Dataset Information

Contact-dependent inhibition of HIV-1 replication in ex vivo human tonsil cultures by polymorphonuclear neutrophils.

ABSTRACT: Polymorphonuclear neutrophils (PMNs), the most abundant white blood cells, are recruited rapidly to sites of infection to exert potent anti-microbial activity. Information regarding their role in infection with human immunodeficiency virus (HIV) is limited. Here we report that addition of PMNs to HIV-infected cultures of human tonsil tissue or peripheral blood mononuclear cells causes immediate and long-lasting suppression of HIV-1 spread and virus-induced depletion of CD4 T cells. This inhibition of HIV-1 spread strictly requires PMN contact with infected cells and is not mediated by soluble factors. 2-Photon (2PM) imaging visualized contacts of PMNs with HIV-1-infected CD4 T cells in tonsil tissue that do not result in lysis or uptake of infected cells. The anti-HIV activity of PMNs also does not involve degranulation, formation of neutrophil extracellular traps, or integrin-dependent cell communication. These results reveal that PMNs efficiently blunt HIV-1 replication in primary target cells and tissue by an unconventional mechanism.

SUBMITTER: Reif T

PROVIDER: S-EPMC8233696 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Contact-dependent inhibition of HIV-1 replication in <i>ex vivo</i> human tonsil cultures by polymorphonuclear neutrophils.

Reif Tatjana T Dyckhoff Gerhard G Hohenberger Ralph R Kolbe Carl-Christian CC Gruell Henning H Klein Florian F Latz Eicke E Stolp Bettina B Fackler Oliver T OT

Cell reports. Medicine 20210615 6

Polymorphonuclear neutrophils (PMNs), the most abundant white blood cells, are recruited rapidly to sites of infection to exert potent anti-microbial activity. Information regarding their role in infection with human immunodeficiency virus (HIV) is limited. Here we report that addition of PMNs to HIV-infected cultures of human tonsil tissue or peripheral blood mononuclear cells causes immediate and long-lasting suppression of HIV-1 spread and virus-induced depletion of CD4 T cells. This inhibiti ...[more]

PMID: 34195682

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Project description:The human vaginal microbiome (VMB) is a complex bacterial community that interacts closely with vaginal epithelial cells (VECs) impacting the mucosal phenotype and its responses to pathogenic insults. The VMB and VEC relationship includes nutrient exchange and regulation of signaling molecules that controls numerous host functions and defends against invading pathogens. To better understand infection and replication of sexually transmitted viral pathogens in the human vaginal mucosa we used our ex vivo VEC multilayer culture system. We tested the hypothesis that selected VMB communities could be identified that alter the replication of sexually transmitted viruses consistent with reported clinical associations. Sterile VEC multilayer cultures or those colonized with VMB dominated by specific Lactobacillus spp., or VMB lacking lactobacilli, were infected with Zika virus, (ZIKV) a single stranded RNA virus, or Herpes Simplex Virus type 2 (HSV-2), a double stranded DNA virus. The virus was added to the apical surface of the cultured VEC multilayer to model transmission during vaginal intercourse. Viral replication was measured 48 h later by qPCR. The results indicated that VEC cultures colonized by VMB containing Staphylococcus spp., previously reported as inflammatory, significantly reduced the quantity of viral genomes produced by ZIKV. HSV-2 titers were decreased by nearly every VMB tested relative to the sterile control, although Lactobacillus spp.-dominated VMBs caused the greatest reduction in HSV-2 titer consistent with clinical observations. To explore the mechanism for reduced ZIKV titers, we investigated inflammation created by ZIKV infection, VMB colonization or pre-exposure to selected TLR agonists. Finally, expression levels of human beta defensins 1-3 were quantified in cultures infected by ZIKV and those colonized by VMBs that impacted ZIKV titers. Human beta defensins 1-3 produced by the VEC showed no association with ZIKV titers. The data presented expands the utility of this ex vivo model system providing controlled and reproducible methods to study the VMB impact on STIs and indicated an association between viral replication and specific bacterial species within the VMB.

Project description:BackgroundThere is increasing evidence that nitric oxide (nitrogen monoxide, NO) significantly influences immune cellular responses, including those from polymorphonuclear leukocytes (PMNs).ObjectiveThe aim of this study was to examine a possible effect of NO on PMNs' function (chemotaxis, production of reactive oxygen species (ROS), and NETosis) using live cell imaging. Moreover, we investigated PMN surface epitope and neutrophil oxidative burst under the influence of NO by flow cytometric analysis.MethodsWhole blood samples were obtained from healthy volunteers, and PMNs were isolated by density centrifugation. Live cell imaging using type I collagen matrix in µSlide IBIDI chemotaxis chambers was conducted in order to observe N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP)-stimulated PMN chemotaxis, ROS production, and NETosis. In the test group, NO was continuously redirected into the climate chamber of the microscope, so the chemotaxis chambers were surrounded by NO. The same experimental setup without NO served as a control. In addition, isolated PMNs were incubated with nitrogen monoxide (NO) or without (the control). Subsequently, flow cytometry was used to analyze neutrophil antigen expression and oxidative burst.ResultsOur live cell imaging results demonstrated a migration-promoting effect of NO on PMNs. We observed that in the case of prior stimulation by fMLP, NO has no effect on the time course of neutrophil ROS production and NET release. However, flow cytometric analyses demonstrated an increase in ROS production after pretreatment with NO. No NO-dependent differences for the expression of CD11b, CD62L, or CD66b could be observed.ConclusionsWe were able to demonstrate a distinct effect of NO on PMNs' function. The complex interaction between NO and PMNs remains a major research focus, as the exact mechanisms and additional influencing factors remain elusive. Future studies should explore how varying NO concentrations and the timing of NO exposure relative to PMN activation affect its influence.

Dataset Information

Contact-dependent inhibition of HIV-1 replication in ex vivo human tonsil cultures by polymorphonuclear neutrophils.

Publications

Contact-dependent inhibition of HIV-1 replication in <i>ex vivo</i> human tonsil cultures by polymorphonuclear neutrophils.

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