Multiple Sclerosis (MS) is characterized by immune-mediated damage to the myelin sheath, disrupting neuronal signaling and permanently damaging the central nervous system (CNS). The vagus nerve has emerged as a key regulator of peripheral inflammatory diseases, with activation or elimination of vagal signaling diminishing or enhancing immune cell activity, respectively, but whether it similarly orchestrates CNS immune responses is only beginning to be explored.

To model the immune-driven demyelination present in MS, susceptible female mice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus (JHMV), which results in acute encephalomyelitis and subsequent spinal cord demyelination. To explore the role of the vagus nerve in MS, cohorts of female mice were subject to either a SHAM surgery or left cervical vagotomy (VGX) prior to infection with JHMV. VGX significantly impaired immune cell trafficking to the CNS. At day 7 post-infection, VGX mice exhibited fewer recruited myeloid cells and subsequently significantly less CD4+ and CD8+ T-cells in the brain with elevated viral loads. CD8 T-cell effector function was diminished in VGX mice, as evidenced by reduced interferon gamma production upon stimulation with JHMV-derived peptides.

By day 21 post-infection when demyelination peaks, VGX mice experienced a significant increase in spinal cord demyelination despite a decrease in T-cells within the spinal cord. qPCR of brain tissue highlighted that VGX mice had persistently elevated mRNA transcripts encoding for Jhmv and T-cell chemokines (Cxcl9, Cxcl10), indicating impaired viral clearance compared to SHAM controls.

These data demonstrate that intact vagal signaling is required to mount an appropriate immune response to JHMV, facilitating immune cell recruitment and viral clearance. This work highlights a novel role for the vagus nerve in modulating CNS immunity and suggests therapeutic potential in targeting vagal pathways for MS and related neuroinflammatory diseases.

BST-2/tTetherin is an interferon-stimulated gene that restricts enveloped viruses by tethering nascent virions at the plasma membrane. Because virions tethered at the cell surface serve as potent antigens for immune recognition, we hypothesized that BST-2 plays additional roles in antiviral immunity by enabling antibody opsonization of tethered particles and promoting the subsequent engagement of Fcγ receptors on natural killer cells and phagocytes to trigger antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Consistent with this hypothesis, we found that BST-2 restricts SARS-CoV-2 egress and that BST-2-mediated virion tethering enhances ADCC and ADCP of infected cells. However, SARS-CoV-2 uses Spike to counteract BST-2 through a physical interaction that causes the lysosomal degradation of BST-2. Remarkably, variants of concern (VOC) exhibit enhanced BST-2 antagonism compared to ancestral strains due to mutations in their Spike that increase Spike-BST-2 binding, thereby promoting more efficient BST-2 downregulation and protection from BST-2-dependent Fc-mediated responses. Hence, our findings indicate that BST-2 antagonism represents a selective pressure shaping the evolution of SARS-CoV-2.

Because ADCC and ADCP are key processes for clearing viral infections, we tested a BST2-like factor (art-tetherin) composed of domains from different proteins that recapitulate BST-2’s topology, subcellular distribution and virion-tethering activity, while diverging at the primary sequence so viruses cannot antagonize art-tetherin. art-tetherin restricted virion release across ancestral and recent strains with comparable efficiency and reinstated the susceptibility of VOC-infected cells to ADCC and ADCP.

Collectively, these data establish BST-2 as a link between innate and adaptive immunity that exerts evolutionary pressure on SARS-CoV-2. Furthermore, our findings indicate that viral escape from BST-2 can be circumvented via synthetic tethering or by disabling Spike-mediated BST-2 downregulation. Hence, our results support that developing interventions to promote virion tethering will enhance immune clearance of SARS-CoV-2-infected cells across current and future VOC.

