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Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 14796

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Special Issue Editors

Dr. Laura Beatriz Talarico

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Guest Editor

1. Laboratory of Infectious Diseases and Molecular Biology, Department of Medicine, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires 1425, Argentina
2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Interests: dengue virus; Zika virus; respiratory syncytial virus; viral immunology; viral pathogenesis; virus–host cell interactions

Dr. Claudia Filomatori

E-Mail Website
Guest Editor

1. Instituto de Química y Fisicoquímica Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina
2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Interests: arboviruses; RNA viruses; chikungunya virus; dengue virus; viral replication; viral genome; virus–host cell interactions
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Special Issue Information

Dear Colleagues,

Arboviruses, including dengue, Zika, chikungunya, and yellow fever viruses, are arthropod-transmitted pathogens that continue to expand their geographic distribution, posing a significant threat to public health worldwide. Despite causing millions of infections each year, effective antiviral treatments and vaccines remain limited for many of them. With global climate change and the increasing spread of arboviruses, there is an urgent need to address the understudied aspects of their pathogenesis to develop effective intervention strategies for future outbreaks.

Respiratory viruses, including influenza virus, rhinovirus, respiratory syncytial virus, parainfluenza virus, metapneumovirus, coronaviruses, and adenoviruses, are the most common causative agents of disease in humans. These viruses are responsible for significant morbidity and mortality, especially in neonates, immunocompromised individuals, and the elderly. Vaccines and antiviral therapy are currently available for only a few of these viruses, which poses a great challenge for continued research on prevention and therapeutic strategies against respiratory viral infections.

With this Special Issue, we aim to explore the pathogenesis of these two important groups of viruses and host immune responses to infections. Understanding viral pathogenesis mechanisms and virus–host immune interactions is crucial for developing safe and effective treatments and vaccines against these viruses with a high impact on global health.

Potential topics of interest for this Special Issue include, but are not limited to, the following:

Mechanisms of infection and spread: entry, replication, and dissemination and tissue tropism;
Viral evasion strategies: modulation of innate immune responses and mechanisms of persistence;
Host factors influencing pathogenesis: genetic and immunological determinants of disease severity and the impact of comorbidities on viral pathogenesis;
Innate immunity: role of pattern recognition receptors and interferon and cytokine responses;
Adaptive immunity: T cell responses and immune memory formation, B cell responses, and neutralizing antibodies;
Cytokine storm and immune dysregulation;
Immune modulation and host-directed therapies.

Dr. Laura Beatriz Talarico
Dr. Claudia Filomatori
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

arboviruses
respiratory viruses
viral pathogenesis
host immune responses
innate immunity
adaptive immunity
viral immune evasion
cytokine storm
interferon response
viral replication
viral transmission
immunopathology
neutralizing antibodies
host–virus interactions

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Published Papers (10 papers)

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Research

Jump to: Review

22 pages, 5476 KB

Open AccessArticle

Genome-Wide RNAi Screening Identifies Novel Host Factors Involved in Influenza A Virus Infection in A549 Cells

by Qingchao Zhang, Lifang Zhang, Xinmeng Yang, Wei Wang, Xiliang Wang, Chengyu Jiang, Fengming Huang and Yanli Zhang

