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Pseudomonas aeruginosa is an opportunistic pathogen that often infects individuals with the genetic disease cystic fibrosis, and contributes to airway blockage and loss of lung function. Natural killer (NK) cells are cytotoxic, granular lymphocytes that are part of the innate immune system. NK cell secretory granules contain the cytolytic proteins granulysin, perforin and granzymes. In addition to their cytotoxic effects on cancer and virally infected cells, NK cells have been shown to play a role in an innate defense against microbes, including bacteria. However, it is not known if NK cells kill extracellular P . aeruginosa or how bacterial killing might occur at the molecular level. Here we show that NK cells directly kill extracellular P . aeruginosa using NK effector molecules. Live cell imaging of a co-culture of YT cells, a human NK cell line, and GFP-expressing P . aeruginosa in the presence of the viability dye propidium iodide demonstrated that YT cell killing of P . aeruginosa is contact-dependent. CRISPR knockout of granulysin or perforin in YT cells had no significant effect on YT cell killing of P . aeruginosa . Pre-treatment of YT and NK cells with the serine protease inhibitor 3,4-dichloroisocoumarin (DCI) to inhibit all granzymes, resulted in an inhibition of killing. Although singular CRISPR knockout of granzyme B or H had no effect, knockout of both in YT cells completely abrogated killing of P . aeruginosa in comparison to wild type YT cell controls. Nitrocefin assays suggest that the bacterial membrane is damaged. Inhibition of killing by antioxidants suggest that ROS are required for the bactericidal mode-of-action. Taken together, these results identify that NK cells kill P . aeruginosa through a membrane damaging, contact-dependent process that requires granzyme induced ROS production, and moreover, that granzyme B and H are redundant in this killing process.

An interesting study fromKhan et al.followed two groups of individuals who tested negative for SARS-CoV-2 infection at the start of the study: individuals with a previously confirmed Middle East respiratory syndrome (MERS)-CoV infection and a control MERS-negative group. Within these groups, 24% of the previously MERS-positive (82 individuals) and 31% of the MERS-negative group (260 individuals) eventually contracted SARS-CoV-2 infection. [...]previous MERS infection did not correlate with higher probability of SARS-CoV-2 infection (symptomatic or not), but the risk of COVID-19-related hospitalization in the MERS-CoV-positive group was significantly higher. [...]Sim et al.investigated potential functions for these cross-reactive antibodies found in the blood of pre-pandemic elderly people and hypothesize that they likely could have two opposing functions: protecting against and enhancing viral infection. The study of asymptomatic or mild disease has increased our understanding of the immune responses important for protection from SARS-CoV2, since the individuals who are asymptomatic or have mild disease are less likely to be monitored.Soares-Schanoski et al.followed a cohort of United States marine recruits who were initially seronegative, with most seroconverting over time.

MS4A4A is a member of the membrane‐spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRβ (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin‐4 (‘alternatively activated’ or M2 macrophages) but not by interferon‐γ and lipopolysaccharide (‘classically’ activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor‐associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.

Cryptococcus yeast species typically display characteristics of opportunistic pathogens, with the exception of C. gattii , which can cause life-threatening respiratory and disseminated brain infections in otherwise healthy people. The pathogenesis of C. gattii is not well understood, but an important characteristic is that C. gattii is capable of evading host cell-mediated immune defenses initiated by DCs. Here, we report that when virulent C. gattii becomes ingested by a DC, the intracellular compartment containing the fungi is covered by a persistent protein cage structure consisting of F-actin. This F-actin cage acts as a barrier to prevent interaction with other intracellular compartments, and as a result, the DC fails to kill the fungi and activate important cell-mediated immune responses. We propose that this unique immune evasion mechanism permits C. gattii to remain unchallenged within host cells, leading to persistent infection. Cryptococcus gattii is a major cause of life-threatening mycosis in immunocompetent individuals and responsible for the ongoing epidemic outbreak of cryptococcosis in the Pacific Northwest of North America. This deadly fungus is known to evade important host immune responses, including dendritic cell (DC) maturation and concomitant T cell immunity, via immune evasion mechanisms that remain unclear. Here, we demonstrate that primary human DCs phagocytose C. gattii but the maturation of phagosomes to phagolysosomes was blocked as a result of sustained filamentous actin (F-actin) that entrapped and concealed the phagosomes from recognition. Superresolution structured illumination microscopy (SR-SIM) revealed that the persistent phagosomal F-actin formed a cage-like structure that sterically hindered and functionally blocked the fusion of lysosomes. Blocking lysosome fusion was sufficient to inhibit phagosomal acidification and subsequent intracellular fungal killing by DCs. Retention of phagosomal F-actin by C. gattii also caused DC immunoparalysis. Disrupting the retained F-actin cage with cytochalasin D not only restored DC phagosomal maturation but also promoted DC costimulatory maturation and robust T cell activation and proliferation. Collectively, these results reveal a unique mechanism of DC immune evasion that enhances intracellular fungal pathogenicity and may explain suppressed cell-mediated immunity. IMPORTANCE Cryptococcus yeast species typically display characteristics of opportunistic pathogens, with the exception of C. gattii , which can cause life-threatening respiratory and disseminated brain infections in otherwise healthy people. The pathogenesis of C. gattii is not well understood, but an important characteristic is that C. gattii is capable of evading host cell-mediated immune defenses initiated by DCs. Here, we report that when virulent C. gattii becomes ingested by a DC, the intracellular compartment containing the fungi is covered by a persistent protein cage structure consisting of F-actin. This F-actin cage acts as a barrier to prevent interaction with other intracellular compartments, and as a result, the DC fails to kill the fungi and activate important cell-mediated immune responses. We propose that this unique immune evasion mechanism permits C. gattii to remain unchallenged within host cells, leading to persistent infection.