Upon recognition of viral infections, the innate immune system triggers signal transduction pathways that induce the expression of mRNAs encoding antiviral factors, such as interferons (IFNs), IFN-stimulated genes (ISGs) and inflammatory cytokines. Regulation of cellular innate immune responses occurs at multiple levels, including nucleocytoplasmic trafficking of proteins and RNAs through the nuclear pore complex (NPC). Influenza A virus (IAV), like other RNA viruses, is susceptible to IFN-induced cellular responses. Consequently, IAV has developed multiple strategies to hijack the cellular machinery responsible for RNA and protein transport, thereby reducing host gene expression and suppressing antiviral responses. Here, we identified the tripartite motif containing 34 protein (TRIM34), an ISG member of the TRIM family, as a positive regulator of IAV replication in vitro. TRIM34 negatively modulates host gene expression and innate immune responses induced after viral infection in vitro and in vivo. Mechanistically, we show that TRIM34 interacts with nucleocytoplasmic transport factors, such as ribonucleic acid export 1 (RAE1) and nuclear pore complex protein 93 (Nup93), even in the absence of IAV infection. Remarkably, these TRIM34 interactions seem independent of TRIM34 E3 ubiquitin ligase activity, and affect the nuclear import of IFN-regulatory factor 3 (IRF3) and the nuclear export of host mRNAs encoding antiviral functions, without affecting the nuclear export of viral mRNAs, providing a likely mechanism by which TRIM34 dampens host innate immune responses. Such regulatory mechanisms are critical to avoid excessive or prolonged immune activation, which can be detrimental to the host. In addition, these TRIM34-mediated effects could be further exploited to develop new antiviral drugs against IAV and potentially other viral infections, as its activity is not restricted to IAV infections.

Background: Recessive deficiency in 2’,5’-oligoadenylate (2-5A) synthetase (OAS) or RNase L can underlie multisystem inflammatory syndrome associated with SARS-CoV-2 infection in children without pneumonia. In adult COVID-19 patients, common genetic variants at the OAS locus were associated with hypoxemic pneumonia. Since the role of OAS in respiratory pathology versus inflammation remains unclear, we investigated OAS variants found in adult COVID-19 patients.

Methods: We analyzed the association of rare OAS1 and OAS3 variants and the common OAS1 rs10774671 polymorphism with clinical severity in 342 COVID-19 patients. We assessed OAS enzymatic activity and RNase L activation by SARS-CoV-2 or synthetic dsRNA, and the impact of gene gain/loss-of-function on viral replication and inflammation. The latter effects were also studied in Oas3^-/- mice challenged with dsRNA or mouse-adapted SARS-CoV-2.

Findings: Nine OAS1 and 15 OAS3 heterozygous variants were predicted to be deleterious. Although several variants displayed defective RNase L activation in response to SARS-CoV-2 or dsRNA, enrichment analysis showed no clear association with COVID-19 pneumonia. However, the OAS1 rs10774671 A/A genotype (OAS1-p42 isoform) was correlated with severe disease. Overexpression of OAS3 and OAS1-p46 isoforms attenuated viral replication in cellular systems, while OAS1-p42 reduced this effect. OAS3 and OAS1-p46 limited inflammatory response, and Oas3-deficiency in mice increased cytokine expression.

Interpretation: OAS1 rs10774671 A/A genotype impaired viral control, despite preserving RNase L activation, and predominated in severe COVID-19 patients. Conversely, heterozygous rare loss-of-function OAS1 and OAS3 variants appeared unrelated to respiratory disease severity, but they may compromise a regulatory mechanism that fine-tunes the control of inflammation.

Acute myeloid leukemia (AML) is the most common leukemia in adults. It is a malignant disease of myeloid hematopoietic stem/progenitor cells, characterized by a high rate of recurrence and mortality. Therefore, more effective therapies are urgently needed. Among the emerging treatment options, oncolytic viruses (OVs)—viruses that selectively replicate in cancer cells and stimulate the patient’s immune system—have recently gained attention. We developed an OV based on Herpes Simplex Virus type I (oHSV-1 mCherry) due to its large genome capacity for genetic insertion, broad tropism, and previously demonstrated antitumor effects in solid tumors. This virus was tested in two human AML cell lines (OCI-AML3 and MV-4-11), demonstrating its ability to infect leukemia cells and effectively induce their death.

However, delivering the desired OV to the bone marrow, the primary site of leukemia proliferation, remains a significant challenge. To overcome this, we propose using human monocytes as carrier cells for oHSV-1, leveraging their natural tropism for cancer cells, ease of isolation, and ability to home to multiple body compartments. We assessed the capacity of human monocytes to deliver oHSV-1 mCherry to AML cells and found that they significantly reduced leukemia cell viability. Moreover, through the use of a migration assay, we confirmed the natural tropism of primary human monocytes for leukemia cells.

Our data suggest that HSV-1-based oncolytic viruses represent a promising therapeutic approach for acute myeloid leukemia (AML), and that human monocytes can efficiently serve as carrier cells, enabling the viruses to reach the tumor microenvironment.

