Evidence of Microglial Immune Response Following Coronavirus PHEV Infection of CNS

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus that invades the host central nervous system (CNS) and causes neurological dysfunction. Microglia are key immune cells in the CNS, however, whether and how they response to PHEV infection remains unclear. Herein, microglial activation and proliferation were detected in the CNS of PHEV-infected mice, as along with the proinflammatory response. Moreover, the production of proinflammatory cytokines induced by moderately activated microglia limited viral replication in the early stage of infection. Microglial depletion assays showed that during late infection, excess activation of microglia aggravated neurological symptoms, BBB destruction, and peripheral monocyte/macrophage infiltration into the CNS. Using an in vitro brain slice model, PHEV was identified to specifically and moderately induce microglial activation in the absence of peripheral immune cells infiltration. Consistently, macrophage clearance from circulating blood indicated that peripheral monocytes/macrophages crossing the BBB of mice were responsible for excess activation of microglia and CNS damage in late PHEV infection. Overall, our findings provide evidence supporting a dual role for microglia in the host CNS in response to coronavirus PHEV invasion.

Loculations and Associated Risk Factors of Childhood Pleural Tuberculosis

Background: Pleural loculation in childhood pleural tuberculosis (TB) remains a problem in practice, it is usually associated with failure drainage. Therefore, to improve the management of childhood pleural TB, a retrospective study was conducted to identify the risk factors associated with loculated effusion in childhood pleural TB.Methods: Between January 2006 and December 2019, consecutive children (≤15 years old) with tuberculous pleural effusion (definite and possible) were included for further analysis. The demographic, clinical, laboratory, and radiographic features were collected from the medical records. Univariate and multivariate logistic regressions were used to explore the factors associated with the presence of pleural loculation in children with pleural TB.Results: A total of 154 children with pleural TB (definite, 123 cases; possible, 31 cases) were included in our study and then were classified as loculated effusion (n = 27) and non-loculated effusion (n = 127) groups by chest X-ray or ultrasonography. Multivariate analysis revealed that male gender (age-adjusted OR = 3.903, 95% CI: 1.201, 12.683), empyema (age-adjusted OR = 4.499, 95% CI: 1.597, 12.673), peripheral monocytes ≤0.46 × 109/L (age-adjusted OR = 4.122, 95% CI: 1.518, 11.193) were associated with the presence of loculated effusion in children with pleural TB.Conclusion: In conclusion, several characteristics, such as male gender, empyema, and peripheral monocyte count have been identified as risk factors for pleural loculation in children with pleural TB. Our findings may be helpful to improve the management of pleural loculation in childhood pleural TB.

Age Related Differences in Monocyte Subsets and Cytokine Pattern during Acute COVID-19—A Prospective Observational Longitudinal Study

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2.

Hematogenous Macrophages: A New Therapeutic Target for Spinal Cord Injury

Spinal cord injury (SCI) is a devastating disease leading to loss of sensory and motor functions, whose pathological process includes mechanical primary injury and secondary injury. Macrophages play an important role in SCI pathology. According to its origin, it can be divided into resident microglia and peripheral monocyte-derived macrophages (hematogenous Mφ). And it can also be divided into M1-type macrophages and M2-type macrophages on the basis of its functional characteristics. Hematogenous macrophages may contribute to the SCI process through infiltrating, scar forming, phagocytizing debris, and inducing inflammatory response. Although some of the activities of hematogenous macrophages are shown to be beneficial, the role of hematogenous macrophages in SCI remains controversial. In this review, following a brief introduction of hematogenous macrophages, we mainly focus on the function and the controversial role of hematogenous macrophages in SCI, and we propose that hematogenous macrophages may be a new therapeutic target for SCI.

Use of peripheral neutrophil to lymphocyte ratio and peripheral monocyte levels to predict survival in fibrotic hypersensitivity pneumonitis (fHP): a multicentre retrospective cohort study

The factors determining disease course and survival in fibrotic hypersensitivity pneumonitis (fHP) have not been fully elucidated.The aim of this study was to describe the characteristics of patients with fHP in a real-world cohort and investigate factors associated with worse outcomes. We aimed to explore the use of neutrophil to lymphocyte ratio (NLR) and peripheral blood monocyte levels in predicting mortality.MethodsA retrospective, multicentre, observational UK cohort study.ResultsPatients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with <0.95 K/uL (33 vs 57 months). In contrast, NLR and monocyte count did not predict survival in the fHP cohort.ConclusionsAlthough fHP has a statistically lower mortality than IPF, absolute survival time of both conditions is poor. High baseline NLR and absolute monocyte counts predict worse survival in IPF but not in fHP, highlighting the potential for divergence in their pathogenic mechanisms.

