Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA) and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been ...shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil) and diets supplemented with ω-3 PUFA (corn oil+fish oil) for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection-induced responses resulting in sepsis. We conclude that as an anti-inflammatory agent, ω-3 PUFA supplementation during infection may prove detrimental when host inflammatory responses are critical for survival.
The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. ...Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.
Abstract
Background
There has been a shift in recent years to using ultrasound (US) and magnetic resonance imaging (MRI) as first-line investigations for suspected cranial large vessel vasculitis ...(LVV) and is a new recommendation by the EULAR 2018 guidelines for imaging in LVV. This cross-sectional study compares the performance of US and MRI and contrast-enhanced magnetic resonance angiography (MRA) for detecting vasculitis in patients with giant cell arteritis (GCA).
Methods
Patients with new-onset or already diagnosed GCA were recruited. The common temporal arteries and supra-aortic large vessels were evaluated by US and MRI/MRA. Blinded experts read the images and applied a dichotomous score (vasculitis: yes/no) in each vessel.
Results
Thirty-seven patients with giant cell arteritis (GCA) were recruited. Two patients were excluded. Of the remaining patients, nine had new-onset disease and 26 had established disease. Mean age was 71 years, and median C-reactive protein (CRP) was 7.5 mg/L. The median time between US and MRI was 1 day. Overall, US revealed vasculitic changes more frequently than MRI (
p
< 0.001). US detected vascular changes in 37% of vessels compared to 21% with MRI. Among patients with chronic disease, US detected vascular changes in 23% of vessels compared to 7% with MRI in (
p
< 0.001). The same was true for patients with new-onset disease. US detected vasculitic changes in 22% of vessels and MRI detected disease in 6% (
p
= 0.0004). Compared to contrast-enhanced MRA, US was more sensitive in detecting vasculitic changes in the large arteries, including the axillary, carotid, and subclavian arteries.
Conclusion
US more frequently detects vasculitic changes in the large arteries compared to contrast-enhanced MRA. When evaluating the cranial vessels, US performs similarly to MRI. This data supports the recommendation that US be considered as a first-line evaluation in patients suspected to have GCA.
•Influenza A virus (IAV) has contributed to multiple pandemics for decades.•Antiviral resistance and immune evasion have become more common over time.•Drug repositioning is a valuable and effective ...means against the IAV.•Various antiviral and vaccination strategies are vital to contain the spread of IAV.•Evolution of IAV holds a critical significance amid the global COVID-19 outbreak.
Influenza virus infection, more commonly known as the ‘cold flu’, is an etiological agent that gives rise to recurrent annual flu and many pandemics. Dated back to the 1918- Spanish Flu, the influenza infection has caused the loss of many human lives and significantly impacted the economy and daily lives. Influenza virus can be classified into four different genera: influenza A-D, with the former two, influenza A and B, relevant to humans. The capacity of antigenic drift and shift in Influenza A has given rise to many novel variants, rendering vaccines and antiviral therapies useless. In light of the emergence of a novel betacoronavirus, the SARS-CoV-2, unravelling the underpinning mechanisms that support the recurrent influenza epidemics and pandemics is essential. Given the symptom similarities between influenza and covid infection, it is crucial to reiterate what we know about the influenza infection. This review aims to describe the origin and evolution of influenza infection. Apart from that, the risk factors entail the implication of co-infections, especially regarding the COVID-19 pandemic is further discussed. In addition, antiviral strategies, including the potential of drug repositioning, are discussed in this context. The diagnostic approach is also critically discussed in an effort to understand better and prepare for upcoming variants and potential influenza pandemics in the future. Lastly, this review encapsulates the challenges in curbing the influenza spread and provides insights for future directions in influenza management.
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The interleukin-1 family member IL-33 participates in both innate and adaptive T helper-2 immune cell responses in models of lung disease. The IL-6-type cytokine Oncostatin M (OSM) elevates lung ...inflammation, Th2-skewed cytokines, alternatively activated (M2) macrophages, and eosinophils in C57Bl/6 mice in vivo. Since OSM induces IL-33 expression, we here test the IL-33 function in OSM-mediated lung inflammation using IL-33-/- mice. Adenoviral OSM (AdOSM) markedly induced IL-33 mRNA and protein levels in wild-type animals while IL-33 was undetectable in IL-33-/- animals. AdOSM treatment showed recruitment of neutrophils, eosinophils, and elevated inflammatory chemokines (KC, eotaxin-1, MIP1a, and MIP1b), Th2 cytokines (IL-4/IL-5), and arginase-1 (M2 macrophage marker) whereas these responses were markedly diminished in IL-33-/- mice. AdOSM-induced IL-33 was unaffected by IL-6-/- deficiency. AdOSM also induced IL-33R+ ILC2 cells in the lung, while IL-6 (AdIL-6) overexpression did not. Flow-sorted ILC2 responded in vitro to IL-33 (but not OSM or IL-6 stimulation). Matrix remodelling genes col3A1, MMP-13, and TIMP-1 were also decreased in IL-33-/- mice. In vitro, IL-33 upregulated expression of OSM in the RAW264.7 macrophage cell line and in bone marrow-derived macrophages. Taken together, IL-33 is a critical mediator of OSM-driven, Th2-skewed, and M2-like responses in mouse lung inflammation and contributes in part through activation of ILC2 cells.
