented case in Jamaica. Early recognition of angiostrongyliasis is important as it may manifest as eosinophilic meningitis which can be fatal without prompt treatment.

Spontaneous tricuspid valve chordal rupture in a dog with severe, irreversible pulmonary hypertension caused by Angiostrongylus vasorum infection.

BACKGROUND: The adult worms of Angiostrongylus vasorum reside in the pulmonary artery of dogs and can lead to cardiac, respiratory, and central neurologic signs. Due to luminal obstruction and perivascular inflammation of the pulmonary artery branches, pulmonary hypertension can arise. Pulmonary hypertension, in turn, can lead to severe damage of the right-sided cardiac structures, leading to right ventricular remodeling and tricuspid valve regurgitation. CASE PRESENTATION: An 8-year-old neutered female English Cocker Spaniel was presented to the author's institution because of abdominal distention and exercise intolerance. Ascites caused by congestive right-sided heart failure was found to be responsible for these problems. The underlying etiology of the right-sided heart failure was a severe pulmonary hypertension caused by Angiostrongylus vasorum infection. Echocardiography revealed, in addition to a severe concentric and eccentric right ventricular hypertrophy, right atrial and pulmonary trunk dilation, severe tricuspid valve regurgitation, and a systolic flail of the anterior leaflet of the tricuspid valve, resulting from ruptured chordae tendineae. As a coincidental finding, a congenital mitral stenosis was found. Oral therapy was initiated with daily administration of fenbendazole for 2 weeks along with daily administration of oral sildenafil until the re-check examination. At the 6-week re-check the dog showed full clinical and partial echocardiographic recovery, and both the blood antigen test for Angiostrongylus vasorum and the fecal Baermann larva isolation test were negative. When the sildenafil therapy was ceased after tapering the daily dosage, the owner reported recurrence of abdominal distension. Re-starting the sildenafil therapy resulted in resolution of this problem. The dog was reported to be clinically healthy with daily sildenafil administration 7 months after the initial presentation. CONCLUSIONS: The present case report describes a dog where angiostrongylosis led to congestive right-sided heart failure resulting from severe pulmonary hypertension. The secondary right ventricular eccentric hypertrophy together with suspected papillary muscular ischemia were the suspected cause of the ruptured major tricuspid chordae tendineae, which led to a severe tricuspid valve regurgitation. Despite eradication of the worms, the severe pulmonary hypertension persisted. Treatment with daily oral sildenafil, a pulmonary arterial vasodilator, was enough to keep the dog free of clinically apparent ascites.

Lidocaine Infusion for Refractory Pain from Rat Lungworm Disease - Honolulu, Hawai'i.

Human infection with Angiostrongyloides cantonensis, or rat lungworm disease, manifests most commonly with neurologic symptoms that often include severe diffuse pain. While pain is reported by the majority of patients with rat lungworm disease, there are presently no published guidelines on the approach to pain management for these patients. Here we report a case of rat lungworm disease where severe refractory pain was the most prominent symptom and an intravenous lidocaine infusion was used as a successful treatment modality. Intravenous lidocaine has been shown to be safe and effective in neuropathic pain, refractory cancer pain, and peri-operative pain management. To our knowledge, this is the first case report on the use of lidocaine infusion for the management of refractory pain from rat lungworm disease, and among the first reports of any approach, to pain management for rat lungworm disease. We suggest that a lidocaine infusion protocol be considered when pain from rat lungworm disease fails to respond to first-line analgesics.

Particularidades de la meningoencefalitis eosinofílica en la era del caracol gigante africano / Particular features of eosinophilic meningoencephalitis in the age of the giant African snail