Formation of multinucleated globoid cells in Krabbe iPSC-derived microglia cultures: a preliminary investigation

Globoid cell leukodystrophy (Krabbe disease) is a severe demyelinating, neurodegenerative lysosomal storage disorder caused by deficiency in glycosphingolipid catabolic enzyme galactosylceramidase (GALC). Histologically, Krabbe disease is characterized by the appearance of large multinucleated globoid cells that express classical macrophage markers (both of brain-resident microglia and peripheral monocyte-derived). Globoid cells reside near areas of degeneration; however, their functional significance in disease progression remains unclear. In the current study, we differentiated microglia-like cells from iPSCs from a donor with infantile Krabbe disease and compared them to microglia generated from two healthy controls and two donors with the lysosomal storage disorder metachromatic leukodystrophy (MLD), which is genetically distinct from Krabbe disease but presents similarly in terms of severity of demyelination and neurodegeneration. We report the novel finding of prominent formation of giant multinucleated globoid cells from the microglia derived from the Krabbe donor, but not from healthy control or MLD donors. The Krabbe microglia displayed reduced IL-6 protein expression upon stimulation with lipopolysaccharide, and the multinucleated globoid cells themselves appeared deficient in phagocytosis of both disease-relevant myelin debris and E. coli, together hinting at an impairment of normal function. The formation of the globoid cells could be attenuated by fully replacing the medium following passaging, suggesting that yet-to-be determined secreted factors are influencing cell fusion in our culture system. While preliminary, our results imply that globoid cells may be detrimental in Krabbe disease by hindering the normal function of brain-residing macrophages.

Alteration of blood monocyte subsets in chronic rhinosinusitis with regard to anti-inflammatory 1,8-Cineol treatment

Background: Chronic rhinosinusitis (CRS) affects about 10% of the european population causing considerable disease burden. The inflammatory microenvironment is mainly Th2 driven, but the impact of monocytes is still poorly understood. Aim of this study was to comprehensively investigate the composition of circulating monocytes and T cells in CRSwNP and CRSsNP patients, particularly with regard to the therapeutic herbal monoterpene 1,8-Cineol. Methodology: We analyzed the distribution of CD14 and CD16 classified monocyte subsets and the T-cell subset composition with respect to their PD-1 and PD-L1 expression in the peripheral blood of CRS patients using flow cytometry. Additionally, the M1/M2 like macrophage infiltration in nasal tissue and polyps was examined by immunofluorescence staining. Results: Data revealed a decrease of classical monocytes accompanied by a significant increase of intermediate CD16+ monocytes in CRSwNP and CRSsNP patients compared to healthy donors. PD-L1 expression on overall monocytes was also significantly increased in CRSwNP and CRSsNP patients. CRS patients with a severe drop of the proportion of classical monocytes showed a significant restoration of this subset in response to two-week 1,8-Cineol treatment. Conclusions: Our data indicate a CRS-induced shift of peripheral monocyte subsets to more inflammatory phenotypes that might be reversed by the herbal drug 1,8-Cineol.

At the Intersection Between SARS-CoV-2, Macrophages and the Adaptive Immune Response: A Key Role for Antibody-Dependent Pathogenesis But Not Enhancement of Infection in COVID-19

Since entering the world stage in December of 2019, SARS-CoV-2 has impacted every corner of the globe with over 1.48 million deaths and caused untold economic damage. Infections in humans range from asymptomatic to severe disease associated with dysregulation of the immune system leading to the development of acute respiratory distress syndrome (ARDs).The distinct shift in peripheral monocyte activation and infiltration of these cells into the respiratory tract in ARDs patients suggests severe COVID-19 may largely result from damage to the respiratory epithelia by improperly activated macrophages. Here, we present evidence that dysregulation of the immune response in COVID-19 begins with activation of macrophages by non-neutralizing antibodies and induction of ACE2 expression, rendering these cells susceptible to killing by SARS-CoV-2. Death of macrophages occurs independently of viral replication and leads to the release of inflammatory mediators and modulation of the susceptibility of downstream epithelial cells to SARS-CoV-2.