Abstract
Background
Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory ...response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited.
Methods
Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion.
Results
The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative.
Conclusions
PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.
This is a small case series describing functional outcomes in previously healthy cryptococcal meningitis patients treated with pulse corticosteroid taper therapy for postinfectious inflammatory syndrome (PIIRS).
Pneumocystis pneumonia remains a common opportunistic infection in the diverse immunosuppressed population. One clear risk factor for susceptibility to Pneumocystis is a declining CD4(+) T cell count ...in the setting of HIV/AIDS or primary immunodeficiency. Non-HIV-infected individuals taking immunosuppressive drug regimens targeting T cell activation are also susceptible. Given the crucial role of CD4(+) T cells in host defense against Pneumocystis, we used RNA sequencing of whole lung early in infection in wild-type and CD4-depleted animals as an unbiased approach to examine mechanisms of fungal clearance. In wild-type mice, a strong eosinophil signature was observed at day 14 post Pneumocystis challenge, and eosinophils were increased in the bronchoalveolar lavage fluid of wild-type mice. Furthermore, eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice were more susceptible to Pneumocystis infection when compared with BALB/c controls, and bone marrow-derived eosinophils had in vitro Pneumocystis killing activity. To drive eosinophilia in vivo, Rag1(-/-) mice were treated with a plasmid expressing IL-5 (pIL5) or an empty plasmid control via hydrodynamic injection. The pIL5-treated mice had increased serum IL-5 and eosinophilia in the lung, as well as reduced Pneumocystis burden, compared with mice treated with control plasmid. In addition, pIL5 treatment could induce eosinophilia and reduce Pneumocystis burden in CD4-depleted C57BL/6 and BALB/c mice, but not eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice. Taken together, these results demonstrate that an early role of CD4(+) T cells is to recruit eosinophils to the lung and that eosinophils are a novel candidate for future therapeutic development in the treatment of Pneumocystis pneumonia in the immunosuppressed population.
IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-β and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The ...identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that
,
, and
genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of
and inhibited
-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated
promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4
T cells was abrogated in CD4-specific
knockout mice (
). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4
T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4
T cells.
is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases ...hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by
To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that
inhibits IL-22 during
lung infection and that
deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner.
mice are more resistant to
infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected
mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from
mice displayed reduced OXPHOS gene expression upon infection with
, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that
macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, ...subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with
, which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with
We established a new mouse model to investigate the relationship between
and
pulmonary infections. In this model, animals exposed to
and coinfected with
exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with
alone. This increased control of
infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in
control in
-coinfected lungs. Our results demonstrate that
, an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact
control in a mouse model.
Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. ...Intracellular pathogens adapt to a resource- poor environment by marshaling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog 2-deoxy-D-glucose (2-DG) armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages, decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This effect promoted the antifungal machinery of macrophages and expanded the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.
Autophagy involving core machinery proteins such as ATG9A is part of a cytoprotective process whose dysregulation is associated with carcinogenesis, neurodegeneration and autoimmunity, but few ...examples exist of monogenic diseases to further insights into human disease. In the present studies, we report a patient with novel compound heterozygous mutations in ATG9A after patient and parental DNA were subjected to whole exome sequencing. The patient developed hyperplastic proliferations of T and B cells in lung and brain and exhibited defects in lymphocyte memory cell populations after developing an infection with Epstein-Barr virus (EBV). Peripheral blood leukocytes from the patient exhibited defects in autophagic activity and EBV-transformed cells redemonstrated this defect which was also associated with defective NFKB (nuclear factor kappa B) signaling and accumulation of the pro-proliferative protein MYC (MYC proto-oncogene, bHLH transcription factor) and anti-apoptotic protein BCL2 (BCL2 apoptosis regulator), leading to increased proliferative capacity. Defects were corrected after transformation with plasmids expressing ATG9A and after treatment of cells as well as the patient with the MTOR (mechanistic target of rapamycin kinase) inhibitor, autophagy-inducing immunosuppressant rapamycin. These results point to a novel role of ATG9A and autophagy in human cellular signaling associated with hyperplasia and lymphocyte biology and provide an example how genetic studies may suggest effective specific therapeutic interventions.
