Reduced monocyte proportions and responsiveness in convalescent COVID-19 patients.

Introduction: The clinical manifestations of acute severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) suggest a dysregulation of the host immune response that leads to inflammation, thrombosis, and organ dysfunction. It is less clear whether these dysregulated processes persist during the convalescent phase of disease or during long COVID. We sought to examine the effects of SARS-CoV-2 infection on the proportions of classical, intermediate, and nonclassical monocytes, their activation status, and their functional properties in convalescent COVID-19 patients.

Reduced Monocyte Proportions and Responsiveness in Convalescent COVID-19 Patients.

The clinical manifestations of acute severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and COVID-19 suggest a dysregulation of the host immune response that leads to inflammation, thrombosis, and organ dysfunction. It is less clear whether these dysregulated processes persist during the convalescent phase of disease or during long COVID. We investigated the effects of SARS-CoV-2 infection on the proportions of classical, intermediate, and non-classical monocytes, their activation status, and their functional properties in convalescent COVID-19 patients and uninfected control subjects.

Dasatinib: effects on the macrophage phospho proteome with a focus on SAMHD1 and HIV-1 infection.

Macrophages are one of the main cellular targets of human immunodeficiency virus type 1 (HIV-1). Macrophage infection by HIV-1 is inefficient due to the presence of the viral restriction factor sterile alpha motif and histidine aspartic acid domain containing protein 1 (SAMHD1). human monocyte-derived macrophages (MDMs) express SAMHD1 in an equilibrium between active (unphosphorylated) and inactive (phosphorylated) states.

HIV-1-induced type I IFNs promote viral latency in macrophages.

Macrophages chronically infected with HIV-1 serve as a reservoir that contributes to HIV-1 persistence during antiretroviral therapy; however, the mechanisms governing the establishment and maintenance of this virus reservoir have not been fully elucidated. Here, we show that HIV-1 enters a state reminiscent of latency in monocyte-derived macrophages (MDMs), characterized by integrated proviral DNA with decreased viral transcription. This quiescent state is associated with decreased NF-κB p65, RNA polymerase II, and p-TEFb recruitment to the HIV-1 promoter as well as maintenance of promoter chromatin in a transcriptionally nonpermissive state.

HIV-1 Accessory Proteins Impart a Modest Interferon Response and Upregulate Cell Cycle-Related Genes in Macrophages.

HIV-1 infection of myeloid cells is associated with the induction of an IFN response. How HIV-1 manipulates and subverts the IFN response is of key interest for the design of therapeutics to improve immune function and mitigate immune dysregulation in people living with HIV. HIV-1 accessory genes function to improve viral fitness by altering host pathways in ways that enable transmission to occur without interference from the immune response.

Interactions with Commensal and Pathogenic Bacteria Induce HIV-1 Latency in Macrophages through Altered Transcription Factor Recruitment to the LTR.

Macrophages are infected by HIV-1 and contribute to both viral spread and pathogenesis. Recent human and animal studies suggest that HIV-1-infected macrophages serve as a reservoir that contributes to HIV-1 persistence during anti-retroviral therapy. The ability of macrophages to serve as persistent viral reservoirs is likely influenced by the local tissue microenvironment, including interactions with pathogenic and commensal microbes.

SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition.

Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1.

Teaching Laboratory Management Principles and Practices Through Mentorship and Graduated Responsibility: The Assistant Medical Directorship.

With the changing landscape of medicine in general, and pathology in particular, a greater emphasis is being placed on laboratory management as a means of controlling spiraling medical costs and improving health-care efficiency. To meet this challenge, pathology residency programs have begun to incorporate formal laboratory management training into their curricula, using institutional curricula and/or online laboratory management courses offered by professional organizations. At the University of Utah, and its affiliated national reference laboratory, ARUP Laboratories, Inc, interested residents are able to supplement the departmental lecture-based and online laboratory management curriculum by participating in assistant medical directorship programs in one of several pathology subspecialty disciplines.

MicroRNA 155 and viral-induced neuroinflammation.