Viruses exhibit remarkable diversity in genome size, ranging from compact RNA genomes of a few kilobases to large DNA or RNA genomes exceeding 30 kilobases. The genome size not only dictates the coding capacity and complexity of viral replication strategies but also influences viral interactions during coinfection. In particular, competition between small- and large-genome viruses within the same host environment has emerged as a key theme in understanding viral pathogenesis and evolution. This study highlights the contrasting interactions of small-genome viruses, such as Newcastle disease virus (NDV) and Influenza A virus (IAV), with large-genome viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human papillomavirus type 1 (HPV-1). While SARS-CoV-2 and HPV-1 possess expansive coding repertoires enabling modulation of host immune pathways and long-term persistence, NDV and IAV rely on streamlined genomes that drive rapid replication and acute pathogenicity. Evidence suggests that during coinfection, small-genome viruses often outcompete larger-genome viruses at the replication level, due to faster life cycles and higher burst sizes. Conversely, large-genome viruses employ sophisticated immune evasion mechanisms and host-cell reprogramming to sustain infection, which may suppress or delay replication of smaller competitors. These dynamics underscore the balance between replication efficiency and immune modulation as central determinants of viral dominance. Understanding these competitive interactions is crucial for predicting disease outcomes in natural coinfections and for harnessing oncolytic or vaccine-based applications, where deliberate viral interference may be advantageous. By integrating comparative virology with host–pathogen interaction studies, we propose that genome size serves as a fundamental parameter shaping viral competition, persistence, and pathogenesis. These insights provide a framework for future investigations into mixed viral infections and their implications for public health and therapeutic strategies.

The Alphavirus chikungunya (CHIKV) is an arbovirus that belongs to the Togaviridae family and causes Chikungunya Fever (CHIKF). As a member of the Alphavirus genus, CHIKV is an arthritogenic virus that causes severe polyarthritis and myalgia along with symptoms like fever, rash and headaches. Following the Kenyan epidemic in 2004, CHIKV has spread to the Indian Ocean Islands and reached Europe, drawing global attention. In 2014, CHIKV reached South America, establishing reemergent outbreaks. Anti-inflammatory drugs and analgesics are the mainstay of treatment for symptomatic relief in infected patients. However, no clinically approved virus-specific drugs are available for CHIKV infection. In this context, plant-derived compounds arise as alternatives for drug research, given its large availability in nature. Our research group has already demonstrated that a glycosylated lignan (GL) from Phyllanthus brasiliensis has antiviral activity against CHIKV and other arboviruses. Therefore, in aiming to describe the GL mechanism of action, we conducted a series of experiments, targeting different moments of the viral infection cycle. First, we evaluated whether the GL can affect the structure of CHIKV particles and their ability to attach cell membranes through a virucidal and adsorption assay, respectively. Both experiments did not demonstrate significance. Thereafter, we conducted an internalization and post-infection assay to measure if the GL could inhibit viral entry and intracellular steps of the CHIKV infectious cycle. Both assays demonstrated significance (p<0,05). Considering that the GL reduced the CHIKV titer in the initial hours after compound addition, we propose that GL acts in the initial steps in the CHIKV infectious cycle, comprising stages between endocytosis and viral replication. These results demonstrate the ability of GL from P. brasiliensis to inhibit CHIKV replication, hinting at its potential to be used as a starting scaffold for further development of antivirals against CHIKF.

CCR5 acts as a co-receptor for R5-tropic human immunodeficiency virus or HIV type 1 infection. Decreasing CCR5 surface expression correlates with reduction in HIV infectivity of susceptible cells. The fundamental role of CCR5 in R5-tropic HIV infection and the few case reports of HIV cure following CCR5delta32 donor cell transplantation buttresses the continued need to investigate the regulation of CCR5 gene expression. Individuals who are homozygous for CCR5delta32 are quite resistant to HIV infection. We report here that the CCR5 3’-untranslated region or UTR region of its mRNA, which is >twice the length of the average 3’-UTR, plays a critical role in post-transcriptional gene regulation of the human CCR5 gene. Post-transcriptional mRNA regulation impacts gene function by affecting mRNA maturation, transport, and stability. Here, we demonstrate that the CCR5 3’-UTR reduced protein expression >25-fold when inserted downstream of a CMV-driven reporter and transfected into activated primary human CD4+ T cells. We also show that hnRNPA0 and hnRNPDL proteins bind to the CCR5 3’-UTR and that genomic knockout of the CCR5 3’-UTR and heteroribonucleoproteins or hnRNPs hnRNPA0, hnRNPDL, and RALY upregulated CCR5 gene expression. KO of the 3'-UTR of CCR5 increased its RNA levels in both the nucleus and cytosol. If CCR5 could somehow be down-regulated post-transcriptionally, this could have a profound impact on HIV cure efforts.

