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Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2026) | Viewed by 9430

Editor

Prof. Dr. Andreas Beineke

E-Mail Website
Guest Editor
Department of Pathology, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany
Interests: pathology of the respiratory system; immune regulation; immunodeficiencies; molecular pathology; morbilliviruses; emerging infectious diseases; zoonotic diseases; animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral infections of the upper and lower respiratory system represent global health issues. Infections can be self-limiting or cause severe acute disease and even fatalities in vulnerable groups such as infants, the elderly, and immunocompromised patients. Moreover, persistent pulmonary changes and long-term respiratory problems can occur following infection. In the last several decades, reported cases of pneumotropic agents causing emerging and re-emerging diseases in humans and animals have increased. Recent research in infectious pulmonary diseases such as measles, influenza, and the current COVID-19 pandemic clearly shows that detailed knowledge about viral properties, virus entry, molecular pathology, and disease pathogenesis is essential for the development of effective prevention and treatment strategies. This Special Issue aims to provide an up-to-date collection of original research and review articles focusing on the progress in infection biology of viral pathogens of the respiratory system. We welcome molecular studies, including in vitro studies and animal experiments, dealing with (but not limited to) host–pathogen interaction, immunology, and pathogenesis, as well as the development of prevention and treatment strategies of viral respiratory diseases in humans and animals.

As volumes 1 and 2 of the Special Issue “Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis” have been successful, we will be exploring this issue further in the International Journal of Molecular Sciences (ISSN 1422-0067, IF 4.9, JCR Category Q1).

Prof. Dr. Andreas Beineke
Guest Editor

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • respiratory diseases
  • pneumonia
  • pneumotropic viruses
  • pathogenesis
  • host–pathogen interaction
  • pulmonary pathology
  • immunopathology
  • immunity
  • disease prevention
  • treatment
  • zoonotic diseases
  • antiviral therapy

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Related Special Issues

Published Papers (6 papers)

