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Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection. IMPORTANCE: In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.
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COVID-19 , Coinfección , Células Epiteliales , Interferón Tipo I , Interleucina-17 , SARS-CoV-2 , Humanos , Interleucina-17/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , COVID-19/inmunología , Coinfección/inmunología , Coinfección/microbiología , Coinfección/virología , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Masculino , SARS-CoV-2/inmunología , Persona de Mediana Edad , Femenino , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Adulto , Mucosa Nasal/inmunología , Mucosa Nasal/microbiología , Anciano , Nasofaringe/microbiología , Candidiasis/inmunología , Candidiasis/microbiología , Micosis/inmunologíaRESUMEN
Background: Many questions remain unanswered regarding the implication of lipid metabolites in severe SARS-CoV-2 infections. By re-analyzed sequencing data from the nasopharynx of a previously published cohort, we found that alox genes, involved in eicosanoid synthesis, were up-regulated in high WHO score patients, especially in goblet cells. Herein, we aimed to further understand the roles played by eicosanoids during severe SARS-CoV-2 infection. Methods and findings: We performed a total fatty acid panel on plasma and bulk RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites revealed that lipid metabolites were increased in SARS-CoV-2 patients including the lipid mediators Arachidonic Acid (AA) and Eicosapentaenoic Acid (EPA). AA, EPA and the fatty acids Docosahexaenoic acid (DHA) and Docosapentaenoic acid (DPA), were positively correlated to WHO disease severity score. Transcriptomic analysis demonstrated that COVID-19 patients can be segregated based on WHO scores. Ontology, KEGG and Reactome analysis identified pathways enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling and, cell cycling pathways. Conclusions: Our study offers an association between nasopharynx mucosa eicosanoid genes expression, specific serum inflammatory lipids and, subsequent DNA damage pathways activation in PBMCs to severity of COVID-19 infection.
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BACKGROUND: Most studies on the safety and efficacy of antitumor necrosis factor alpha (anti-TNF) agents in the treatment of inflammatory bowel disease have included few Black patients. AIMS: We aimed to evaluate the therapeutic response rate in Black IBD patients compared with White patients. METHODS: We conducted a retrospective review of IBD patients who were treated with anti-TNF agents and assessed those with therapeutic drug levels for clinical, endoscopic, and radiologic response to anti-TNF treatment. RESULTS: We identified 118 patients who met the inclusion criteria. Black IBD patients had significantly higher prevalence of endoscopic and radiologic active disease compared with White patients (62% and 34%, respectively; P = .023), despite similar proportions reaching therapeutic titers (67% and 55%, respectively; P = .20). Moreover, Black patients had significantly higher rate of IBD-related hospitalizations than White patients (30% vs 13%, respectively; P = .025) while on anti-TNF agents. CONCLUSIONS: Black IBD patients on anti-TNF agents had a significantly higher prevalence of active disease and more IBD-related hospitalizations than White patients.
This study explores the question of how IBD therapeutic efficacy may vary among racial groups.
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Enfermedades Inflamatorias del Intestino , Inhibidores del Factor de Necrosis Tumoral , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/epidemiología , Estudios Retrospectivos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Negro o Afroamericano , BlancoRESUMEN
BACKGROUND: Most facets of Inflammatory Bowel Disease (IBD) have not been thoroughly compared among minority populations, including Black patients. Our study was designed to characterize the demographics, phenotypes, outcomes, healthcare utilization, and treatment of IBD in a large cohort with 38% Black patients. METHODS: Electronic health records of 3272 IBD patients seen in a tertiary academic medical network from 2012 to July 15th, 2019 were analyzed. RESULTS: Black patients with Crohn's disease were significantly more likely than White patients to suffer from perianal (p < 0.001), fistulizing (p < 0.001), and fibrostenotic phenotypes (p < 0.001). Black patients with IBD were significantly more likely to undergo IBD-related surgery (pâ¯=â¯0.042) and experience an IBD-related complication (p < 0.001). The proportion of patients with at least one colonoscopy, one visit to the gastroenterology clinic, one visit to the emergency department (ED), and one hospital admission were higher in Black patients (p < 0.001, pâ¯=â¯0.005, p < 0.001, and p < 0.001; respectively). CONCLUSIONS: Black IBD patients had more severe disease phenotypes and worse healthcare outcomes than White patients. Black patients also used healthcare facilities and IBD medications to an equal or greater extent, despite being of a lower average socioeconomic class than their White counterparts. Our study suggests that underlying factors that do not pertain to the utilization of healthcare resources may be responsible for these worse outcomes in Black patients.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Población Negra , Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/epidemiología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/terapia , Estudios Retrospectivos , Población BlancaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is the causative agent of the COVID-19 disease. COVID-19 viral infection can affect many cell types, including epithelial cells of the lungs and airways. Extracellular vesicles (EVs) are released by virtually all cell types, and their packaged cargo allows for intercellular communication, cell differentiation, and signal transduction. Cargo from virus-infected cells may include virally derived metabolites, miRNAs, nucleic acids, and proteins. We hypothesized that COVID-19 plasma EVs can induce the formation of signaling platforms known as lipid rafts after uptake by normal human small airway epithelial cells (SAECs). Circulating EVs from patients with or without COVID-19 were characterized by nanoparticle tracking analysis, Western blotting using specific antibodies, and transmission electron microscopy. Primary cultures of normal human small airway epithelial cells were challenged with EVs from the two patient groups, and lipid raft formation was measured by fluorescence microscopy and assessed by sucrose density gradient analysis. Collectively, our data suggest that circulating EVs from COVID-19-infected patients can induce the formation of lipid rafts in normal human small airway epithelial cells. These results suggest the need for future studies aimed at investigating whether the increased density of lipid rafts in these cells promotes viral entry and alteration of specific signaling pathways in the recipient cells.
