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Roles of Macrophages in Viral Infections

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 23225

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Prof. Dr. Wenzhe Ho

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Guest Editor

Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
Interests: innate immunity and viral infections (HIV and HCV); non-immune cell-mediated antiviral innate immunity; impact of drugs of abuse on host innate immunity against HIV

Prof. Dr. Stefano Aquaro

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Guest Editor

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: virus evolution; macrophages; HIV pathogenesis; antivirals; HIV chemotherapy; microbicides; viral resistance; neuroAIDS; mechanisms of virus entry; chemokines and chemokine receptors; role of astrocytes and neurons in HIV infection
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Dear Colleagues,

As one of the major components of the immune system, macrophages can activate both innate and adaptive immune responses, as they are professional antigen-presenting cells and serve as the first line of defense against invading pathogens, including viruses. The importance of macrophages in the control and pathogenesis of viral infections has been highlighted by their dual roles in viral infections, where, on the one hand, they participate in host antiviral immunity for the detection and control of virus infection, and, on the other hand, they can carry and spread the viruses or become a target for some of them, such as human immunodeficiency virus, human cytomegalovirus, and H5N1 subtype highly pathogenic avian influenza viruses. Evidently, the complicated roles of macrophages in the antiviral immunity and pathogenesis of viral infections require more studies to understand how macrophages interfere with viral infection/replication and regulate the inflammatory cytokines, which are crucial for identifying novel cellular targets in order to develop antivirals therapy. In this Special Issue, we will focus on the roles played by macrophages of different tissues and organs (microglia, Kupffer cells, and Langherans cells) in viral infections. We welcome original research papers, communications, as well as review articles that report research work on macrophages and viral infections.

Prof. Dr. Wenzhe Ho
Prof. Dr. Stefano Aquaro
Guest Editors

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Keywords

macrophage
microglia
Kupffer cells
viral infection
antiviral immunity
inflammatory cytokines
langerhans cell
antiviral drugs
viral pathogenesis

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Published Papers (10 papers)

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Editorial

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3 pages, 144 KiB

Open AccessEditorial

Roles of Macrophages in Viral Infections

by Xiao-Long Wang, Xu Wang and Wen-Zhe Ho

Viruses 2024, 16(10), 1643; https://doi.org/10.3390/v16101643 - 21 Oct 2024

Viewed by 1042

Abstract

Macrophages are an important component of the first-line defense against pathogens, including viruses [...] Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

Research

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15 pages, 6461 KiB

Open AccessArticle

EcoHIV Infection of Primary Murine Brain Cell Cultures to Model HIV Replication and Neuropathogenesis

by Boe-Hyun Kim, Wei Chao, Eran Hadas, Alejandra Borjabad, Mary Jane Potash and David J. Volsky

Viruses 2024, 16(5), 693; https://doi.org/10.3390/v16050693 - 27 Apr 2024

Cited by 3 | Viewed by 2035

Abstract

Background. EcoHIV is a chimeric HIV that replicates in mice in CD4+ T cells, macrophages, and microglia (but not in neurons), causing lasting neurocognitive impairment resembling neurocognitive disease in people living with HIV. The present study was designed to develop EcoHIV-susceptible primary mouse brain cultures to investigate the indirect effects of HIV infection on neuronal integrity. Results. We used two EcoHIV clones encoding EGFP and mouse bone marrow-derived macrophages (BMM), mixed mouse brain cells, or enriched mouse glial cells from two wild-type mouse strains to test EcoHIV replication efficiency, the identity of productively infected cells, and neuronal apoptosis and integrity. EcoHIV replicated efficiently in BMM. In mixed brain cell cultures, EcoHIV targeted microglia but did not cause neuronal apoptosis. Instead, the productive infection of the microglia activated them and impaired synaptophysin expression, dendritic density, and axonal structure in the neurons. EcoHIV replication in the microglia and neuronal structural changes during infection were prevented by culture with an antiretroviral. Conclusions. In murine brain cell cultures, EcoHIV replication in the microglia is largely responsible for the aspects of neuronal dysfunction relevant to cognitive disease in infected mice and people living with HIV. These cultures provide a tool for further study of HIV neuropathogenesis and its control. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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21 pages, 7862 KiB