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Research

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38 pages, 735 KB  
Article
Disentangling Shared and Differential Genetic Architectures Between COVID-19 and Other Respiratory Disorders—A Genome-Wide Multi-Omics Framework
by Xiao Xue, Yu-Ping Lin, Yaning Feng and Hon-Cheong So
Int. J. Mol. Sci. 2026, 27(14), 6536; https://doi.org/10.3390/ijms27146536 - 22 Jul 2026
Viewed by 648
Abstract
A bidirectional relationship has been observed between COVID-19 and respiratory disorders, where respiratory comorbidities increase severity, and COVID-19 induces respiratory sequelae. The underlying biological and genetic mechanisms remain unclear. While previous studies have identified overlapping genetic loci, few have systematically disentangled the genetic [...] Read more.
A bidirectional relationship has been observed between COVID-19 and respiratory disorders, where respiratory comorbidities increase severity, and COVID-19 induces respiratory sequelae. The underlying biological and genetic mechanisms remain unclear. While previous studies have identified overlapping genetic loci, few have systematically disentangled the genetic factors shared between these conditions versus those specific to COVID-19, particularly at a multi-omics level. We developed and applied a unified analytical framework to compare three COVID-19 phenotypes with eight respiratory disorders (including asthma, COPD, IPF, and pneumonia). Utilizing the cofdr method for shared genetic signal analysis and DDx/mtCOJO for differentiation, we integrated genome-wide association statistics with multi-omics data (transcriptome, splicing, and proteome). This approach allowed for the simultaneous identification of shared genetic signals (concordant or discordant) and disease-specific variants across expression (TWAS), alternative splicing (spTWAS), and protein abundance (PWAS). We delineated a comprehensive atlas of 214 differential and numerous shared loci across 24 pairwise comparisons. The shared genetic architecture was characterized by pleiotropic effects in genes such as ATP11A (exhibiting opposing effects in COVID-19 vs. IPF) and GSDMB (shared with COPD). Crucially, differentiation analysis revealed that severe COVID-19 is genetically distinct from other respiratory infections (e.g., pneumonia and influenza) through dysregulated Type I/III interferon signaling and specific defects in alveolar epithelial and macrophage function, as well as GM-CSF/surfactant metabolism pathways. These findings provide human genetic evidence consistent with the therapeutic rationale underlying GM-CSF modulators and interferon-lambda for COVID-19, both of which have entered clinical trials. Furthermore, multi-trait conditional analysis prioritized FYCO1 and HCN3 as potential COVID-19-specific risk genes. Splicing analysis underscored the critical role of alternative splicing in both shared and differential architectures, highlighting IFNAR2 isoform regulation as a key discriminator between COVID-19 and other respiratory traits. This study provides the first genome-wide, multi-omics map revealing the shared and differential genetic landscapes of COVID-19 and other respiratory phenotypes. By uncovering specific molecular mechanisms that distinguish COVID-19 pathology, specifically involving surfactant homeostasis and interferon pathways, our findings offer novel insights for targeted drug repurposing and precision risk stratification. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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14 pages, 5687 KB  
Article
Extracts from Valsonectria inflata, a Soil-Derived Fungus, Inhibit Human Coronavirus OC43 Replication
by Chunghyeon Lee, Siyun Lee, Seungju Cho, Sumin Kim, SeonJu Park, Mi Hyeon Cho, Eunji Cho, Jayhyun Park, Hyung-Gwan Lee, Hye Yeon Mun, Chang Soo Lee and Junsoo Park
Int. J. Mol. Sci. 2026, 27(14), 6328; https://doi.org/10.3390/ijms27146328 - 16 Jul 2026
Viewed by 334
Abstract
Coronaviruses are responsible for both severe diseases, such as COVID-19, and mild illnesses, such as the common cold. Because coronaviruses are expected to remain continuously prevalent, alternative therapeutic strategies against coronavirus infections should be developed to respond to newly emerging variants. Since many [...] Read more.
Coronaviruses are responsible for both severe diseases, such as COVID-19, and mild illnesses, such as the common cold. Because coronaviruses are expected to remain continuously prevalent, alternative therapeutic strategies against coronavirus infections should be developed to respond to newly emerging variants. Since many antibiotics, including penicillin, have been isolated from fungi, we screened fungal extracts for antiviral activity against human coronavirus and found that the extract of Valsonectria inflata (VIE) exhibited antiviral effects against human coronavirus. Western blot analysis showed that VIE treatment decreased coronavirus protein expression. Quantitative RT-PCR (qRT-PCR) and plaque formation assays demonstrated that VIE treatment reduced coronavirus production, while scanning electron microscopy (SEM) analysis further confirmed a decrease in the production of infectious viral particles. Finally, VIE treatment ameliorated coronavirus-induced cytotoxicity. We also analyzed the components of VIE, and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) revealed that VIE contains various secondary metabolites, including terpenoids. These results suggest that VIE may serve as a potential antiviral agent against coronavirus infections. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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19 pages, 1644 KB  
Article
Omicron Subvariants Infection Kinetics and Nirmatrelvir Efficacy in Transgenic K18-hACE2 Mice
by Vijeta Sharma, Enriko Dolgov, Taylor Tillery, Camila Mendez Romero, Alberto Rojas-Triana, Diana M. Villalba Guzman, Kira Goldgirsh, Risha Rasheed, Irene Gonzalez-Jimenez, Nadine Alvarez, Steven Park, Madhuvika Murugan, Andrew M. Nelson and David S. Perlin
Int. J. Mol. Sci. 2025, 26(19), 9509; https://doi.org/10.3390/ijms26199509 - 29 Sep 2025
Cited by 1 | Viewed by 1379
Abstract
The persistent evolution of SARS-CoV-2 has led to the emergence of antigenically distinct Omicron subvariants exhibiting increased transmissibility, immune evasion, and altered pathogenicity. Among these, recent subvariants such as JN.1, KP.3.1.1, and LB.1 possess unique antigenic and virological features, underscoring the need for [...] Read more.