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COVID-19 , Vesículas Extracelulares , Humanos , SARS-CoV-2 , Células Epiteliales , Vesículas Extracelulares/metabolismo , Microdominios de Membrana/metabolismoRESUMEN
Recent case reports and epidemiological data suggest fungal infections represent an under-appreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing (scRNA-seq) dataset characterizing the upper respiratory microenvironment during COVID-19, and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals, including confirmatory diagnostic testing demonstrating elevated serum (1, 3)-ß-D-glucan and/or confirmed fungal culture of the predicted pathogen. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL-17 stimulation and anti-fungal immunity. Further, we observe significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggests that IL-17 stimulation - in part driven by Candida colonization - and blunted type I/III interferon signaling represents a common feature of severe COVID-19 infection.
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NKTR-255 is a PEG conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans or cis presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naive and memory OVA-specific CD8+ T cells (OT-I) and NK cells in mice. NKTR-255 induced a 2.5- and 2.0-fold expansion of CD8+ T and NK cells, respectively, in WT mice. In adoptive transfer studies, proliferation of naive and memory WT OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα-/- mice, suggesting trans presentation was not utilized by NKTR-255. Interestingly, naive IL-15Rα-/- OT-I cells had deficient responses to NKTR-255, while memory IL-15Rα-/- OT-I cell responses were partially impaired, suggesting that naive CD8+ T cells are more dependent on cis presentation of NKTR-255 than memory CD8+ T cells. In bone marrow chimera studies, IL-15Rα-/- and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells, showing that conversion to IL-15Rß agonist biases the response toward NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis presentation and act as an IL-15Rαß agonist on CD8+ T cells.
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Linfocitos T CD8-positivos/efectos de los fármacos , Interleucina-15/farmacología , Células Asesinas Naturales/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/inmunología , Femenino , Memoria Inmunológica , Interleucina-15/química , Subunidad alfa del Receptor de Interleucina-15/fisiología , Subunidad beta del Receptor de Interleucina-2/agonistas , Células Asesinas Naturales/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Polietilenglicoles/químicaRESUMEN
SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ "hillock"-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.
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COVID-19/inmunología , COVID-19/virología , Inmunidad , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Efecto Espectador , COVID-19/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nasofaringe/patología , Nasofaringe/virología , ARN Viral/análisis , ARN Viral/genética , Mucosa Respiratoria/patología , Mucosa Respiratoria/virología , Transcripción Genética , Carga ViralRESUMEN
To investigate the relationship between intestinal microbiota and SARS-CoV-2-mediated pathogenicity in a United States, majority African American cohort. We prospectively collected fecal samples from 50 SARS-CoV-2 infected patients, 9 SARS-CoV-2 recovered patients, and 34 uninfected subjects seen by the hospital with unrelated respiratory medical conditions (controls). 16S rRNA sequencing and qPCR analysis was performed on fecal DNA/RNA. The fecal microbial composition was found to be significantly different between SARS-CoV-2 patients and controls (PERMANOVA FDR-P = .004), independent of antibiotic exposure. Peptoniphilus, Corynebacterium and Campylobacter were identified as the three most significantly enriched genera in COVID-19 patients compared to controls. Actively infected patients were also found to have a different gut microbiota than recovered patients (PERMANOVA FDR-P = .003), and the most enriched genus in infected patients was Campylobacter, with Agathobacter and Faecalibacterium being enriched in the recovered patients. No difference in microbial community structure between recovered patients and uninfected controls was observed, nor a difference in alpha diversity between the three groups. 24 of the 50 COVID-19 patients (48%) tested positive via RT-qPCR for fecal SARS-CoV-2 RNA. A significant difference in gut microbial composition between SARS-CoV-2 positive and negative samples was observed, with Klebsiella and Agathobacter being enriched in the positive cohort. No significant associations between microbiome composition and disease severity was found. The intestinal microbiota is sensitive to the presence of SARS-CoV-2, with increased relative abundance of genera (Campylobacter, Klebsiella) associated with gastrointestinal (GI) disease. Further studies are needed to investigate the functional impact of SARS-CoV-2 on GI health.
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COVID-19/microbiología , Microbioma Gastrointestinal , Anciano , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , COVID-19/diagnóstico , COVID-19/virología , Estudios de Cohortes , Heces/microbiología , Heces/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S/genética , ARN Viral/genética , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.
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Enfermedades Gastrointestinales , Enfermedades Genéticas Congénitas , Inmunoglobulina G/inmunología , Intestino Delgado/inmunología , Mastocitosis , Triptasas , Adulto , Células Epiteliales/inmunología , Femenino , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/patología , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Congénitas/patología , Genotipo , Humanos , Inmunoglobulina G/sangre , Intestino Delgado/citología , Intestino Delgado/patología , Masculino , Mastocitos/inmunología , Mastocitosis/sangre , Mastocitosis/genética , Mastocitosis/inmunología , Mastocitosis/patología , Persona de Mediana Edad , Piroptosis , Triptasas/sangre , Triptasas/genética , Adulto JovenRESUMEN
Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL, TMPRSS2) or response (e.g., MX1, IFITM3, EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19.
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During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/genética , Subgrupos de Linfocitos T/inmunología , Linfocitos T CD4-Positivos/virología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Regulación Viral de la Expresión Génica , Infecciones por VIH/virología , Duplicado del Terminal Largo de VIH , VIH-1/fisiología , Humanos , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Subgrupos de Linfocitos T/virología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virología , Replicación ViralRESUMEN
This review provides an in-depth description of the preclinical and clinical studies demonstrating the effectiveness and limitations of IL-15 and IL-15 analogs given as an exogenous immuno-oncology agent. IL-15 is a cytokine that primarily stimulates the proliferation and cytotoxic functions of CD8T cells and NK cells leading to enhanced anti-tumor responses. While initially showing promise as a cancer therapeutic, the efficacy of IL-15 was limited by its short in vivo half-life. More recently, various approaches have been developed to improve the in vivo half-life and efficacy of IL-15, largely by generating IL-15/IL-15Rα conjugates. These new IL-15 based agents renew the prospect of IL-15 as a cancer immunotherapeutic agent. While having some efficacy in inducing tumor regression as a monotherapy, IL-15 agents also show great potential in being used in combination with other immuno-oncological therapies. Indeed, IL-15 used in combination therapy yields even better anti-tumor responses and prolongs survival than IL-15 treatment alone in numerous murine cancer models. The promising results from these preclinical studies have led to the implementation of several clinical trials to test the safety and efficacy of IL-15-based agents as a stand-alone treatment or in conjunction with other therapies to treat both advanced solid tumors and hematological malignancies.
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Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Interleucina-15/uso terapéutico , Células Asesinas Naturales/inmunología , Neoplasias/terapia , Animales , Proliferación Celular , Ensayos Clínicos como Asunto , Citotoxicidad Inmunológica , Humanos , Neoplasias/inmunología , Estabilidad Proteica , Receptores de Interleucina-15/metabolismoRESUMEN
Monocytes and macrophages play fundamental roles in defense against microbes, clearance of senescent and dead cells, and immunoregulation. Although blood monocytes are the source of intestinal macrophages in the developed mucosal immune system, blood monocytes and intestinal macrophages from healthy human subjects display distinct phenotypic and functional differences. Blood monocytes can be induced to polarize into M1 and M2 macrophages, whereas intestinal macrophages appear to be terminally differentiated and are unable to undergo such inducible polarization. Nevertheless, in response to local conditions, monocytes differentiated into intestinal macrophages display phenotypic and functional characteristics that enhance their capacity to provide non-inflammatory host defense and participate in local immunoregulation. Using the protocols described here, this unit presents the key phenotypic and functional differences between human blood monocytes and intestinal macrophages, as well as between mouse and human intestinal macrophages. © 2017 by John Wiley & Sons, Inc.
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Intestinos/citología , Macrófagos , Monocitos , Animales , Humanos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Monocitos/citología , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismoRESUMEN
Previous in vitro studies have shown that the HIV-1 virus can alter the cytokine/chemokine profile of polarized macrophages which may lead to their increased susceptibility to viral infection. Here, we found that M2 monocyte derived macrophages (MDM) were significantly more permissive to productive infection by R5-tropic HIV-1 strains, including transmitted founder (T/F) viruses, than M1 MDM. Previous in vitro studies by our lab showed that regulatory T cells (Tregs) suppress HIV-1 infection in non-Treg CD4 T cells. Here, we investigated potential inhibitory effects of Tregs on HIV-1 infection of polarized MDM. We found that Tregs significantly increased HIV-1 infection in M1 and M2 MDM via a mechanism that was cell contact dependent. These findings suggest a potential role for Tregs in HIV-1 infection of tissue resident macrophages of M1 and M2 phenotype, which may contribute to the establishment and pathogenesis of HIV-1 disease.