MicroRNA (miRNA) regulation of gene expression is becoming an increasingly recognized mechanism by which host immune responses are governed following microbial infection. miRNAs are short, non-coding RNAs that repress translation of target genes, and have been implicated in a number of activities that modulate host immune responses, including the regulation of immune cell proliferation, survival, expansion, differentiation, migration, polarization, and effector function. This review highlights several examples in which mammalian-encoded miR-155 influences immune responses following viral infection of the CNS.

Decapping protein 1 phosphorylation modulates IL-8 expression during respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a negative-strand RNA virus that is an important cause of bronchiolitis and pneumonia. We investigated the effect of RSV infection on the expression patterns of cellular proteins involved in regulating mRNA translation and degradation, and found that a processing-body protein involved in mRNA degradation, decapping protein 1a (DCP1), was phosphorylated rapidly following infection. UV-inactivated and sucrose-purified RSV were sufficient to mediate DCP1 phosphorylation, indicating that it occurs as a consequence of an early event in RSV infection.

Nuclear receptor signaling inhibits HIV-1 replication in macrophages through multiple trans-repression mechanisms.

Sexually transmitted pathogens activate HIV-1 replication and inflammatory gene expression in macrophages through engagement of Toll-like receptors (TLRs). Ligand-activated nuclear receptor (NR) transcription factors, including glucocorticoid receptor (GR), peroxisome proliferator-activated receptor gamma (PPARγ), and liver X receptor (LXR), are potent inhibitors of TLR-induced inflammatory gene expression. We therefore hypothesized that ligand-activated NRs repress both basal and pathogen-enhanced HIV-1 replication in macrophages by directly repressing HIV-1 transcription and by ameliorating the local proinflammatory response to pathogens.

PPARgamma and LXR signaling inhibit dendritic cell-mediated HIV-1 capture and trans-infection.

Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination.

Retinoic acid inhibition of chromatin remodeling at the human immunodeficiency virus type 1 promoter. Uncoupling of histone acetylation and chromatin remodeling.

All-trans retinoic acid (RA) represses HIV-1 transcription and replication in cultured monocytic cells and in primary monocyte-derived macrophages. Here we examine the role of histone acetylation and chromatin remodeling in RA-mediated repression. RA pretreatment of latently infected U1 promonocytes inhibits HIV-1 expression in response to the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA).

Retinoid-dependent restriction of human immunodeficiency virus type 1 replication in monocytes/macrophages.

Vitamin A deficiency has been correlated with increased severity of human immunodeficiency virus type 1 (HIV-1)-associated disease. Moreover, vitamin A supplementation can reduce AIDS-associated morbidity and mortality. Our group and others have shown that retinoids, the bioactive metabolites of vitamin A, repress HIV-1 replication in monocytic cell lines and primary macrophages by blocking long-terminal-repeat (LTR)-directed transcription.

Activation of autoreactive B cells by CpG dsDNA.

The proliferative response of autoreactive rheumatoid factor (RF) B cells to mammalian chromatin-containing immune complexes (ICs) results from the sequential engagement of the B cell receptor (BCR) and Toll-like receptor 9 (TLR9). We have used ICs constructed from anti-hapten antibodies and defined haptenated dsDNA fragments to determine the form of mammalian DNA that mediates this process. Despite their relatively low abundance in mammalian DNA, we found that inclusion of hypomethylated CpG motifs in these ICs was necessary for effective activation.

Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry.

We previously reported that monoclonal antibodies to protein-disulfide isomerase (PDI) and other membrane-impermeant PDI inhibitors prevented HIV-1 infection. PDI is present at the surface of HIV-1 target cells and reduces disulfide bonds in a model peptide attached to the cell membrane. Here we show that soluble PDI cleaves disulfide bonds in recombinant envelope glycoprotein gp120 and that gp120 bound to the surface receptor CD4 undergoes a disulfide reduction that is prevented by PDI inhibitors.

Interleukin 1 beta and interleukin 6 potentiate retinoic acid-mediated repression of human immunodeficiency virus type 1 replication in macrophages.

All-trans-retinoic acid (RA) has been shown either to activate or repress human immunodeficiency virus type 1 (HIV-1) replication in primary monocyte-derived-macrophages (MDMs). We systematically investigated the contribution that cell donor and virus differences make to this variability. We found that the effect of RA was cell donor dependent.