Introducción: la meningoencefalitis eosinofílica es una enfermedad inflamatoria infecciosa reportada en Cuba desde la década de los ochenta del siglo pasado y actualmente extendida al continente americano. Es producida por el parásito Angiostrongylus cantonensis. Objetivo: determinar si existen diferencias entre los pacientes que sufrieron meningoencefalitis eosinofílica antes y después de la introducción del caracol gigante africano. Métodos: se estudiaron un total de 19 muestras de líquido cefalorraquídeo y suero tomadas simultáneamente a cada paciente diagnosticados con meningoencefalitis eosinofílica, perteneciente a la seroraquioteca del Laboratorio Central del Líquido Cefalorraquídeo (LABCEL). Para la determinación de las proteínas albúmina e IgG se empleó como método de laboratorio la inmunodifusión radial. Resultados: el 14 por ciento de los pacientes fueron adultos antes de la aparición de este molusco, en contraste con el momento actual, donde el 50 por ciento son pacientes con edades superiores a 18 años. El porcentaje de síntesis de IgG intratecal media fue mayor en los enfermos actuales, aunque no de manera significativa. Conclusiones: . existen diferencias antes y después de la aparición del caracol gigante africano dado por la respuesta de síntesis intratecal en los pacientes asociados con el molusco que denota una mayor agresividad del parásito. La edad promedio mayor de los enfermos confirma que estos son los que más manipulan y dispersan el molusco(AU)

Introduction: eosinophilic meningoencephalitis is an infectious inflammatory disease reported in Cuba since the 1980s and currently extended to the American continent. This condition is caused by the parasite Angiostrongylus cantonensis. Objective: determine whether there are differences between the patients suffering from eosinophilic meningoencephalitis before and after the introduction of the giant African snail. Methods: a study was conducted of a total 19 cerebrospinal fluid and serum samples taken simultaneously from each of the patients diagnosed with eosinophilic meningoencephalitis and kept at the sample collection of the Central Cerebrospinal Fluid Laboratory (LABCEL). Radial immunodiffusion was the laboratory method used for determination of the proteins albumin and IgG. Results: of the patients studied, 14 percent were adults before the appearance of this mollusc, in contrast with the present moment, when 50 percent are patients aged over 18 years. The percentage of mean intrathecal synthesis of IgG was higher in the current sufferers, though not significantly. Conclusions: there are differences before and after the appearance of the giant African snail, given the intrathecal synthesis response of patients associated to the mollusc, which denotes greater aggressiveness by the parasite. The higher mean age of sufferers confirms that these are the ones who most often handle and disperse the mollusc(AU)

Case Report: Angiostrongylus cantonensis Meningoencephalitis in a 9-Month-Old Baby in Vietnam.

Meningoencephalitis is not a rare disease in small children. However, eosinophilic meningitis due to Angiostrongylus cantonensis is unusual in a baby. We describe the case of a 9-month-old baby from North Vietnam with eosinophilic meningoencephalitis. The baby lived in a rural area, where farming is widespread, and presented with fever and seizures. Laboratory results showed peripheral eosinophilia (16.1%), cerebrospinal fluid (CSF) white blood cell count 220/mm3 (26% eosinophils), CSF antibody test positive for Ascaris, CSF ELISA positive for Angiostrongylus cantonensis, and blood ELISA positive for A. cantonensis. A mobile worm was identified in the CSF. The presentation was consistent with a diagnosis of A. cantonensis eosinophilic meningitis. The baby recovered fully after administering albendazole (200 mg/day for 2 weeks), and intravenous dexamethasone (0.6 mg/kg/day every 8 hours) and mannitol (1.5 g/kg/day every 8 hours) for the first 3 days, followed by 5 days of oral prednisolone (2 mg/kg/day).

Angiostrongyliasis infection masquerading as granulomatosis with polyangiitis: a case-based review.

Pulmonary angiitis is a small vessel vasculitis commonly reported in granulomatosis with polyangiitis (GPA) but is rarely attributed to angiostrongyliasis. We report a case of a patient with well-controlled rheumatoid arthritis, who was treated for GPA based on lung biopsy results with glucocorticoids (GC). Upon re-review of the initial pathology, along with peripheral eosinophilia and history of recent travel, the patient was eventually diagnosed with angiostrongylus-like nematode infection. GCs were subsequently discontinued and instead, the patient was treated with anthelmintics with complete resolution of symptoms. Commonly associated with eosinophilic meningitis or abdominal angiostrongyliasis in humans, clinical pulmonary manifestations of this parasite species are rare. With parasitic infiltration of the pulmonary vessels mimicking clinical GPA, diagnosis and treatment can be difficult in these patients. We discuss the third-reported case and first-reported survivor of Angiostrongylus-induced pulmonary angiitis followed by a focused review of the literature.