The alphaviruses Chikungunya (CHIKV) and Mayaro (MAYV) are responsible for acute febrile illnesses, often accompanied by severe and persistent joint and muscle pain. Due to the lack of specific treatment, research into antivirals against these emerging viruses is seen as an urgent need. Previous studies demonstrated that silymarin exhibits potent antiviral activity against CHIKV and MAYV. Here, we evaluate the effects of silymarin in an animal model of alphavirus-induced arthritis and myositis. For this, BALB/c mice were infected with CHIKV or MAYV in the right hind paw pad. The treated groups received silymarin orally (200 mg/kg/day). Animals were monitored daily for 21 days to assess clinical progression. At 7- and 12-days post-infection (dpi), the animals were euthanized and various tissues collected (liver, spleen, paws, quadriceps, extensor digitorum longus, tibial and soleus muscles) for virological and histopathological analyses. Clinical observation revealed reduced paw edema in silymarin-treated animals. In infected and treated animals, the CHIKV viral load was reduced in the spleen (7 and 12dpi), paw (7dpi), soleus muscle, and liver (12dpi). For MAYV, viral load decreased in the spleen (7 and 12dpi), liver, quadriceps, soleus muscle (7dpi), and paw (12dpi). Histological analysis revealed decreased inflammatory infiltrates in the liver, paw, and muscles, as well as reduced number and area of lymphoid nodules in the spleen (12dpi). Additionally, silymarin treatment reduced TNF-α levels in the paw (7 and 12dpi) and quadriceps (12dpi). Then, we concluded that silymarin not only limits viral replication but also mitigates inflammation in various tissues, including muscles and joints, supporting its therapeutic potential against Chikungunya and Mayaro fevers.

Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are oncogenic gammaherpesviruses with biphasic lifecycles. Both can reactivate from latency in response to various stimuli. In sub-Saharan Africa, EBV and KSHV prevalence is high, often obscured by co-infections such as HIV, tuberculosis, and, more recently, SARS-CoV-2.

SARS-CoV-2, the causative agent of COVID-19, has caused substantial morbidity in SA. Its dysregulated immune responses, including cytokine storms, may trigger the reactivation of latent viruses. Both EBV and KSHV have been reported to reactivate in severe COVID-19 cases, exacerbating outcomes.

Given their reactivation potential in immunocompromised individuals, we investigated EBV/KSHV dynamics in 407 non-hospitalized people living with HIV during the COVID-19 pandemic. To further study the viruses’ interaction, a tissue-culture-based system was established using EBV latently infected cell lines (Raji, Namalwa, IARC-171, AGS-EBV) and EBV-KSHV dually infected BC-1 cells. Cultures were then exposed to chemical stimulants, SARS-CoV-2 pseudovirus and a COVID-19 “cytokine cocktail”. Reactivation was quantified via real-time qPCR.

Clinically, EBV viral load (VL) was detectable in 97.0% of patients, with 12.4% exhibiting elevated VL (≥1×10^5 copies/10^6 cells). In contrast, KSHV VL was detectable in only 21% of patients. SARS-CoV-2 exposure and COVID-19 vaccination did not significantly influence EBV reactivation; however, KSHV reactivation increased post-SARS-CoV-2 exposure in unvaccinated individuals. Logistic regression confirmed higher odds of KSHV reactivation in previously SARS-CoV-2-exposed patients and in patients with elevated EBV VL.

In vitro, SARS-CoV-2 infection did not induce EBV or KSHV reactivation in the tested cell lines. These findings warrant further investigation into whether the SARS-CoV-2-induced cytokine storm contributes to EBV or KSHV reactivation.

Our in vitro studies support the clinical observations that EBV and KSHV reactivation is unlikely to be driven by SARS-CoV-2 itself, but rather results from the dysregulated inflammatory response. This may have long-term percussions for gammaherpesvirus-associated tumorigenesis outlasting the pandemic.