Viruses 2026, 18(3), 374; https://doi.org/10.3390/v18030374 - 17 Mar 2026

Viewed by 955

Abstract

Influenza A virus (IAV) remains a major global health threat, and host-directed antivirals may help overcome rapid viral mutation and drug resistance. Here, we performed a genome-wide siRNA screen in A549 cells using cell viability as an integrated endpoint to identify host determinants of IAV (PR8/H1N1) infection. Using plate-normalized viability ratios, we identified 2134 genes with >40% viability change after infection (2048 UP and 86 DOWN; two-tailed t-test, n = 3; p < 0.05, FDR < 0.1). MetaCore pathway analysis showed enrichment of programs linked to host response and tissue injury control, including RAS-related signaling and multiple metabolic pathways such as estradiol, ubiquinone/mitochondrial redox, and benzo[a]pyrene/xenobiotic metabolism. DAVID Gene Ontology analysis further highlighted biological processes relevant to infection, including endocytosis, transcription, and translation, consistent with host pathways supporting viral replication. Benchmarking against meta-analyzed RNAi and CRISPR resources revealed that shared hits were enriched for translation, nucleocytoplasmic transport, and ER-Golgi trafficking, supporting external validity, whereas the large unique UP fraction was dominated by hormone metabolism, detoxification, and mitochondrial redox/CoQ pathways, consistent with viability-specific, tolerance-associated host response programs. Integrating the screen with DrugBank identified 174 druggable host genes corresponding to 345 candidate compounds. Together, these findings provide a systematic resource of host factors influencing H1N1 infection, improve understanding of influenza virus–host interactions, and offer a foundation for future development of host-directed antiviral strategies and drug repurposing efforts. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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18 pages, 33058 KB

Open AccessArticle

IFN-λ4 Exhibits Differential Induction and Antiviral Activity in RSV and HMPV Infections

by Iván Martínez-Espinoza, Pius I. Babawale and Antonieta Guerrero-Plata

Viruses 2026, 18(1), 111; https://doi.org/10.3390/v18010111 - 14 Jan 2026

Cited by 2 | Viewed by 1022

Abstract

Interferons (IFNs) are essential mediators of the innate immune response to viral infections. Among the type III IFNs, the role of IFN-λ4 in respiratory viral infections remains largely understudied. Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are clinically significant pneumoviruses that elicit divergent IFN responses in epithelial cells. Here, we investigate the virus-specific induction and antiviral activity of IFN-λ4 by HMPV and RSV infections. We demonstrate that RSV induces a limited expression of IFN-λ4, which is regulated by the expression of the NS1 protein. Furthermore, RSV and HMPV rely primarily on RIG-I for IFN-λ4 induction. Finally, we show that IFN-λ4 exerts antiviral activity against both viruses, with RSV displaying greater sensitivity. These findings highlight the antiviral role of IFN-λ4 to clinically relevant respiratory viruses. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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16 pages, 6723 KB

Open AccessArticle

Virus-like Particles and Spectral Flow Cytometry for Identification of Dengue Virus-Specific B Cells in Mice and Humans

by Katherine Segura, Fabiola Martel, Manuel A. Franco, Federico Perdomo-Celis and Carlos F. Narváez

Viruses 2026, 18(1), 58; https://doi.org/10.3390/v18010058 - 30 Dec 2025

Viewed by 1236

Abstract

Severe dengue virus (DENV) infections are associated with circulating non-neutralizing antibodies generated during heterotypic infections. Although antibodies are key mediators of both protection and pathogenesis, the specific dynamics of B cells (Bc) and their antibody responses remain insufficiently characterized due to limited methods of identifying DENV-specific Bc (DENV-Bc) and the absence of animal models resembling the human disease. Here, we developed a spectral flow cytometry assay employing biotinylated virus-like particles (VLPs) to detect DENV-Bc in C57BL/6 mice and children hospitalized with dengue. DENV-1 and DENV-2 VLPs were biotinylated, and the efficiency of biotin incorporation was assessed with an HABA-avidin assay and ELISA. Serotype specificity and optimal binding conditions were confirmed using hybridomas 4G2 (pan-flavivirus) and 3H5-1 (DENV-2 specific). Fluorescent agglutimers were subsequently generated by coupling biotinylated VLPs to streptavidin–fluorochrome complexes. Splenocytes from intraperitoneally DENV-infected mice and peripheral blood mononuclear cells (PBMCs) from naturally infected pediatric patients were stained with these VLPs and Bc-lineage markers. Biotinylated VLPs bound specifically to hybridomas, and this binding was competitively inhibited by unlabeled VLPs. After secondary DENV challenge, VLPs identified DENV-specific class-switched plasmablasts in mice. Circulating DENV-specific plasmablasts were also detected in children, with agglutimers enabling the discrimination of serotype-specific and cross-reactive responses in primary and secondary infections. This VLP-based approach represents a scalable platform to investigate the protective and pathogenic roles of DENV-Bc in infection and vaccination. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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17 pages, 3420 KB