First cases of Angiostrongylus cantonensis infection reported in Martinique, 2002-2017.

Neuroangiostrongyliasis is a parasitic disease caused by the accidental ingestion of the nematode Angiostrongylus cantonensis in its larval form. Human infection can lead to eosinophilic meningitis, sometimes complicated by life-threatening radiculomyelitis or encephalitis. Although some cases have been reported from other Caribbean Islands, no cases have been diagnosed in Martinique so far. Here, we report the first eight laboratory-confirmed cases of neuroangiostrongyliasis on the island of Martinique, French West Indies, between 1 January 2002 and 31 December 2017. One case was fatal and five resulted in neurological sequelae. The medical community should consider the risk of A. cantonensis infection in patients living in or returning from Martinique.

TITLE: Premiers cas d'angiostrongylose à Angiostrongylus cantonensis à la Martinique, de 2002 à 2017. ABSTRACT: L'angiostrongylose neuroméningée est une maladie parasitaire causée par l'ingestion accidentelle du nématode Angiostrongylus cantonensis sous sa forme larvaire. L'infection humaine peut conduire à une méningite à éosinophiles, pouvant évoluer en radiculomyélite ou encéphalite menaçant le pronostic vital. Bien que des cas aient été rapportés dans d'autres îles des Caraïbes, aucun cas n'avait été diagnostiqué à la Martinique jusqu'à présent. Dans cet article, nous caractérisons les huit premiers cas d'angiostrongylose neuroméningée biologiquement diagnostiqués à la Martinique, Antilles françaises, entre le 1er janvier 2002 et le 31 décembre 2017. Un cas s'est révélé mortel et cinq ont engendré des séquelles neurologiques. La communauté médicale doit désormais considérer le risque d'infection à A. cantonensis chez les patients vivant ou revenant d'un voyage à la Martinique.

Angiostrongylus cantonensis activates inflammasomes in meningoencephalitic BALB/c mice.

Angiostrongylus cantonensis is a metastrongyloid nematode that causes eosinophilic meningoencephalitis in humans. A high infestation of A. cantonensis can cause permanent brain damage or even death. The inflammasome is an oligomeric molecular platform that can detect microbial pathogens and activate inflammatory cytokines. The recognition of larval surface antigens by pattern recognition receptors (PRRs) can cause oligomerization of the NOD-like receptor (NLR) or absent in melanoma 2 (AIM2) with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to form a caspase-1-activating scaffold. Activated caspase-1 converts pro-inflammatory cytokines into their mature, active forms. Helminths infection has been shown to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes. In this study, we aimed to investigate the mechanism of inflammasome activation upon A. cantonensis infection in a mouse model. This study provides evidence that A. cantonensis infection can activate NLRP1B and NLRC4 inflammasomes and promote pyroptosis to cause meningoencephalitis.

Factores de riesgo asociados a la meningitis eosinofílica causada por Angiostrongylus cantonensis (Nematoda: Metastrongylidae) en Chone, Ecuador / Risk factors associated to eosinophilic meningitis caused by Angiostrongylus cantonensis (Nematoda: Metastrongylidae) in Chone, Ecuador

Introducción: El parásito Angiostrongylus cantonensis es el principal causante de meningitis eosinofílica. En el 2008 se reportó el primer caso en Ecuador y un estudio reciente en la Ciudad de Chone, Manabí, Ecuador determinó una alta prevalencia del parásito en el caracol africano (Achatina fulica). Objetivo: Identificar los factores de riesgo asociados a la meningitis eosinofílica causada por A. cantonensis en la ciudad de Chone. Métodos: Se entrevistaron a 500 personas residentes en la ciudad de Chone y se revisaron las historias clínicas del Hospital General de Chone. Resultados: Se observó que la población de Chone, está expuesta a los siguientes factores de riesgos: consumo de caracoles crudos (7,40 por ciento), el frecuente contacto de las personas con el caracol africano en la casa (67 por ciento), como en el trabajo (51,20 por ciento), el contacto que tienen los niños con caracoles, al jugar en el jardín (76,80 por ciento) y la incorrecta limpieza de los alimentos (54,40 por ciento). En el entorno de la población, se evidenció la presencia del caracol africano cerca de las casas en el 35,20 por ciento y las ratas, en el 50,80 por ciento. Además, el 34 por ciento de la muestra de estudio presentó sintomatología relacionada con meningitis eosinofílica. Se encontró que existía asociación entre la presencia de vectores cerca de las casas y la cantidad de síntomas manifestados por las personas. Conclusiones: Se evidenció que la población de Chone, manifiesta hábitos que exponen a la gente de esta localidad a un alto riesgo de contagio de meningitis eosinofílica(AU)