Open AccessArticle

A Comparative Study of Human Pluripotent Stem Cell-Derived Macrophages in Modeling Viral Infections

by Yaxuan Zhang, Hui Qiu, Fuyu Duan, Haoran An, Huimin Qiao, Xingwu Zhang, Jing-Ren Zhang, Qiang Ding and Jie Na

Viruses 2024, 16(4), 552; https://doi.org/10.3390/v16040552 - 1 Apr 2024

Cited by 1 | Viewed by 2127

Abstract

Macrophages play multiple roles in innate immunity including phagocytosing pathogens, modulating the inflammatory response, presenting antigens, and recruiting other immune cells. Tissue-resident macrophages (TRMs) adapt to the local microenvironment and can exhibit different immune responses upon encountering distinct pathogens. In this study, we generated induced macrophages (iMACs) derived from human pluripotent stem cells (hPSCs) to investigate the interactions between the macrophages and various human pathogens, including the hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Streptococcus pneumoniae. iMACs can engulf all three pathogens. A comparison of the RNA-seq data of the iMACs encountering these pathogens revealed that the pathogens activated distinct gene networks related to viral response and inflammation in iMACs. Interestingly, in the presence of both HCV and host cells, iMACs upregulated different sets of genes involved in immune cell migration and chemotaxis. Finally, we constructed an image-based high-content analysis system consisting of iMACs, recombinant GFP-HCV, and hepatic cells to evaluate the effect of a chemical inhibitor on HCV infection. In summary, we developed a human cell-based in vitro model to study the macrophage response to human viral and bacterial infections; the results of the transcriptome analysis indicated that the iMACs were a useful resource for modeling pathogen–macrophage–tissue microenvironment interactions. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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14 pages, 2115 KiB

Open AccessArticle

Macrophage-Derived Factors with the Potential to Contribute to Pathogenicity of HIV-1 and HIV-2: Role of CCL-2/MCP-1

by Chunling Gao, Weiming Ouyang, Joseph Kutza, Tobias A. Grimm, Karen Fields, Carla S. R. Lankford, Franziska Schwartzkopff, Mark Paciga, Tzanko Stantchev, Linda Tiffany, Klaus Strebel and Kathleen A. Clouse

Viruses 2023, 15(11), 2160; https://doi.org/10.3390/v15112160 - 27 Oct 2023

Cited by 1 | Viewed by 1590

Abstract

Human immunodeficiency virus type 2 (HIV-2) is known to be less pathogenic than HIV-1. However, the mechanism(s) underlying the decreased HIV-2 pathogenicity is not fully understood. Herein, we report that β-chemokine CCL2 expression was increased in HIV-1-infected human monocyte-derived macrophages (MDM) but decreased in HIV-2-infected MDM when compared to uninfected MDM. Inhibition of CCL2 expression following HIV-2 infection occurred at both protein and mRNA levels. By microarray analysis, quantitative PCR, and Western blotting, we identified that Signal Transducer and Activator of Transcription 1 (STAT1), a critical transcription factor for inducing CCL2 gene expression, was also reduced in HIV-2-infected MDM. Blockade of STAT1 in HIV-infected MDM using a STAT1 inhibitor significantly reduced the production of CCL2. In contrast, transduction of STAT1-expressing pseudo-retrovirus restored CCL2 production in HIV-2-infected MDM. These findings support the concept that CCL2 inhibition in HIV-2-infected MDM is meditated by reduction of STAT1. Furthermore, we showed that STAT1 reduction in HIV-2-infected MDM was regulated by the CUL2/RBX1 ubiquitin E3 ligase complex-dependent proteasome pathway. Knockdown of CUL2 or RBX1 restored the expression of STAT1 and CCL2 in HIV-2-infected MDM. Taken together, our findings suggest that differential regulation of the STAT1—CCL2 axis may be one of the mechanisms underlying the different pathogenicity observed for HIV-1 and HIV-2. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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11 pages, 2341 KiB

Open AccessArticle

EBV Impact in Peripheral Macrophages’ Polarization Cytokines in Pediatric Patients

by Agustina Moyano, Natalia Ferressini Gerpe, Maria Eugenia Amarillo, Elena De Matteo, Maria Victoria Preciado, Maria Soledad Caldirola and Paola Chabay