Open AccessArticle

H6N6 Avian Influenza Virus Infection Induced Pyroptosis of M1 Macrophages by Activating Caspase-1

by Hui Zhu, Dongfang He, Sicong Liu, Xiaohui Fan, Lingxi Gao, Liping Guo and Zengfeng Zhang

Viruses 2025, 17(11), 1492; https://doi.org/10.3390/v17111492 - 12 Nov 2025

Viewed by 1282

Abstract

The H6N6 avian influenza virus has expanded its host range from birds to mammals. Some strains can now bind to human-like receptors, raising concerns about human infection. Although H6N6 is a low-pathogenic avian influenza virus (LPAIV), it is unclear whether it triggers pyroptosis in human lungs, a process linked to cytokine storms in infections like H7N9. Here, we found that the chicken-origin H6N6 LPAIV can effectively replicate in and infect human alveolar macrophages and their M1 macrophages. Viral infection of M1 macrophages upregulated the mRNA levels of NLRP3, caspase-1, and Gasdermin D (GSDMD). Subsequently, caspase-1 was activated and cleaved GSDMD protein into its N-terminal fragment (GSDMD-N), which formed pores in the cell membrane and triggered the release of IL-1β and IL-18. Further analysis demonstrated that inhibition of the NLRP3/Caspase-1/GSDMD pathway by specific inhibitors attenuated pyroptosis in infected M1 macrophages. In summary, our study revealed that H6N6 virus infection induces M1 macrophage pyroptosis via the NLRP3/caspase-1/GSDMD pathway. Notably, M1 macrophages inherently produce pro-inflammatory cytokines; their pyroptosis, accompanied by the release of IL-1β and IL-18, can amplify inflammation and potentially trigger a cytokine storm in the lungs. These findings reveal novel pathogenic mechanisms and potential therapeutic targets for avian influenza viruses. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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18 pages, 2033 KB

Open AccessArticle

Imiquimod, a Promising Broad-Spectrum Antiviral, Prevents SARS-CoV-2 and Canine Coronavirus Multiplication Through the MAPK/ERK Signaling Pathway

by Josefina Vicente, Freddy Armando Peñaranda Figueredo, Stefania Mantovani, Daniela Laura Papademetrio, Sergio Ivan Nemirovsky, Andrea Alejandra Barquero, Carina Shayo and Carlos Alberto Bueno

Viruses 2025, 17(6), 801; https://doi.org/10.3390/v17060801 - 31 May 2025

Cited by 2 | Viewed by 2499

Abstract

Respiratory viruses can cause life-threatening conditions such as sepsis and acute respiratory distress syndrome. However, vaccines and effective antivirals are available for only a limited number of infections. The majority of approved antivirals are direct-acting agents, which target viral proteins essential for infection. Unfortunately, mutations have already emerged that confer resistance to these antivirals. In addition, there is an urgent need for broad-spectrum antivirals to address the unpredictable emergence of new viruses with pandemic potential. One promising strategy involves modulating the innate immune response and cellular signaling. Imiquimod, a Toll-like receptor 7 (TLR7) agonist, has shown efficacy in murine models of influenza and respiratory syncytial virus (RSV). Additionally, it demonstrates antiviral activity against herpes simplex virus type 1 (HSV-1) and RSV independent of the TLR7/nuclear factor kappa B (NF-κB) pathway, with protein kinase A (PKA) as a crucial downstream effector. In this study, we demonstrate that imiquimod exhibits concentration-dependent antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and canine coronavirus (CCoV) in epithelial cells, underscoring its broad-spectrum action against coronaviruses. Moreover, its anti-coronavirus effect appears to be independent of the TLR/NF-κB and PKA/exchange protein directly activated by cyclic adenosine monophosphate (EPAC) pathways and may instead be linked to the activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. The ability of imiquimod to inhibit coronavirus replication via the MEK/ERK pathway, coupled with its immunomodulatory properties, highlights its potential as a broad-spectrum antiviral. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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Review

