Catharine M. Bosio’s research while affiliated with National Institute of Allergy and Infectious Diseases, National Institutes of Health and other places

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Publications (151)


Figure 1. Loss of myeloid lipin-1 delays inflammation resolution. (A) Lipin-1 m KO mice and littermate control mice were subjected to zymosan challenge (0.1 mg/mouse). PMNs and macrophages were quantified from the peritoneal cavity by flow cytometry. (B) Total number of cells isolated from the peritoneal cavity. (C) Total number of PMNs isolated from the peritoneal cavity. Resolution interval (Ri) was determined. (D) Total number of macrophages isolated from the peritoneal cavity. The illustration in panel A was created using BioRender.com. A minimum of 3 mice per group per time point were analyzed. Values are mean ± SEM. Unpaired 2-tailed t tests were performed between groups at each time point. � P ≤ 0.05. MΦ, macrophage.
Figure 5. Inhibition of the CIC and de novo ceramide biosynthesis restores efferocytic capacity in lipin-1 m ko macrophages. (A) BMDMs from lipin-1 m KO mice and littermate control mice were stimulated with IL-4 for 6 h and then subsequently challenged with CFSE-labeled ACs. (B) Illustration of the de novo FA biosynthesis pathway and checkpoints of inhibition. (C) Lipin-1 m KO mice and littermate control BMDMs were treated with 10 µM inhibitors (FAS: C75; ACC: Cpd9; CTP: CTPi) and dimethyl sulfoxide vehicle (VEH) for 12 h and subsequently cotreated with 40 ng/mL IL-4 and 10 µM of respective inhibitors for 6 h. Images were taken at 20× and zoomed at 1.5× to generate representative images. The experiment was done twice, each time with 3 unique pairs of individual WT and full KO BMDMs (n ¼ 6). At least 3 random images of each group were taken, quantified (C), and grouped to give individual dots. Individual experiments incorporated all inhibitors, so each inhibitor group had the same vehicle control group. (D-E) BMDMs from lipin-1 m KO mice and littermate control mice were treated with increasing concentrations of SCT (1 mM, 3 mM, 6 mM) for 2 h before cotreatment with IL-4 for 6 h (D) and 4 h (E). Subsequently, in vitro efferocytosis (D) and FFA estimation (E) were carried out. (F) In vitro efferocytosis with 10 µM Myriocin. Lipin-1 m KO mice and littermate control BMDMs were treated with Myriocin for 2 h and cotreated with Myriocin and IL-4 for 6 h before the AC challenge. The illustration in panel B was created using BioRender.com. Bars represent SEM. Significance was determined by 2-way analysis of variance. � P ≤ 0.05; �� P ≤ 0.01; ��� P ≤ 0.001; ���� P ≤ 0.001. MYR, Myriocin; UNT, untreated.
Figure 7. Inhibition of the CIC restores inflammation resolution in lipin-1 m KO mice. (A) Lipin-1 m KO mice and littermate control mice were injected with 50 mg/kg CTP-2 at 12 h and 18 h post-zymosan injection. Intraperitoneal (I.P.) lavage was collected over a time course for flow cytometric analysis. (B) Time course flow cytometry analysis of I.P. lavage after acute (0.1 mg/mouse) zymosan injection. Illustrations in panels A and C were created using BioRender.com. Bars represent SEM. Significance was determined by 1-way analysis of variance. Ri, resolution interval.
Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution
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January 2025

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Oluwakemi O Igiehon

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Matthew D Woolard
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Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine

September 2024

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19 Reads

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.


Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS‐CoV‐2‐infected mice

May 2024

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14 Reads

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2 Citations

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection involves an initial viral infection phase followed by a host‐response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti‐viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti‐inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS‐CoV‐2 infection in a mouse model with human angiotensin‐converting enzyme 2 (ACE2) expression. Mice were infected with SARS‐CoV‐2 and treated with either vehicle or the sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU). At day 5 post‐infection, SARS‐CoV‐2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6–8 post‐infection. SARS‐CoV‐2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral‐induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS‐CoV‐2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.