The persistent evolution of SARS-CoV-2 has led to the emergence of antigenically distinct Omicron subvariants exhibiting increased transmissibility, immune evasion, and altered pathogenicity. Among these, recent subvariants such as JN.1, KP.3.1.1, and LB.1 possess unique antigenic and virological features, underscoring the need for continued surveillance and therapeutic evaluation. As vaccines and commercial monoclonal antibodies show reduced effectiveness against these variants, the role of direct-acting antivirals, such as Nirmatrelvir, targeting conserved viral elements like the main protease inhibitor, becomes increasingly crucial. In this study, we investigated the replication kinetics, host immune responses, and therapeutic susceptibility of three recently circulating Omicron subvariants in the K18-hACE2 transgenic mouse model, using the SARS-CoV-2 parent WA1/2020 strain as a reference. Omicron subvariants exhibited a marked temporal shift in viral infection kinetics characterized by an early lung viral titer peak (~7–8 Log PFU) at 2 days post-infection (dpi), followed by a decline (1–3 Log PFU) by 4 dpi. Pulmonary cytokine and chemokine responses (GM-CSF, TNF-α, IL-1β, IL-6) showed an earlier increase in subvariant-infected mice compared to a gradual response in WA1/2020 infection. Notably, Nirmatrelvir treatment led to significant reductions in lung viral titers in subvariant-infected mice compared to WA1/2020, surpassing its efficacy against the parent strain. These findings highlight that infection with Omicron subvariants yields a broad dynamic range in viral burden with minimum variability, while retaining a prominent therapeutic response to Nirmatrelvir. This study provides insights into the emerging subvariants’ pathogenesis and therapeutic responsiveness, reinforcing the importance of continued variant monitoring and the development of effective countermeasures. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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13 pages, 2073 KB  
Article
The X-Linked TLR7 rs179008 T Allele Is Associated with an Increased Risk of Severe Multisystem Inflammatory Syndrome in Children/Kawasaki-like Syndrome in SARS-CoV-2-Infected Boys
by Adriana de Souza Andrade, Aline Almeida Bentes, Lilian Martins Diniz, Silvia Hees Carvalho, Erna Geessien Kroon and Marco Antonio Campos
Int. J. Mol. Sci. 2025, 26(17), 8491; https://doi.org/10.3390/ijms26178491 - 1 Sep 2025
Cited by 1 | Viewed by 1336
Abstract
The X-linked TLR7 rs179008 T allele has been associated with altered antiviral immunity. Given their shared inflammatory pathways and higher pediatric mortality rates in Brazil during the pandemic, we investigated their association with multisystem inflammatory syndrome in children (MIS-C) together with Kawasaki disease [...] Read more.
The X-linked TLR7 rs179008 T allele has been associated with altered antiviral immunity. Given their shared inflammatory pathways and higher pediatric mortality rates in Brazil during the pandemic, we investigated their association with multisystem inflammatory syndrome in children (MIS-C) together with Kawasaki disease (KS) following SARS-CoV-2 infection. A cross-sectional study (2021–2022) analyzed 73 hospitalized children (<13 years) with confirmed COVID-19. Genotyping for TLR7 rs179008, TLR8 (rs3764879, rs2407992), and TLR3 rs3775291 was performed via PCR and Sanger sequencing. MIS-C/KS cases were identified using CDC criteria, with severity classified by the need for ICU care. Statistical analysis included Fisher’s exact test and relative risk (RR) calculations. Hemizygous boys carrying the TLR7 T allele had a 1.87-fold higher risk of MIS-C/KS (p = 0.007) and a 1.75-fold increased risk of severe or critical outcomes. The T allele frequency was 2.6× higher in MIS-C/KS cases versus other COVID-19 presentations. All fatalities occurred in boys (3/8 MIS-C cases) with one T-allele carrier. No associations were found for TLR8 or TLR3 variants. The TLR7 rs179008 T allele is a potential genetic risk factor for severe post-COVID-19 inflammatory syndromes in boys, likely due to impaired immune signaling. These findings highlight its utility as a biomarker for risk stratification in pediatric populations. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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17 pages, 2296 KB  
Article
Subgenomic RNA and Limited Cross-Reactive Neutralising Antibodies Point to Potential Improvements in SARS-CoV-2 Clinical Handling
by Carlos Davina-Nunez, Sonia Perez-Castro, Jorge Julio Cabrera-Alvargonzalez, Elena Gonzalez-Alonso, Sergio Silva-Bea, Miriam Rodriguez-Perez, Maria del Pilar Figueroa-Lamas, Alexandre Perez-Gonzalez, Victor del Campo, Almudena Rojas, Joaquin Mendoza and Benito Regueiro-Garcia
Int. J. Mol. Sci. 2025, 26(7), 2948; https://doi.org/10.3390/ijms26072948 - 24 Mar 2025
Viewed by 1461
Abstract
The current clinical management of SARS-CoV-2 disease control and immunity may be not optimal anymore. Reverse transcription polymerase chain reaction (RT-PCR) of genomic viral RNA is broadly used for diagnosis, even though the virus may still be detectable when it is already non-infectious. [...] Read more.
The current clinical management of SARS-CoV-2 disease control and immunity may be not optimal anymore. Reverse transcription polymerase chain reaction (RT-PCR) of genomic viral RNA is broadly used for diagnosis, even though the virus may still be detectable when it is already non-infectious. Regarding serology, commercial assays mostly still rely on ancestral spike detection despite significant changes in the genetic sequence of the current circulating variants. We followed a group of 105 non-vaccinated individuals, measuring their viral shedding until negativity and antibody response up to six months. The mean viral detection period until a negative RT-PCR result was 2.2 weeks when using subgenomic RNA-E as a detection target, and 5.2 weeks when using genomic RNA as a detection target. Our neutralising antibody results suggest that, when challenged against a variant different from the variant of first exposure, commercial immunoassays are suboptimal at predicting the neutralising capacity of sera. Additionally, anti-Alpha and anti-Delta antibodies showed very low cross-reactivity between variants. This study provides insights into viral shedding and immune response in pre-Omicron variants like Alpha and Delta, which have been understudied in the published literature. These conclusions point to potential improvements in the clinical management of SARS-CoV-2 cases in order to organise vaccination campaigns and select monoclonal antibody treatments. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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Review