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37 pages, 12756 KB

Open AccessReview

Advances in Antiviral Drug Development Targeting Enteroviruses: From Viral Proteins to Host Factors

by Jiaying Lu, Congyi Li, Wenzhe Cui, Yining Du, Jiayi Geng and Wenyan Zhang

Viruses 2026, 18(4), 476; https://doi.org/10.3390/v18040476 - 18 Apr 2026

Viewed by 1372

Abstract

Enteroviruses represent important human pathogens, posing a substantial disease burden, particularly in children under 5 years of age. Enteroviruses are the primary causative agents of hand-foot-and-mouth disease (HFMD) and are strongly associated with acute flaccid myelitis (AFM), with severe cases potentially resulting in significant neurological complications. Inactivated vaccines against EV-A71 based on the C4 genotype are currently available. However, there are no licensed direct antiviral agents for severe cases. By focusing on viral proteins and host factors, researchers have made great strides in the creation of antiviral medications that target enteroviruses. However, several viral candidates failed to progress in clinical development due to limited efficacy or side effects. This review discusses key findings in enterovirus antiviral research, analyzes the advantages and limitations of each drug target, and highlights knowledge gaps that need to be addressed to advance further development in this field. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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21 pages, 4684 KB

Open AccessReview

Decoding Self vs. Non-Self: Alphavirus Cap0 Recognition and Immune Evasion

by Santiago E. Faraj and Claudia V. Filomatori

Viruses 2026, 18(4), 439; https://doi.org/10.3390/v18040439 - 5 Apr 2026

Viewed by 950

Abstract

Host receptors can detect traces of non-self-pathogenic RNAs within a sea of cellular mRNA molecules. In host cells, mRNA cap methylation occurs in the nucleus, generating Cap1 and Cap2 structures (m⁷GpppNm and m⁷GpppNmNm, respectively). By contrast, alphavirus genomes carry a Cap0 structure (m⁷GpppN), which lacks 2′-O-methylation. This difference in the structure of the host and viral caps serves as a molecular signature that enables discrimination between self and non-self RNAs. Several host immune sensors, such as RIG-I and IFIT1, recognize the alphavirus Cap0 structure and trigger an antiviral response to restrict viral replication. It has been proposed that IFIT1 sequesters aberrant RNAs, preventing their translation by host ribosomes and blocking viral protein synthesis. However, alphaviruses have evolved molecular strategies to circumvent IFIT1-mediated restriction and facilitate infection in mammalian cells. One such strategy involves the folding of a 5′ RNA structure that hides the cap from host immune sensors. This highlights the dynamic interplay between viral evasion tactics and host immune defenses. This review will discuss how specific modifications at the 5′ end of alphavirus RNA modulate host defenses and how a deeper understanding of the virus–host interaction may inform the development of novel vaccine strategies. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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16 pages, 703 KB

Open AccessReview

The Complexity of Immunoglobulin A Immune Responses in Respiratory Syncytial Virus Infection

by Ashley Ferrier Esposito, Diego R. Hijano and Stephania A. Cormier

Viruses 2026, 18(2), 150; https://doi.org/10.3390/v18020150 - 23 Jan 2026

Cited by 1 | Viewed by 1110

Abstract

Respiratory syncytial virus (RSV) remains a leading cause of severe lower respiratory tract disease in infants worldwide. Despite extensive study in animal models and humans, fundamental age-dependent differences in mucosal immunity continue to limit the development of durable protective strategies in early life. Compared to adults, infants mount weaker humoral responses to RSV, underscoring the urgent need for effective vaccines in this age group. Immunoglobulin A (IgA), the dominant antibody isotype at respiratory mucosal surfaces, plays a central role in limiting viral replication and disease severity during RSV infection. While IgA limits RSV severity in adults, infants fail to generate robust IgA responses. Impaired IgA responses in infancy reflect unique immune regulatory pathways that shape early-life antiviral immunity. Emerging evidence highlights a critical role for regulatory B cells (Bregs), particularly neonatal Bregs (nBregs), in suppressing antiviral responses, limiting class switch recombination, and contributing to severe RSV disease. This review summarizes current evidence on IgA regulation during RSV infection, with particular emphasis on age-specific B-cell responses and the emerging role of Bregs. Improved understanding of these mechanisms has direct implications for the rational design of vaccines and immunomodulatory strategies tailored to infants. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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31 pages, 2327 KB