Resistin-like molecule alpha (RELMα) and YM-1 are secreted proteins implicated in murine models of alternatively activated macrophage (AA/M2) accumulation and Th2-skewed inflammation. Since the gp130 ...cytokine Oncostatin M (OSM) induces a Th2-like cytokine and AA/M2 skewed inflammation in mouse lung, we here investigated regulation of RELMα and YM-1. Transient pulmonary overexpression of OSM by Adenovirus vector (AdOSM) markedly induced RELMα and YM-1 protein expression in total lung. In situ hybridization showed that RELMα mRNA was highly induced in airway epithelial cells (AEC) and was co-expressed with CD68 mRNA in some but not all CD68+ cells in parenchyma. IL-6 overexpression (a comparator gp130 cytokine) induced RELMα, but at significantly lower levels. IL-6 (assessing IL-6
mice) was not required, nor was STAT6 (IL-4/13 canonical signalling) for AdOSM-induction of RELMα in AEC. AEC responded directly to OSM in vitro as assessed by pSTAT3 activation. RELMα-deficient mice showed similar inflammatory cell infiltration and cytokine responses to wt in response to AdOSM, but showed less accumulation of CD206+ AA/M2 macrophages, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, and TIMP1, and reduced parenchymal alpha smooth muscle actin. Thus, RELMα is regulated by OSM in AEC and contributes to extracellular matrix remodelling in mouse lung.
Molnupiravir is a β-d-N4-hydroxycytidine-5′-isopropyl ester (NHC) compound that exerts antiviral activity against various RNA viruses such as influenza, SARS, and Ebola viruses. Thus, the repurposing ...of Molnupiravir has gained significant attention for combatting infection with SARS-CoV-2, the etiological agent of COVID-19. Recently, Molnupiravir was granted authorization for the treatment of mild-to-moderate COVID-19 in adults. Findings from in vitro experiments, in vivo studies and clinical trials reveal that Molnupiravir is effective against SARS-CoV-2 by inducing viral RNA mutagenesis, thereby giving rise to mutated complementary RNA strands that generate non-functional viruses. To date, the data collectively suggest that Molnupiravir possesses promising antiviral activity as well as favorable prophylactic efficacy, attributed to its effective mutagenic property of disrupting viral replication. This review discusses the mechanisms of action of Molnupiravir and highlights its clinical utility by disabling SARS-CoV-2 replication, thereby ameliorating COVID-19 severity. Despite relatively few short-term adverse effects thus far, further detailed clinical studies and long-term pharmacovigilance are needed in view of its mutagenic effects.
The family of Suppressor of Cytokine Signalling (SOCS) proteins plays pivotal roles in cytokine and immune regulation. Despite their key roles, little attention has been given to the SOCS family as ...compared to other feedback regulators. To date, SOCS proteins have been found to be exploited by viruses such as herpes simplex virus (HSV), hepatitis B virus (HBV), hepatitis C virus (HCV), Zika virus, respiratory syncytial virus (RSV), Ebola virus, influenza A virus (IAV) and SARS-CoV, just to name a few. The hijacking and subsequent upregulation of the SOCS proteins upon viral infection, suppress the associated JAK-STAT signalling activities, thereby reducing the host antiviral response and promoting viral replication. Two SOCS protein family members, SOCS1 and SOCS3 are well-studied and their roles in the JAK-STAT signalling pathway are defined as attenuating interferon (IFN) signalling upon viral infection. The upregulation of SOCS protein by SARS-CoV during the early stages of infection implies strong similarity with SARS-CoV-2, given their closely related genomic organisation. Thus, this review aims to outline the plausibility of SOCS protein inhibitors as a potential therapeutic regimen for COVID-19 patients. We also discuss the antagonists against SOCS protein to offer an overview on the previous 'successes' of SOCS protein inhibition in various viral infections that may portray possible clues for COVID-19 disease management.
Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute ...respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.
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