COVID-19 has caused more than 7 million deaths worldwide, and according to the World Health Organization, it continues to result in more than 1000 reported deaths per month at the time of this writing. It is crucial to understand the immune response to COVID-19 since the virus continues to persist. Natural killer (NK) cells play a critical role in the immune defense against viral infections, including COVID-19. While it is well documented that infected patients have a reduction in lymphocytes and NK cells, gaps in knowledge exist regarding the function of NK cells. To study the function of NK cells in patients hospitalized with COVID-19, peripheral blood was obtained from patients admitted to the medical (non-ICU) wards at a large tertiary hospital. We demonstrated a decrease in the mature cytotoxic subset of NK cells within the peripheral blood of patients hospitalized with COVID-19. We also observed a notable reduction in the cytotoxic function of NK cells against tumor targets. We examined the mechanisms leading to NK cell killing. We found reductions in the intracellular levels of effector molecules, the degranulation of cytotoxic granules, and the extracellular concentrations of released effector molecules. We identified dysfunctional intracellular granule trafficking required to position the granules for degranulation, which would be consistent with the reduced release of effector molecules. We found clusters of inhibitory receptors were upregulated in subsets of NK cells, in keeping with inhibition of cytotoxicity. Additionally, males with COVID-19 showed NK cell defects compared to healthy males, while no significant differences were observed in females. Our findings highlight defects in cytolytic effector molecules, granule trafficking and release, and increased expression of inhibitory receptors on NK cells in patients hospitalized with COVID-19, in addition to a sex difference in cytolytic function, which contributes to defective NK cell function in COVID-19.

CCDC88B is a risk factor for several chronic inflammatory diseases in humans and its inactivation causes a migratory defect in DCs in mice. CCDC88B belongs to a family of cytoskeleton-associated scaffold proteins that feature protein:protein interaction domains. Here, we identified the Rho/Rac Guanine Nucleotide Exchange Factor 2 (ARHGEF2) and the RAS Protein Activator Like 3 (RASAL3) as CCDC88B physical and functional interactors. Mice defective in Arhgef2 or Rasal3 show dampened neuroinflammation, and display altered cellular response and susceptibility to colitis; ARHGEF2 maps to a human Chromosome 1 locus associated with susceptibility to IBD. Arhgef2 and Rasal3 mutant DCs show altered migration and motility in vitro, causing either reduced ( Arhgef2 ) or enhanced ( Rasal3 ) migratory properties. The CCDC88B/RASAL3/ARHGEF2 complex appears to regulate DCs migration by modulating activation of RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions, providing a molecular mechanism for the involvement of these proteins in DCs immune functions. CCDC88B physically interacts with ARHGEF2 and RASAL3; defective mice show dampened neuroinflammation, altered susceptibility to colitis and altered DCs motility by modulating RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions.

Cerebral malaria infection can provoke fatal neuroinflammation. Gros and colleagues identify an ubiquitin-modification axis that exacerbates neuroinflammation and that involves TRIM25 and USP15, which jointly promote type I interferon production. Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 ( Usp15 L749R ) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15 L749R -associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ . In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation.

Nat. Immunol.; 10.1038/ni.3581; corrected online 24 October 2016 In the version of this article initially published online, the symbol for the gene encoding granzyme B was incorrect (Gmzb) in the text in the third paragraph of the fourth subsection of Results and Figure 5d, and the symbol for the gene encoding granzyme A was incorrect (Gmza) in Figure 6h.

In addition, insurance can't replace the tablecloth purchased in Vienna which has accompanied us on our journeys for 25 years. Or make up the months it will take to earn the money to replace items. Money will never be able to replace my treasured high school grad present -- my camera equipment.