Open AccessReview

Hidden in Plain Sight: Alphavirus Persistence and Its Potential for Driving Chronic Pathogenesis

by Maria del Mar Villanueva Guzman, Zhenlan Yao, Melody M. H. Li and Maria Gabriela Noval

Viruses 2026, 18(1), 30; https://doi.org/10.3390/v18010030 - 24 Dec 2025

Cited by 1 | Viewed by 1733

Abstract

Alphaviruses have historically been viewed as acute, self-limiting pathogens. However, growing evidence shows that viral RNA and antigens can persist in vertebrate hosts long after the resolution of acute infection, a phenomenon known as viral persistence. Viral persistence reflects a dynamic interplay between viral replication—including shifts from lytic to non-lytic infection—and host defenses, which together establish cellular and tissue niches that enable evasion of immune-mediated clearance. Within vertebrate hosts, alphaviruses exhibit broad tissue tropism, infecting diverse cell types that may differentially support long-term persistence. Emerging evidence suggests that viral persistence arises through three interconnected processes: (i) selective infection of specific cellular niches, (ii) reprogramming of host cellular pathways, and (iii) modulation of immune responses. Yet, the extent to which viral or host determinants shape this balance, and how persistence contributes to chronic disease, remains unresolved. Here, we synthesize current in vitro and in vivo evidence of alphavirus persistence in vertebrate hosts and discuss potential mechanisms by which alphaviruses establish and maintain persistent infection beyond the acute phase. We further underscore critical gaps in current knowledge and outline future research avenues essential for elucidating the mechanisms underlying alphavirus pathogenesis. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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16 pages, 1386 KB

Open AccessReview

The Role of Innate Cells During Alphavirus Chikungunya Infection

by Juliane Santos de França da Silva, Livian Maria Silva dos Santos, Célio Valdevino Ferreira Junior, Nathalie de Sena Pereira, Juliana Navarro Ueda Yaochite, Valter Ferreira de Andrade Neto, Paulo Marcos da Matta Guedes, Rafael Freitas De Oliveira França, Ramayana Morais de Medeiros Brito and Manuela Sales Lima Nascimento

Viruses 2025, 17(11), 1469; https://doi.org/10.3390/v17111469 - 1 Nov 2025

Cited by 2 | Viewed by 1512

Abstract

Alphavirus chikungunya (CHIKV) is an arthropod-borne alphavirus of the Togaviridae family, transmitted primarily by Aedes aegypti and Ae. albopictus mosquitoes. CHIKV infection often results in debilitating manifestations that compromise quality of life and generate significant socioeconomic impacts. Recurrent epidemics in tropical and subtropical regions underscore the urgent need to better understand the host immune responses and their contribution to disease outcome. CHIKV establishes infection by overcoming the host’s initial immunological barriers. Innate immune cells, including fibroblasts, dendritic cells, macrophages, monocytes, neutrophils and natural killer (NK) cells, are among the first to respond to infection, ensuring a rapid antiviral defense and supporting the development of adaptive immune responses. However, excessive release of inflammatory mediators and prolonged infiltration of innate cells into joint tissues contribute to disease chronicity and the persistence of arthralgia. In this review, we provide a comprehensive synthesis of current evidence on innate cells that serve as targets for CHIKV infection, highlighting mechanisms that promote effective antiviral defense as well as those responsible for pathological inflammation and chronic disease and identifying key gaps that remain to be addressed. Full article

(This article belongs to the Special Issue Advances in Understanding Viral Pathogenesis and Host Immune Responses to Arboviruses and Respiratory Viruses)

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