Unraveling the immune dynamics of lung tissue infected with Francisella tularensis in a spatial context

May 2024

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1 Read

The Journal of Immunology

Francisella tularensis (Ftt) is a highly virulent bacterial pathogen whose vaccine offers only short-lived immunity. While CD4+ T cells are required for protection, the mechanism behind waning immunity remains unclear. One potential reason is that the local environment induced by the bacteria inhibits T cell function. We therefore carried out a multi-omics study of the infection microenvironment following vaccination and secondary challenge in mice. Flow cytometry and single cell sequencing analysis revealed that during Ftt secondary challenge, the CD4+ T cells in vaccinated animals show a delayed proliferative response and produced high levels of IFN-γ which correlated with an up-regulation of indoleamine 2,3-dioxygenase (IDO1) by endothelial cells. Importantly, increased IDO1 expression corresponded with decreased levels of tryptophan in the lung as measured by LC/MS. Given the requirement for tryptophan in optimal T cell proliferation, we investigated if IDO1 expression was spatially associated with sites of bacterial replication. We performed multiplex immunohistochemistry targeting bacterial antigen, immune cells, and nutrient depleting enzymes and quantified the proximity of CD4+ T cells to IDO1-expressing cells which arose just outside the points of bacterial replication. Overall, this research uncovered a potential systems level of regulation that is inhibiting T cell function. All studies were approved by the IACUC and was supported by the IRP of the NIH/NIAID


The immunological aftermath of SARS-CoV-2: How prior infection impacts subsequent pulmonary injury

May 2024

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1 Read

The Journal of Immunology

Following pulmonary insults there are persistent alterations in the lung that influence responsiveness to subsequent injury. Over 600 million individuals have survived SARS-CoV-2 (SCV2) infection. Thus, the impact of SCV2 on the ability of the newly remodeled lung to handle various pulmonary challenges is of significant interest and therapeutic importance. Using the K18-hACE2 mouse model, we found that SCV2 resulted in an expanded pool of recruited alveolar macrophages along with persistent lymphocytic perivascular cuffs up to 90 days post-infection in the absence of detectable viral antigen. SCV2 resolved lungs had only modest changes following an OVA-specific allergic response compared to mock infected controls. In contrast, despite no differences in bacterial burdens, SCV2 experienced lungs had significantly less inflammation following infection with Bordetella pertussis compared to mock controls. However, this was not consistent for all bacterial driven inflammatory responses. Specifically, we observed an exacerbation of LPS derived inflammation in mice that had recovered from SCV2. The balance of inflammatory responses in these models was associated with specific changes in lipid mediators (LMs). Together, our data reveal the impact of SCV2 infection on the ability of the lung to optimally respond to a variety of inflammation provoking stimuli and underscore the potential role of LMs in the trained innate immune response.



The PINK1/Parkin pathway of mitophagy exerts a protective effect during prion disease

February 2024

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19 Reads

The PINK1/Parkin pathway of mitophagy has been implicated in the pathogenesis of Parkinson’s disease. In prion diseases, a transmissible neurodegenerative disease caused by the misfolded and infectious prion protein (PrPSc), expression of both PINK1 and Parkin are elevated, suggesting that PINK1/Parkin mediated mitophagy may also play a role in prion pathogenesis. Using mice in which expression of either PINK1 (PINK1KO) or Parkin (ParkinKO) has been ablated, we analyzed the potential role of PINK1 and Parkin in prion pathogenesis. Prion infected PINK1KO and ParkinKO mice succumbed to disease more rapidly (153 and 150 days, respectively) than wild-type control C57Bl/6 mice (161 days). Faster incubation times in PINK1KO and ParkinKO mice did not correlate with altered prion pathology in the brain, altered expression of proteins associated with mitochondrial dynamics, or prion-related changes in mitochondrial respiration. However, the expression level of mitochondrial respiration Complex I, a major site for the formation of reactive oxygen species (ROS), was higher in prion infected PINK1KO and ParkinKO mice when compared to prion infected control mice. Our results demonstrate a protective role for PINK1/Parkin mitophagy during prion disease, likely by helping to minimize ROS formation via Complex I, leading to slower prion disease progression.