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31 pages, 2566 KB  
Review
Dysregulated Resolution of Inflammation After Respiratory Viral Infections: Molecular Pathways Linking Neuroinflammation to Post-Viral Neuropathic Pain—A Narrative Review
by Andrei Emilian Popa, Elena Popa, Tatiana Dramba, Elena Adorata Coman, Mihaela Poroch, Monica Ungureanu, Agnes Bacusca, Ana Maria Slanina, Gema Bacoanu and Vladimir Poroch
Int. J. Mol. Sci. 2025, 26(23), 11383; https://doi.org/10.3390/ijms262311383 - 25 Nov 2025
Cited by 3 | Viewed by 3343
Abstract
Post-viral neuroinflammatory syndromes, particularly those occurring after SARS-CoV-2 infection, have received increasing attention due to their complex and persistent neurological manifestations. The aim of this narrative review is to integrate current evidence on the molecular and cellular mechanisms underlying chronic neuroinflammation following viral [...] Read more.
Post-viral neuroinflammatory syndromes, particularly those occurring after SARS-CoV-2 infection, have received increasing attention due to their complex and persistent neurological manifestations. The aim of this narrative review is to integrate current evidence on the molecular and cellular mechanisms underlying chronic neuroinflammation following viral infections, with a focus on dysregulated innate immune responses, macrophage–microglia interactions, oxidative–mitochondrial stress, and impaired inflammation resolution pathways. Our synthesis shows that prolonged activation of macrophages and glial cells promotes the continuous release of pro-inflammatory mediators, while defective phagocytosis and inadequate clearance of cellular debris maintain an inflammatory microenvironment. Mitochondrial dysfunction further amplifies immune activation by stimulating metabolic stress and reactive oxygen species production. In parallel, deficiencies in mediators specialized in inflammation resolution impede the transition from inflammation to resolution, allowing neuroimmune imbalance and nociceptive sensitization to persist long after virus clearance. Key conclusions indicate that these interconnected mechanisms collectively contribute to the long-term neurological symptoms observed in post-viral states, including cognitive impairment, neuropathic pain, and fatigue. Emerging therapeutic strategies targeting cytokine signaling, microglial reactivity, mitochondrial function, and resolution pathways are promising, but remain insufficiently validated in clinical practice. Overall, evidence suggests that post-viral neuroinflammation results from the convergence of sustained immune activation and failure of endogenous resolution mechanisms, highlighting the need for further mechanistic studies and targeted interventions. Full article
(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis: 3rd Edition)
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