Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.

Trained Innate Immunity Induced by Vaccination with Low-Virulence Candida Species Mediates Protection against Several Forms of Fungal Sepsis via Ly6G + Gr-1 + Leukocytes

Trained innate immunity (TII) is induced following immunization with live attenuated microbes and represents a clinically important strategy to enhance innate defenses. TII was initially demonstrated following intravenous inoculation with low-virulence Candida albicans , with protection against a subsequent lethal C. albicans intravenous bloodstream infection (BSI) mediated by monocytes with enhanced cytokine responses.

Aspiration pneumonia complicated by disseminated fungal sepsis in the setting of incidental esophagitis cystica: A rare autopsy case report with review of the literature

Introduction/Objective Esophageal retention cysts are presumed to arise from obstruction of the excretory ducts of the submucosal glands of the esophagus. Since the first description by Kuhne in 1899, different terminologies have been used to denote these lesions including retention cysts, mucocele, esophagitis cystica, and cyst of esophageal submucosal gland duct. Esophageal retention cysts are generally benign, asymptomatic and discovered incidentally. However, a few studies have reported symptomatic dysphagia and to date, only one autopsy case report described esophageal retention cysts contributing to aspiration pneumonia and cause of death. Methods/Case Report We present a case of aspiration pneumonia, associated with both reduced oropharyngeal tone secondary to alcohol consumption and esophageal dysphagia due to esophagitis cystica in a 69 year old female with alcohol use disorder complicated by alcoholic liver disease. The patient was found unresponsive at home with bloody oral secretions and evidence of head trauma. On autopsy all lung lobes demonstrated that large and small airways and alveoli were filled with vegetable matter, associated with prominent bacterial and fungal forms. EVG stain demonstrated vascular disruption with red blood cell extravasation, next to a focus of aspiration pneumonia. This explained the patient’s “bloody oral secretions”, originating from the respiratory tract. Demonstration of fungal hyphae in sections from lungs as well as necrotic colon was consistent with disseminated fungal sepsis. While sections from esophagus showed no varices which could explain the patient’s “bloody oral secretions” in the setting of alcoholic liver disease, there were numerous dilated esophageal submucosal cysts. Cysts were lined by a single to double layer of cuboidal epithelium with eosinophilic cytoplasm and basally-located, bland-appearing nuclei. Conclusion In summary, we present a rare case of esophageal retention cyst associated aspiration pneumonia complicated by pulmonary hemorrhage, adding to the growing body of knowledge regarding fatal complications of these usually incidental lesions.

Organism specific platelet response in neonatal sepsis in neonates weighing ≤1800 gm

Background: Thrombocytopenia is an important but non-specific marker of severity of neonatal sepsis. Few studies have observed organism-specific response in platelet count, however this finding in not consistently seen in various studies. We carried out this study to look for organism-specific response of platelet count and indices in neonatal sepsis in our setup.Methods: A prospective analytical study was conducted during December, 2019 to November, 2020 at tertiary care centre of central Gujarat. Neonates weighing ≤1800 gm (n=100) were enrolled according to eligibility criteria. Sepsis screen including TLC, ANC, platelet count, platelet indices, micro ESR, CRP, and blood culture was done. Patients with culture-proven sepsis were divided according to organisms isolated from blood or CSF. Patients were followed up to the final outcome of their hospital stay. Appropriate analytical tests were used for the results.Results: Out of 100 patients, 69 had culture-proven sepsis, of which 40 (58%) were gram-negative, 21 (30%) were gram-positive and 8 (12%) had fungal sepsis. Of these 48/69 (70%) patients had thrombocytopenia. Of these patients with thrombocytopenia 60%, 30% and 10% in the first sample while 48%, 38% and 16% in the second sample had gram positive, gram negative and fungal sepsis respectively. Commonest organisms isolated were Enterococcus and MRCONS, and thrombocytopenia was not having specific correlation with any particular organism. There was no significant difference between mean and median platelet count of gram-positive, gram-negative, and fungal sepsis.Conclusions: Thrombocytopenia is significantly associated with neonatal sepsis. The effects of sepsis on platelet count are not organism-specific.

Preventing Fungal Sepsis in Preterm Infants: The Impact of Changing to Prophylactic Nystatin in a Tertiary Neonatal Unit

Fungal organisms pose a life-threatening risk to vulnerable premature infants. In this review, all cases of fungal sepsis in a large tertiary neonatal unit over the last 10 years (2008-2018) in premature neonates (<30 weeks gestation) were reviewed. This time frame spanned a change in prophylaxis policy from fluconazole to nystatin in 2012. The most common fungal organism causing sepsis was Candida albicans in 80% of cases and Candida parapsilosis in 13%. All fungal organisms cultured were fully sensitive; no resistant cases were seen in the last 10 years. Encouragingly, rates of infection were static (between 0 and 3 cases/year) over the last 10 years, despite the unit’s policy for antifungal prophylaxis changing from fluconazole to nystatin in 2012.