BCL2: BCL2 apoptosis regulator; BCL10: BCL10 immune signaling adaptor; CARD11: caspase recruitment domain family member 11; CBM: CARD11-BCL10-MALT1; CR2: complement C3d receptor 2; EBNA: Epstein Barr nuclear antigen; EBV: Epstein-Barr virus; FCGR3A; Fc gamma receptor IIIa; GLILD: granulomatous-lymphocytic interstitial lung disease; HV: healthy volunteer; IKBKB/IKB kinase: inhibitor of nuclear factor kappa B kinase subunit beta; IL2RA: interleukin 2 receptor subunit alpha; MALT1: MALT1 paracaspase; MS4A1: membrane spanning 4-domain A1; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH: transcription factor; NCAM1: neural cell adhesion molecule 1; NFKB: nuclear factor kappa B; NIAID: National Institute of Allergy and Infectious Diseases; NK: natural killer; PTPRC: protein tyrosine phosphatase receptor type C; SELL: selectin L; PBMCs: peripheral blood mononuclear cells; TR: T cell receptor; Tregs: regulatory T cells; WT: wild-type
Abstract
Background
Pneumococcal pneumonia is the main cause of morbidity in children younger than 2 years of age and people older than 65 years old. We have published that exogenous recombinant ...Interleukin-22 (IL-22) decreases bacterial burden in lung and extrapulmonary organs in a murine model of pneumococcal pneumonia. This beneficial effect was the result of increased phagocytosis due to IL-22 induced hepatic complement component 3. IL-22, secreted by cells of the lymphoid lineage, is the ligand for IL-22 receptor (IL-22ra1) and the decoy receptor IL-22 binding protein (IL-22bp). We hypothesized that absence of IL-22bp, the negative regulator of IL-22, would increase free IL-22, thus decreasing bacterial burden upon pneumococcal pneumonia.
Methods
We infected IL-22bp knockout (IL-22bp−/−) mice and littermate controls with Streptococcus pneumoniae 106 cfu/mouse and sacrificed them at 48 hours. We assessed lung bacterial burden, flowcytometry sorting of cell lung populations to assess IL-22bp expression, RNA sequence of bronchial brushes to assess gene expression and in vivo knockdown of Lysozyme 1 in IL-22bp−/− mice.
Results
IL-22bp−/− mice had twice the amount of IL-22 in serum compared with controls at naïve state, and once infected with pneumococcus, there was higher Il22 expression in IL-22bp−/− lungs. There was 1.5 log reduction in pneumococcal burden in IL-22bp−/− mice compared with controls. Furthermore, sorting of CD45+ and in CD45− lung cells, showed higher expression of IL-22bp in alveolar and conductive airway epithelial cells at naïve state in control mice. As IL-22ra1, the site of action of IL-22, is mostly expressed in the airway epithelium, we performed RNA sequence of bronchial brushes of infected IL-22bp−/− and control mice. Our data show higher expression of secreted antimicrobial peptides genes like Lyzosyme 1 (Lyz1), Surfactant protein C, WAP four - disulfide core domain (Wfdc)18 and Wfdc12 in infected IL22bp−/− mice compared with controls. Furthermore, knocking down of Lyz1 by siRNA in vivo in IL-22bp−/− mice reversed the protective phenotype upon infection.
Conclusion
In conclusion, our data suggest that absence of IL-22bp allows a permissive environment for IL-22 activity in the lung by increasing secretion of Lysozyme 1 from the bronchial epithelium, which is advantageous to the host upon pneumococcal lung infection.
Disclosures
All authors: No reported disclosures.
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