Introduction: The parasite Angiostrongylus cantonensis is the main causative agent of eosinophilic meningitis. The first case in Ecuador was reported in 2008, and a recent study conducted in the city of Chone, Manabí, Ecuador, determined a high prevalence of the parasite in the African snail (Achatina fulica). Objective: Identify the risk factors associated to eosinophilic meningitis caused by A. cantonensis in the city of Chone. Methods: Interviews were conducted with 500 residents from the city of Chone and a review was carried out of the medical records at Chone General Hospital. Results: It was found that the population of Chone is exposed to the following risk factors: eating raw snails (7.40 percent), frequent contact between people and African snails both at home (67 percent) and at work (51.20 percent), contact between children and snails while playing in gardens (76.80 percent) and washing food items incorrectly (54.40 percent). In the areas surrounding people's households the African snail was found in 35.20 percent and rats in 50.80 percent . Additionally, 34 percent of the study sample had symptoms of eosinophilic meningitis. An association was found between the presence of vectors near the houses and the number of symptoms occurring in people. Conclusions: It was evident that the population of Chone has habits which expose them to a high risk for eosinophilic meningitis(AU)

Eosinophilic meningitis due to Angiostrongylus cantonensis in Europe.

OBJECTIVES: To describe and analyse the epidemiological and clinical characteristics of imported human angiostrongyliasis in Europe. METHODS: A systematic literature review of cases of human angiostrongyliasis in Europe was performed. Seven databases were searched. The epidemiological and clinical characteristics were extracted from included records and simple summary statistics were performed on extracted data. RESULTS: Twenty-two cases reported between 1988 and 2019 were identified. They were mainly from French Polynesia, Southeast Asia, and the Caribbean Islands. The dominant suspected mode of transmission was ingestion of prawns, shrimp, or salad. For patients with data, 90% had a history of headache, often lasting, and half had paresthesia. Eighty-nine percent had eosinophilia, 93% had cerebrospinal fluid (CSF) eosinophilia, and 92% had elevated CSF protein. Central nervous system (CNS) imaging was normal in most cases. Two-thirds received albendazole or mebendazole treatment, although this is not currently recommended. CONCLUSIONS: We have increased previous numbers to 22 reported cases in total since 1988. Angiostrongyliasis should generally be suspected in patients with a lasting headache who have returned from Southeast Asia, China, the Caribbean Islands, Australia, or French Polynesia, as well as parts of North America and Tenerife, Spain, although one autochthonous case from mainland Europe has also been reported. A dietary history should focus on prawns, shrimp, and salad, whilst also including slugs and snails and other paratenic hosts where relevant. The clinical diagnosis is supported by the presence of blood eosinophilia, CSF eosinophilia, and elevated CSF protein. A definitive laboratory diagnosis should be sought, and CNS imaging should be used to support, not to rule out the diagnosis. The most up-to-date evidence should always be consulted before initiating treatment. Current recommendations include analgesics, corticosteroids, and periodic removal of CSF for symptom relief, while antihelminthic treatment is debated.

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung.

Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis, suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 -/- mice with N. brasiliensis Unexpectedly, compared with wild-type (WT) mice, infected Nlrp3 -/- mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected Nlrp3 -/- mice exhibited elevated type 2 gene expression compared with WT mice. Notably, inflammasome activation was not evident early postinfection with N. brasiliensis, and in contrast to Nlrp3 -/- mice, antihelminth responses were unaffected in caspase-1/11-deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 has a role in constraining lung neutrophilia, helminth killing, and type 2 immune responses in an inflammasome-independent manner.