The intracellular growth of the vacuolar pathogen Legionella pneumophila is dependent on the acyl chain composition of host membranes

February 2024

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74 Reads

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2 Citations

Frontiers in Bacteriology

Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires' disease. As a prototypical vacuolar pathogen L. pneumophila establishes a unique endoplasmic reticulum (ER)-derived organelle within which bacterial replication takes place. Bacteria-derived proteins are deposited in the host cytosol and in the lumen of the pathogen-occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of the Legionella-containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes-such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously from de novo synthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis and L. pneumophila intracellular replication. Using saturated fatty acids as well as cis-and trans-isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidification L. pneumophila intracellular replication was significantly reduced. Palmitoleic acid-a C16:1 monounsaturated fatty acid-that promotes Frontiers in Bacteriology


Differences between two adult cohorts (October, N = 20 and May, N = 30) of captive Jamaican fruit bats (Artibeus jamaicensis) in intestinal microbial community composition and diversity immediately after relocation between facilities. Samples taken after acclimation. (a) Percent abundance of selected microbial families in the intestinal tract across all bats (pie chart), by cohort (top right), and by individual bat (bottom). Unclassified reads at the family level and reads classified as mitochondria, chloroplasts, or non-prokaryotes were removed. Families with less than 0.5% abundance in either cohort were categorized as “Other” for visualization purposes. (b) Alpha diversity metrics (left to right: Shannon entropy, Simpson’s diversity, Faith’s phylogenetic diversity, and observed features) of the intestinal microbiome by cohort. Median and 95% confidence intervals with individual points overlaid. Significant p-values indicated; Mann–Whitney test (N = 20/30). (c) Principal coordinate analysis of unweighted UniFrac distance showing microbial community composition differences (left) and log10(linear discriminant analysis score) of differentially abundant families (LEfSE, p < 0.05) between cohorts (right).
Intestinal microbial community composition and diversity of October and May cohort bats by sex (male, N = 10 October; N = 9 May and female, N = 10 October; N = 21 May) and pregnancy status (pregnant, N = 2 October; N = 10 May and not pregnant, N = 8 October; N = 11 May). (a) Alpha diversity metrics (left to right: Shannon entropy, Simpson’s diversity, Faith’s phylogenetic diversity, and observed features) of the October (top) and May (bottom) cohort intestinal microbiome by sex. Median and 95% confidence intervals with individual points overlaid. Significant p-values indicated; Mann–Whitney test (N = 10, October; N = 9 (males) and 21 (females), May). (b) Principal coordinate analysis showing unweighted UniFrac distance by sex and pregnancy status in the October cohort (left), and Bray–Curtis distance by sex and pregnancy status in the May cohort (right). Ellipses denote significant (kmeans, p < 0.05) clusters. Points colored by sex and pregnancy status. (c) log10(linear discriminant analysis score) of differentially abundant families (LEfSE, p < 0.05) between male and female bats at intake in the October (left) and May (right) cohorts.
Intestinal microbial community composition and diversity of May cohort bats at study beginning (D0, N = 9) and end (D28, N = 9). (a) Alpha diversity metrics (left to right: Shannon entropy, Simpson’s diversity, Faith’s phylogenetic diversity, and observed features) of the intestinal microbiome. Median and 95% confidence intervals with individual points overlaid. Gray lines indicate points belonging to the same animal. Significant p-values indicated; Wilcoxon matched pairs test of bats euthanized at study endpoint (N = 9). (b) Principal coordinate analysis showing unweighted UniFrac distance between baseline and endpoint samples. Ellipses denote significant (kmeans, p < 0.05) clusters. Points colored by sampling time point. (c) