Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease.

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

Congenital Zika virus infection impacts on male mouse offspring's reproductive biology.

In brief: Congenital ZIKV infection promotes alarming effects on male offspring's reproductive biology. This study showed the presence of the ZIKV antigen in the testis parenchyma, decreased testosterone levels, and sperm abnormalities in male offspring born to infected mothers. Abstract: Infection with ZIKV during pregnancy is associated with fetal developmental problems. Although neurological issues are being explored more in experimental studies, limited research has focused on the reproductive health consequences for offspring born to infected mothers. In this context, this study aimed to assess the impact of ZIKV infection during pregnancy on the testes and sperm of adult male offspring. Female mice were intraperitoneally inoculated with a Brazil strain of ZIKV during the 5.5th day of embryonic gestation. The offspring were evaluated 12 weeks after birth to analyze cellular and molecular changes in the testes and sperm. A novel approach combining variable-angle spectroscopic ellipsometry and machine learning modeling was also introduced for sperm sample analysis. The study revealed the presence of ZIKV protein in the testis parenchyma of adult male offspring born to infected mothers. It was shown that the testes exhibited altered steroidogenesis and inflammatory mediators, in addition to significant issues with spermiogenesis that resulted in sperm with DNA fragmentation, head defects, and protamination failure. Additionally, sperm dielectric properties and artificial intelligence showed potential for rapid identification and classification of sperm samples from infected mice. These findings provide crucial insights into the reproductive risks for men born from ZIKV-infected pregnant women.

Tumour necrosis factor plays a deleterious role in the pathogenesis of chikungunya virus infection.

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1-/- ) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time-points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1-/- mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV-induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV-infected patients and that TNF inhibitors should ideally be used in combination with anti-viral drugs.

TNF/iNOS/NO pathway mediates host susceptibility to endothelial-dependent circulatory failure and death induced by betacoronavirus infection.

Poor disease outcomes and lethality are directly related to endothelial dysfunction in betacoronavirus infections. Here, we investigated the mechanisms underlying the vascular dysfunction caused by the betacoronaviruses MHV-3 and SARS-CoV-2. Wild-type C57BL/6 (WT) and knockout mice for inducible nitric oxide synthase (iNOS-/-) or TNF receptor 1 (TNFR1-/-) were infected with MHV-3, and K18-hACE2 transgenic mice expressing human ACE2 were infected with SARS-CoV-2. Isometric tension was used to evaluate vascular function. Protein expression was determined by immunofluorescence. Tail-cuff plethysmography and Doppler were used to assess blood pressure and flow, respectively. Nitric oxide (NO) was quantified with the DAF probe. ELISA was used to assess cytokine production. Survival curves were estimated using Kaplan-Meier. MHV-3 infection reduced aortic and vena cava contractility, arterial blood pressure, and blood flow, resulting in death. Resistance mesenteric arteries showed increased contractility. The contractility of the aorta was normalized by removing the endothelium, inhibiting iNOS, genetically deleting iNOS, or scavenging NO. In the aorta, iNOS and phospho-NF-kB p65 subunit expression was enhanced, along with basal NO production. TNF production was increased in plasma and vascular tissue. Genetic deletion of TNFR1 prevented vascular changes triggered by MHV-3, and death. Basal NO production and iNOS expression were also increased by SARS-CoV-2. In conclusion, betacoronavirus induces an endothelium-dependent decrease in contractility in macro-arteries and veins, leading to circulatory failure and death via TNF/iNOS/NO. These data highlight the key role of the vascular endothelium and TNF in the pathogenesis and lethality of coronaviruses.

A suitable model to investigate acute neurological consequences of coronavirus infection.

OBJECTIVE AND DESIGN: The present study aimed to investigate the neurochemical and behavioral effects of the acute consequences after coronavirus infection through a murine model. MATERIAL: Wild-type C57BL/6 mice were infected intranasally (i.n) with the murine coronavirus 3 (MHV-3). METHODS: Mice underwent behavioral tests. Euthanasia was performed on the fifth day after infection (5 dpi), and the brain tissue was subjected to plaque assays for viral titration, ELISA, histopathological, immunohistochemical and synaptosome analysis. RESULTS: Increased viral titers and mild histological changes, including signs of neuronal degeneration, were observed in the cerebral cortex of infected mice. Importantly, MHV-3 infection induced an increase in cortical levels of glutamate and calcium, which is indicative of excitotoxicity, as well as increased levels of pro-inflammatory cytokines (IL-6, IFN-γ) and reduced levels of neuroprotective mediators (BDNF and CX3CL1) in the mice brain. Finally, behavioral analysis showed impaired motor, anhedonia-like and anxiety-like behaviors in animals infected with MHV-3. CONCLUSIONS: In conclusion, the data presented emulate many aspects of the acute neurological outcomes seen in patients with COVID-19. Therefore, this model may provide a preclinical platform to study acute neurological sequelae induced by coronavirus infection and test possible therapies.

A Biosafety Level 2 Mouse Model for Studying Betacoronavirus-Induced Acute Lung Damage and Systemic Manifestations.

The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1ß), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.

cis-Aconitic Acid, a Constituent of Echinodorus grandiflorus Leaves, Inhibits Antigen-Induced Arthritis and Gout in Mice.

cis-Aconitic acid is a constituent from the leaves of Echinodorus grandiflorus, a medicinal plant traditionally used in Brazil to treat inflammatory conditions, including arthritic diseases. The present study aimed to investigate the anti-arthritic effect of cis-aconitic acid in murine models of antigen-induced arthritis and monosodium urate-induced gout. The possible underlying mechanisms of action was evaluated in THP-1 macrophages. Oral treatment with cis-aconitic acid (10, 30, and 90 mg/kg) reduced leukocyte accumulation in the joint cavity and C-X-C motif chemokine ligand 1 and IL-1ß levels in periarticular tissue. cis-Aconitic acid treatment reduced joint inflammation in tissue sections of antigen-induced arthritis mice and these effects were associated with decreased mechanical hypernociception. Administration of cis-aconitic acid (30 mg/kg p. o.) also reduced leukocyte accumulation in the joint cavity after the injection of monosodium urate crystals. cis-Aconitic acid reduced in vitro the release of TNF-α and phosphorylation of IκBα in lipopolysaccharide-stimulated THP-1 macrophages, suggesting that inhibition of nuclear factor kappa B activation was an underlying mechanism of cis-aconitic acid-induced anti-inflammatory effects. In conclusion, cis-aconitic acid has significant anti-inflammatory effects in antigen-induced arthritis and monosodium urate-induced arthritis in mice, suggesting its potential for the treatment of inflammatory diseases of the joint in humans. Additionally, our findings suggest that this compound may contribute to the anti-inflammatory effect previously reported for E. grandiflorus extracts.

Host target-based approaches against arboviral diseases.

In the 20th century, socioeconomic and environmental changes facilitated the reintroduction of mosquitoes in developing cities, resulting in the reinsertion of mosquito-borne viral diseases and the dispersal of their causative agents on a worldwide scale. Recurrent outbreaks of arboviral diseases are being reported, even in regions without a previous history of arboviral disease transmission. Of note, arboviral infections represented approximately 30% of all emerging vector-borne diseases in the last decade. Therapeutic strategies against infectious viral diseases include the use of different classes of molecules that act directly on the pathogen and/or act by optimizing the host immune response. Drugs targeting the virus usually provide amelioration of symptoms by suppressing and controlling the infection. However, it is limited by the short-window of effectiveness, ineffectiveness against latent viruses, development of drug-resistant mutants and toxic side effects. Disease may also be a consequence of an excessive, uncontrolled or misplaced inflammatory response, treatments that interfere in host immune response are interesting options and can be used isolated or in combination with virus-targeted therapies. The use of host-targeted therapies requires specific knowledge regarding host immune patterns that may trigger dengue virus (DENV), chikungunya virus (CHIKV) or Zika virus (ZIKV) disease.

Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection.

Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted mass spectrometry-based serum metabolic profiling from a model using humanized mice (humice) with DENV serotype 2 infection at 0, 3, 7, 14, and 28 days postinfection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acids and derivatives, free fatty acids, and bile acid. These metabolites showed a reversible-change trend-most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that the metabolites might serve as prognostic markers of the disease in humice. The major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid ß-oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, and bile acid biosynthesis. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses to DENV infection between humice and humans and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.IMPORTANCE Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. There is currently no effective treatment for the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small-molecule metabolites and is a useful tool for finding metabolic pathways related to disease processes. Here, we conducted a serum metabolomics study on a model using humanized mice with dengue infection that had significant levels of human platelets, monocytes/macrophages, and hepatocytes. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways found to be altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.

Effect of the Hydroethanolic Extract from Echinodorus grandiflorus Leaves and a Fraction Enriched in Flavone-C-Glycosides on Antigen-Induced Arthritis in Mice.

The leaves of Echinodorus grandiflorus are traditionally used in Brazil to treat several inflammatory conditions, including arthritis. This study aimed to investigate the antiarthritis activity of the 70% ethanol extract of E. grandiflorus leaves and a standardized flavonoid-rich fraction in an antigen-induced arthritis model in mice. Previously immunized mice were treated per os with saline (control group), 70% ethanol extract (100-1000 mg/kg), or a flavonoid-rich fraction (0.7-7.2 mg/kg) 40 minutes before and 3 and 6 hours after the challenge with antigen into the knee joint. The administration of the 70% ethanol extract and flavonoid-rich fraction to mice significantly reduced neutrophil recruitment to the joint cavity and in periarticular tissue. The levels of chemokine (C-X-C motif) ligand 1, tumor necrosis factor-α, and interleukin-1ß quantified by the enzyme-linked immunosorbent assay (ELISA) in the periarticular tissue were also diminished in mice treated with the 70% ethanol extract and flavonoid-rich fraction, as well as mechanical hypernociception. Histological analysis confirmed that both the 70% ethanol extract and flavonoid-rich fraction suppressed joint inflammation and inhibited cartilage and bone destruction when compared to the control group. Our results demonstrate, for the first time, that E. grandiflorus has anti-inflammatory activity in an experimental arthritis model and highlights the role of flavonoids in the observed response.

Inflammatory and innate immune responses in dengue infection: protection versus disease induction.

Dengue disease is a mosquito-borne viral disease of expanding geographical range and incidence. Infection by one of the four serotypes of dengue virus induces a spectrum of disease manifestations, ranging from asymptomatic to life-threatening Dengue hemorrhagic fever/dengue shock syndrome. Many efforts have been made to elucidate several aspects of dengue virus-induced disease, but the pathogenesis of disease is complex and remains unclear. Understanding the mechanisms involved in the early stages of infection is crucial to determine and develop safe therapeutics to prevent the severe outcomes of disease without interfering with control of infection. In this review, we discuss the dual role of the innate and inflammatory pathways activated during dengue disease in mediating both protection and exacerbation of disease. We show that some mediators involved in each of these responses differ substantially, suggesting that interfering in disease-associated immune pathways may represent a potential therapeutic opportunity for the treatment of severe dengue.

Special Issue "Viral-Induced Inflammation".

Inflammation is a protective host response essential for controlling viral replication and promoting tissue repair [...].

Resolution pharmacology and the treatment of infectious diseases.

Inflammation is elicited by the host in response to microbes, and is believed to be essential for protection against infection. However, we have previously hypothesized that excessive or misplaced inflammation may be a major contributor to tissue dysfunction and death associated with viral and bacterial infections. The resolutive phase of inflammation is a necessary condition to achieve homeostasis after acute inflammation. It is possible that targeting inflammation resolution may be beneficial for the host during infection. In this review, we summarize the evidence demonstrating the expression, roles and effects of the best described pro-resolving molecules in the context of bacterial and viral infections. Pro-resolving molecules play a pivotal role in modulating a spectrum of pathways associated with tissue inflammation and damage during both viral and bacterial infections. These molecules offer a blend of anti-inflammatory, pro-resolving and sometimes anti-infective benefits, all the while circumventing the undesired and immune-suppressive unwanted effects associated with glucocorticoids. Whether these beneficial effects will translate into benefits to patients clearly deserve further investigation.

The glycosaminoglycan-binding chemokine fragment CXCL9(74-103) reduces inflammation and tissue damage in mouse models of coronavirus infection.

Introduction: Pulmonary diseases represent a significant burden to patients and the healthcare system and are one of the leading causes of mortality worldwide. Particularly, the COVID-19 pandemic has had a profound global impact, affecting public health, economies, and daily life. While the peak of the crisis has subsided, the global number of reported COVID-19 cases remains significantly high, according to medical agencies around the world. Furthermore, despite the success of vaccines in reducing the number of deaths caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there remains a gap in the treatment of the disease, especially in addressing uncontrolled inflammation. The massive recruitment of leukocytes to lung tissue and alveoli is a hallmark factor in COVID-19, being essential for effectively responding to the pulmonary insult but also linked to inflammation and lung damage. In this context, mice models are a crucial tool, offering valuable insights into both the pathogenesis of the disease and potential therapeutic approaches. Methods: Here, we investigated the anti-inflammatory effect of the glycosaminoglycan (GAG)-binding chemokine fragment CXCL9(74-103), a molecule that potentially decreases neutrophil transmigration by competing with chemokines for GAG-binding sites, in two models of pneumonia caused by coronavirus infection. Results: In a murine model of betacoronavirus MHV-3 infection, the treatment with CXCL9(74-103) decreased the accumulation of total leukocytes, mainly neutrophils, to the alveolar space and improved several parameters of lung dysfunction 3 days after infection. Additionally, this treatment also reduced the lung damage. In the SARS-CoV-2 model in K18-hACE2-mice, CXCL9(74-103) significantly improved the clinical manifestations of the disease, reducing pulmonary damage and decreasing viral titers in the lungs. Discussion: These findings indicate that CXCL9(74-103) resulted in highly favorable outcomes in controlling pneumonia caused by coronavirus, as it effectively diminishes the clinical consequences of the infections and reduces both local and systemic inflammation.

siRNA lipid nanoparticles for CXCL12 silencing modulate brain immune response during Zika infection.

CXCL12 is a key chemokine implicated in neuroinflammation, particularly during Zika virus (ZIKV) infection. Specifically, CXCL12 is upregulated in circulating cells of ZIKV infected patients. Here, we developed a lipid nanoparticle (LNP) to deliver siRNA in vivo to assess the impact of CXCL12 silencing in the context of ZIKV infection. The biodistribution of the LNP was assessed in vivo after intravenous injection using fluorescently tagged siRNA. Next, we investigated the ability of the developed LNP to silence CXCL12 in vivo and assessed the resulting effects in a murine model of ZIKV infection. The LNP encapsulating siRNA significantly inhibited CXCL12 levels in the spleen and induced microglial activation in the brain during ZIKV infection. This activation was evidenced by the enhanced expression of iNOS, TNF-α, and CD206 within microglial cells. Moreover, T cell subsets exhibited reduced secretion of IFN-É£ and IL-17 following LNP treatment. Despite no observable alteration in viral load, CXCL12 silencing led to a significant reduction in type-I interferon production compared to both ZIKV-infected and uninfected groups. Furthermore, we found grip strength deficits in the group treated with siRNA-LNP compared to the other groups. Our data suggest a correlation between the upregulated pro-inflammatory cytokines and the observed decrease in strength. Collectively, our results provide evidence that CXCL12 silencing exerts a regulatory influence on the immune response in the brain during ZIKV infection. In addition, the modulation of T-cell activation following CXCL12 silencing provides valuable insights into potential protective mechanisms against ZIKV, offering novel perspectives for combating this infection.

Experimental arthritis triggers periodontal disease in mice: involvement of TNF-α and the oral Microbiota.

Rheumatoid arthritis (RA) and periodontal disease (PD) are prevalent chronic inflammatory disorders that affect bone structures. Individuals with RA are more likely to experience PD, but how disease in joints could induce PD remains unknown. This study aimed to experimentally mimic clinical parameters of RA-induced PD and to provide mechanistic findings to explain this association. Chronic Ag-induced arthritis (AIA) was triggered by injection of methylated BSA in the knee joint of immunized mice. Anti-TNF-α was used to assess the role of this cytokine. Intra-articular challenge induced infiltration of cells, synovial hyperplasia, bone resorption, proteoglycan loss, and increased expression of cytokines exclusively in challenged joints. Simultaneously, AIA resulted in severe alveolar bone loss, migration of osteoclasts, and release of proinflammatory cytokines in maxillae. Anti-TNF-α therapy prevented the development of both AIA and PD. AIA did not modify bacterial counts in the oral cavity. PD, but not AIA, induced by injection of Ag in immunized mice was decreased by local treatment with antiseptic, which decreased the oral microbiota. AIA was associated with an increase in serum C-reactive protein levels and the expression of the transcription factors RORγ and Foxp3 in cervical lymph nodes. There were higher titers of anti-collagen I IgG, and splenocytes were more responsive to collagen I in AIA mice. In conclusion, AIA-induced PD was dependent on TNF-α and the oral microbiota. Moreover, PD was associated with changes in expression of lymphocyte transcription factors, presence of anti-collagen Abs, and increased reactivity to autoantigens.

The Multifaceted Role of Annexin A1 in Viral Infections.

Dysregulated inflammatory responses are often correlated with disease severity during viral infections. Annexin A1 (AnxA1) is an endogenous pro-resolving protein that timely regulates inflammation by activating signaling pathways that culminate with the termination of response, clearance of pathogen and restoration of tissue homeostasis. Harnessing the pro-resolution actions of AnxA1 holds promise as a therapeutic strategy to control the severity of the clinical presentation of viral infections. In contrast, AnxA1 signaling might also be hijacked by viruses to promote pathogen survival and replication. Therefore, the role of AnxA1 during viral infections is complex and dynamic. In this review, we provide an in-depth view of the role of AnxA1 during viral infections, from pre-clinical to clinical studies. In addition, this review discusses the therapeutic potential for AnxA1 and AnxA1 mimetics in treating viral infections.

Uncovering new insights into the role of the ubiquitin ligase Smurf1 on the regulation of innate immune signaling and resistance to infection.

Innate immunity is the body's first line of defense against infections. Innate immune cells express pattern recognition receptors in distinct cellular compartments that are responsible to detect either pathogens-associated molecules or cellular components derived from damaged cells, to trigger intracellular signaling pathways that lead to the activation of inflammatory responses. Inflammation is essential to coordinate immune cell recruitment, pathogen elimination and to keep normal tissue homeostasis. However, uncontrolled, misplaced or aberrant inflammatory responses could lead to tissue damage and drive chronic inflammatory diseases and autoimmunity. In this context, molecular mechanisms that tightly regulate the expression of molecules required for the signaling of innate immune receptors are crucial to prevent pathological immune responses. In this review, we discuss the ubiquitination process and its importance in the regulation of innate immune signaling and inflammation. Then, we summarize the roles of Smurf1, a protein that works on ubiquitination, on the regulation of innate immune signaling and antimicrobial mechanisms, emphasizing its substrates and highlighting its potential as a therapeutic target for infectious and inflammatory conditions.

Natural Products and Derivatives as Potential Zika virus Inhibitors: A Comprehensive Review.

Zika virus (ZIKV) is an arbovirus whose infection in humans can lead to severe outcomes. This article reviews studies reporting the anti-ZIKV activity of natural products (NPs) and derivatives published from 1997 to 2022, which were carried out with NPs obtained from plants (82.4%) or semisynthetic/synthetic derivatives, fungi (3.1%), bacteria (7.6%), animals (1.2%) and marine organisms (1.9%) along with miscellaneous compounds (3.8%). Classes of NPs reported to present anti-ZIKV activity include polyphenols, triterpenes, alkaloids, and steroids, among others. The highest values of the selectivity index, the ratio between cytotoxicity and antiviral activity (SI = CC50/EC50), were reported for epigallocatechin gallate (SI ≥ 25,000) and anisomycin (SI ≥ 11,900) obtained from Streptomyces bacteria, dolastane (SI = 1246) isolated from the marine seaweed Canistrocarpus cervicorni, and the flavonol myricetin (SI ≥ 862). NPs mostly act at the stages of viral adsorption and internalization in addition to presenting virucidal effect. The data demonstrate the potential of NPs for developing new anti-ZIKV agents and highlight the lack of studies addressing their molecular mechanisms of action and pre-clinical studies of efficacy and safety in animal models. To the best of our knowledge, none of the active compounds has been submitted to clinical studies.

Dietary Vitamin D Mitigates Coronavirus-Induced Lung Inflammation and Damage in Mice.

The COVID-19 pandemic caused by the SARS-CoV-2 (ß-CoV) betacoronavirus has posed a significant threat to global health. Despite the availability of vaccines, the virus continues to spread, and there is a need for alternative strategies to alleviate its impact. Vitamin D, a secosteroid hormone best known for its role in bone health, exhibits immunomodulatory effects in certain viral infections. Here, we have shown that bioactive vitamin D (calcitriol) limits in vitro replication of SARS-CoV-2 and murine coronaviruses MHV-3 and MHV-A59. Comparative studies involving wild-type mice intranasally infected with MHV-3, a model for studying ß-CoV respiratory infections, confirmed the protective effect of vitamin D in vivo. Accordingly, mice fed a standard diet rapidly succumbed to MHV-3 infection, whereas those on a vitamin D-rich diet (10,000 IU of Vitamin D3/kg) displayed increased resistance to acute respiratory damage and systemic complications. Consistent with these findings, the vitamin D-supplemented group exhibited lower viral titers in their lungs and reduced levels of TNF, IL-6, IL-1ß, and IFN-γ, alongside an enhanced type I interferon response. Altogether, our findings suggest vitamin D supplementation ameliorates ß-CoV-triggered respiratory illness and systemic complications in mice, likely via modulation of the host's immune response to the virus.