The ability of Legionella pneumophila to cause pneumonia is determined by its capability to evade the immune system and grow within human monocytes and their derived macrophages. Human monocytes efficiently activate caspase-1 in response to Salmonella but not to L. pneumophila. The molecular mechanism for the lack of inflammasome activation during L. pneumophila infection is unknown. Evaluation of the expression of several inflammasome components in human monocytes during L. pneumophila infection revealed that the expression of the apoptosis-associated speck-like protein (ASC) and the NOD-like receptor NLRC4 are significantly down-regulated in human monocytes. Exogenous expression of ASC maintained the protein level constant during L. pneumophila infection and conveyed caspase-1 activation and restricted the growth of the pathogen. Further depletion of ASC with siRNA was accompanied with improved NF-κB activation and enhanced L. pneumophila growth. Therefore, our data demonstrate that L. pneumophila manipulates ASC levels to evade inflammasome activation and grow in human monocytes. By targeting ASC, L. pneumophila modulates the inflammasome, the apoptosome, and NF-κB pathway simultaneously.

The apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) is an adaptor molecule that mediates inflammatory and apoptotic signals. Legionella pneumophila is an intracellular bacterium and the causative agent of Legionnaire's pneumonia. L. pneumophila is able to cause pneumonia in immuno-compromised humans but not in most inbred mice. Murine macrophages that lack the ability to activate caspase-1, such as caspase-1−/− and Nlrc4−/− allow L. pneumophila infection. This permissiveness is attributed mainly to the lack of active caspase-1 and the absence of its down stream substrates such as caspase-7. However, the role of Asc in control of L. pneumophila infection in mice is unclear. Here we show that caspase-1 is moderately activated in Asc−/− macrophages and that this limited activation is required and sufficient to restrict L. pneumophila growth. Moreover, Asc-independent activation of caspase-1 requires bacterial flagellin and is mainly detected in cellular extracts but not in culture supernatants. We also demonstrate that the depletion of Asc from permissive macrophages enhances bacterial growth by promoting L. pneumophila-mediated activation of the NF-κB pathway and decreasing caspase-3 activation. Taken together, our data demonstrate that L. pneumophila infection in murine macrophages is controlled by several mechanisms: Asc-independent activation of caspase-1 and Asc-dependent regulation of NF-κB and caspase-3 activation.

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

Citation: Hassan ZA, Arafa MH, Soliman WI, Atteia HH, Al-Saeed HF (2014) The Effects of Monosodium Glutamate on Thymic and Splenic Immune Functions and Role of Recovery (Biochemical and Histological study). AbstractMonosodium glutamate (MSG), a flavor enhancer, is used in modern nutrition to improve food palatability.The objectives of the current study were to investigate the effect of MSG on thymus as well as spleen structures and functions. Also, to evaluate the possibility of recovery after cessation of administration. Adult male rats were divided into three groups: control, MSG (3 g MSG/kg body weight daily for 8 weeks by oral gavages), and Recovery (MSG for same period and then left untreated for additional 4 weeks). The results showed that MSG treatments significantly increased serum interleukin (IL)-1β as well as thymic and splenic malondialdehyde and decreased serum levels of IL-10 and also reduced glutathione (GSH) levels and both catalase and superoxide dismutase activities in the thymus and spleen. Histological examination showed that MSG induced a remarkable disruption in the lobular architecture of the thymus with marked decrease of the T lymphocytes with darkly stained nuclei and dilated blood sinusoid in the cortical region. Medullary region were enlarged and repopulated with small lymphocytes and dilated blood sinusoids. The cortical-medullary differentiation was difficult to be determined. Small sized splenic lymphatic follicles with absence of germinal centers and large congested blood vessels were also noticed. The differentiation between the red and the white pulps was indistinct. Recovery groups showed preserved thymic lobular architecture with repopulation of the cortical thymocytes enclosing the paler staining medulla .Splenic lymphatic follicles of different sizes with absence of germinal centers were noticed. Marginal zone is differentiated from the red pulp. Immunohistochemical staining of MSG group demonstrated a marked decrease in CD3-positive T-lymphocytes in both thymus and spleen that significantly increased in recovery group. Taken together, the data showed that MSG consumption may have immunotoxic effects on the thymus and spleen of adult rats which is reversible but the normal structure of the spleen would need time to be regained. It is recommended that further studies aimed at corroborating these findings be carried out.

Pediatric high-grade gliomas (HGG) are rare aggressive tumors that present a prognostic and therapeutic challenge. Diffuse midline glioma, H3K27M–mutant is a new entity introduced to HGG in the latest WHO classification. In this study we evaluated the presence of H3K27M mutation in 105 tumor samples histologically classified into low-grade gliomas (LGG) (n = 45), and HGG (n = 60). Samples were screened for the mutation in histone H3.3 and H3.1 variants to examine its prevalence, prognostic impact, and assess its potential clinical value in limited resource settings. H3K27M mutation was detected in 28 of 105 (26.7%) samples, and its distribution was significantly associated with midline locations (p-value < 0.0001) and HGG (p-value = 0.003). Overall and event- free survival (OS and EFS, respectively) of patients with mutant tumors did not differ significantly, neither according to histologic grade (OS p-value = 0.736, EFS p-value = 0.75) nor across anatomical sites (OS p-value = 0.068, EFS p-value = 0.153). Detection of H3K27M mutation in pediatric gliomas provides more precise risk stratification compared to traditional histopathological techniques. Hence, mutation detection should be pursued in all pediatric gliomas. Meanwhile, focusing on midline LGG can be an alternative in lower-middle-income countries to maximally optimize patients’ treatment options.