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Influenza A virus (IAV) infection causes an acute respiratory disease characterized by a strong inflammatory immune response and severe immunopathology. Proinflammatory mechanisms are well described in the murine IAV infection model, but less is known about the mechanisms leading to the resolution of inflammation. Here, we analyzed the contribution of CD11b\(^{+}\)Ly6C\(^{++}\)Ly6G\(^{-}\) cells to this process. An accumulation of CD11b\(^{+}\)Ly6C\(^{++}\)Ly6G\(^{-}\) cells within the lungs was observed during the course of IAV infection. Phenotypic characterization of these CD11b\(^{+}\)Ly6C\(^{++}\)Ly6G\(^{-}\) cells by flow cytometry and RNA-Seq revealed an activated phenotype showing both pro- and anti-inflammatory features, including the expression of inducible nitric oxide synthase (iNOS) by a fraction of cells in an IFN-γ-dependent manner. Moreover, CD11b\(^{+}\)Ly6C\(^{++}\)Ly6G\(^{-}\) cells isolated from lungs of IAV-infected animals displayed suppressive activity when tested in vitro, and iNOS inhibitors could abrogate this suppressive activity. Collectively, our data suggest that during IAV infection, CD11b\(^{+}\)Ly6C\(^{++}\)Ly6G\(^{-}\) cells acquire immunoregulatory function, which might contribute to the prevention of pathology during this life-threatening disease.
Monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic MDSCs (G-MDSCs) have been found to be massively induced in TB patients as well in murine Mtb infection models. However, the interaction of mycobacteria with MDSCs and its role in TB infection is not well studied. Here, we investigated the role of Cav-1 for MDSCs infected with Mycobacterium bovis Bacille-Calmette-Guerín (BCG). MDSCs that were generated from murine bone marrow (MDSCs) of wild-type (WT) or Cav1\(^{−/−}\) mice upregulated Cav-1, TLR4 and TLR2 expression after BCG infection on the cell surface. However, Cav-1 deficiency resulted in a selective defect of intracellular TLR2 levels predominantly in the M-MDSC subset. Further analysis indicated no difference in the phagocytosis of BCG by M-MDSCs from WT and Cav1\(^{−/−}\) mice or caveosome formation, but a reduced capacity to up-regulate surface markers, to secrete various cytokines, to induce iNOS and NO production required for suppression of T cell proliferation, whereas Arg-1 was not affected. Among the signaling pathways affected by Cav-1 deficiency, we found lower phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Together, our findings implicate that (i) Cav-1 is dispensable for the internalization of BCG, (ii) vesicular TLR2 signaling in M-MDSCs is a major signaling pathway induced by BCG, (iii) vesicular TLR2 signals are controlled by Cav-1, (iv) vesicular TLR2/Cav-1 signaling is required for T cell suppressor functions.
Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention.
Background
Infections with polyomavirus BK virus (BKV) are a common cause of renal dysfunction after renal transplantation and may also be harmful in surgical patients with shock. The aim of the present study was to determine the frequency of BKV viremia in critically ill surgical patients with septic or hemorrhagic shock, and, if viremia is detectable, whether viremia may be associated with renal dysfunction.
Findings
A total of 125 plasma samples from 44 critically ill surgical patients with septic or hemorrhagic shock were tested by real-time polymerase chain reaction (PCR) for BKV DNA during their stay on the intensive care unit (ICU). BKV viremia occurred in four patients, i.e. in three of the septic and in one of the hemorrhagic shock group. There was no association between viremia and renal dysfunction. All positive samples contained a low viral load (< 500 copies/ml).
Conclusions
Since BK viremia was rarely found and with low viral load only in critically ill surgical patients with shock, it is very unlikely that BK viremia results in BK nephropathy later on.
Background
The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS).
Methods
This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay.
Results
Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009).
Conclusions
COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.
We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs.
Two cellular proteins, membrane cofactor protein (MCP) and moesin, were reported recently to be functionally associated with the initiation of a measles virus infection. We bave analyzed the interaction of measles virus with cell surface proteins, using an overlay binding assay with cellular proteins immobilized on nitrocellulose. Among surface-biotinylated proteins from a human rectal tumor cellline (HRT), measles virus, was able to bind only to a 67-kDa proteinthat was identified as MCP. The virus recognized dift'erent isoforms of MCP expressed from human (HRT and HeLa) and simian (Vero) celllines. The binding of measles virus to MCP was abolished after cleavage of the disulfide bonds by reducing agents as weil as after enzymatic release of N-linked oligosaccharides. By contrast, removal of sialic acid or 0-linked oligosaccharides did not aft'ect the recognition of MCP by measles virus. These data indicate that the receptor determinant of MCP is dependent on a conformation of the protein that is maintained by disulfide bonds and N-glycans present in tbe complement binding domains. Our results are consistent with a roJe of MCP as primary attacbment site for measles virus in the initial stage of an infection. The functional relationship between MCP and moesin in a measles virus infection is discussed.
Background: Dendritic cells (DC) can act tolerogenic at a semi-mature stage by induction of protective CD4+ T cell and NKT cell responses. Methodology/Principal Findings: Here we studied the role of the co-inhibitory molecule B7-H1 (PD-L1, CD274) on semimature DC that were generated from bone marrow (BM) cells of B7-H12/2 mice and applied to the model of Experimental Autoimmune Encephalomyelitis (EAE). Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC. Injections of B7-H12/2 TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-c production in the CNS. Experiments in CD1d2/2 and Ja2812/2 mice as well as with type I and II NKT cell lines indicated that only type II NKT cells but not type I NKT cells (invariant NKT cells) could be stimulated by an endogenous CD1d-ligand on DC and were responsible for the increased serum cytokine production in the absence of B7-H1. Conclusions/Significance: Together, our data indicate that BM-DC express an endogenous CD1d ligand and B7-H1 to ihibit type II but not type I NKT cells. In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4+ and NKT cell responses is enhanced.