Viruses 2023, 15(10), 2105; https://doi.org/10.3390/v15102105 - 17 Oct 2023

Cited by 1 | Viewed by 1635

Abstract

Macrophages are exceptionally flexible cells. The presence of inflammatory cytokines such as IFN-γ and TNF-α results in an M1 (CD68) activation, while cytokines such as IL-10 or TGF-β induce the M2 (CD163) activation. Our aim was to study the behavior of peripheral cytokines involved in macrophage polarization and relate them with tissue findings to further comprehend the role of macrophages in EBV pediatric infection. We studied cytokine expression in tonsils and peripheral blood samples of children in different stages of infection. Peripheral cytokines were compared with macrophage polarization markers and viral protein expression in tonsils. Only IL-10 showed a negative correlation between compartments, exclusively in patients undergoing viral reactivation (R). Higher expressions of peripheral IL-1β, IL-23, and IL-12p40 in R children were observed. Lower expressions of local and peripheral TNF-α in patients with broader expressions of latent and lytic viral proteins were demonstrated. In healthy carrier (HC) patients, IL-23 positively correlated with CD163, and IP-10 positively correlated with CD68. Our results indicated that EBV might modulate antigen expression in the presence of TNF-α and influence peripheral cytokine expression differently in each stage of infection. Moreover, peripheral cytokines might have a particular role in macrophage polarization in HC. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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19 pages, 5223 KiB

Open AccessArticle

The Extract of Scutellaria baicalensis Attenuates the Pattern Recognition Receptor Pathway Activation Induced by Influenza A Virus in Macrophages

by Mingrui Yang, Luyao Ma, Rina Su, Rui Guo, Na Zhou, Menghua Liu, Jun Wu, Yi Wang and Yu Hao

Viruses 2023, 15(7), 1524; https://doi.org/10.3390/v15071524 - 8 Jul 2023

Cited by 3 | Viewed by 1953

Abstract

The dual strategy of inhibiting the viral life cycle and reducing the host inflammatory response should be considered in the development of therapeutic drugs for influenza A virus (IAV). In this study, an extract of Scutellaria baicalinase (SBE) containing seven flavonoids was identified to exert both antiviral and anti-inflammatory effects in macrophages infected with IAV. We performed transcriptome analysis using high-throughput RNA sequencing and identified 315 genes whose transcription levels were increased after IAV infection but were able to be decreased after SBE intervention. Combined with Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, these genes were mainly involved in TLR3/7/8, RIG-I/MDA5, NLRP3 and cGAS pattern recognition receptor (PRR)-mediated signaling pathways. SBE inhibited the transcription of essential genes in the above pathways and nuclear translocation of NF-κB p65 as confirmed by RT-qPCR and immunofluorescence, respectively, indicating that SBE reversed PR8-induced over-activation of the PRR signaling pathway and inflammation in macrophages. This study provides an experimental basis for applying Scutellaria baicalensis and its main effects in the clinical treatment of viral pneumonia. It also provides novel targets for screening and developing novel drugs to prevent and treat IAV infectious diseases. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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11 pages, 3562 KiB

Open AccessArticle

CVB3 Inhibits NLRP3 Inflammasome Activation by Suppressing NF-κB Pathway and ROS Production in LPS-Induced Macrophages

by Yanqi Wang, Zhirong Sun, Hongkai Zhang, Yahui Song, Yi Wang, Wei Xu and Min Li

Viruses 2023, 15(5), 1078; https://doi.org/10.3390/v15051078 - 28 Apr 2023

Cited by 5 | Viewed by 2109

Abstract

Inflammasomes are cytosolic sensors of pathogens. Their activation can lead to the induction of caspase-1-mediated inflammatory responses and the release of several proinflammatory cytokines, including IL-1β. There is a complex relationship between viral infection and the nucleotide-binding oligomerization domain-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome is essential for antiviral immunity, while excessive NLRP3 inflammasome activation may lead to excessive inflammation and pathological damage. Meanwhile, viruses have evolved strategies to suppress the activation of inflammasome signaling pathways, thus escaping immune responses. In this study, we investigated the inhibitory effect of coxsackievirus B3 (CVB3), a positive single-strand RNA virus, on the activation of the NLRP3 inflammasome in macrophages. CVB3-infected mice had significantly lower production of IL-1β and a lower level of NLRP3 in the small intestine after LPS stimulation. Furthermore, we found that CVB3 infection inhibited NLRP3 inflammasome activation and IL-1β production in macrophages by suppressing the NF-κB signaling pathway and ROS production. Additionally, CVB3 infection increased the susceptibility of mice to Escherichia coli infection by decreasing IL-1β production. Collectively, our study revealed a novel mechanism of NLRP3 inflammasome activation by suppressing the NF-κB pathway and ROS production in LPS-induced macrophages. Our findings may provide new ideas for antiviral treatment and drug development for CVB3 infection. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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Review

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43 pages, 4738 KiB

Open AccessReview

New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs

by Maria Marra, Alessia Catalano, Maria Stefania Sinicropi, Jessica Ceramella, Domenico Iacopetta, Romina Salpini, Valentina Svicher, Stefania Marsico, Stefano Aquaro and Michele Pellegrino

Viruses 2024, 16(9), 1484; https://doi.org/10.3390/v16091484 - 18 Sep 2024

Cited by 1 | Viewed by 3427

Abstract

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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30 pages, 2197 KiB

Open AccessReview

Macrophages: Key Cellular Players in HIV Infection and Pathogenesis

by Marie Woottum, Sen Yan, Sophie Sayettat, Séverine Grinberg, Dominique Cathelin, Nassima Bekaddour, Jean-Philippe Herbeuval and Serge Benichou

Viruses 2024, 16(2), 288; https://doi.org/10.3390/v16020288 - 13 Feb 2024

Cited by 8 | Viewed by 3424

Abstract

Although cells of the myeloid lineages, including tissue macrophages and conventional dendritic cells, were rapidly recognized, in addition to CD4+ T lymphocytes, as target cells of HIV-1, their specific roles in the pathophysiology of infection were initially largely neglected. However, numerous studies performed over the past decade, both in vitro in cell culture systems and in vivo in monkey and humanized mouse animal models, led to growing evidence that macrophages play important direct and indirect roles as HIV-1 target cells and in pathogenesis. It has been recently proposed that macrophages are likely involved in all stages of HIV-1 pathogenesis, including virus transmission and dissemination, but above all, in viral persistence through the establishment, together with latently infected CD4+ T cells, of virus reservoirs in many host tissues, the major obstacle to virus eradication in people living with HIV. Infected macrophages are indeed found, very often as multinucleated giant cells expressing viral antigens, in almost all lymphoid and non-lymphoid tissues of HIV-1-infected patients, where they can probably persist for long period of time. In addition, macrophages also likely participate, directly as HIV-1 targets or indirectly as key regulators of innate immunity and inflammation, in the chronic inflammation and associated clinical disorders observed in people living with HIV, even in patients receiving effective antiretroviral therapy. The main objective of this review is therefore to summarize the recent findings, and also to revisit older data, regarding the critical functions of tissue macrophages in the pathophysiology of HIV-1 infection, both as major HIV-1-infected target cells likely found in almost all tissues, as well as regulators of innate immunity and inflammation during the different stages of HIV-1 pathogenesis. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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Other

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10 pages, 2010 KiB

Open AccessBrief Report

Flagellin Restricts HIV-1 Infection of Macrophages through Modulation of Viral Entry Receptors and CC Chemokines

by Lina Zhou, Xu Wang, Qianhao Xiao, Shazheb Khan and Wen-Zhe Ho

Viruses 2024, 16(7), 1063; https://doi.org/10.3390/v16071063 - 30 Jun 2024

Cited by 1 | Viewed by 1504

Abstract

Both bacteria product flagellin and macrophages are implicated in HIV-1 infection/disease progression. However, the impact of their interaction on HIV-1 infection and the associated mechanisms remain to be determined. We thus examined the effect of the flagellins on HIV-1 infection of primary human macrophages. We observed that the pretreatment of macrophages with the flagellins from the different bacteria significantly inhibited HIV-1 infection. The mechanistic investigation showed that the flagellin treatment of macrophages downregulated the major HIV-1 entry receptors (CD4 and CCR5) and upregulated the CC chemokines (MIP-1α, MIP-1β and RANTES), the ligands of CCR5. These effects of the flagellin could be compromised by a toll-like receptor 5 (TLR5) antagonist. Given the important role of flagellin as a vaccine adjuvant in TLR5 activation-mediated immune regulation and in HIV-1 infection of macrophages, future investigations are necessary to determine the in vivo impact of flagellin–TLR5 interaction on macrophage-mediated innate immunity against HIV-1 infection and the effectiveness of flagellin adjuvant-based vaccines studies. Full article

(This article belongs to the Special Issue Roles of Macrophages in Viral Infections)

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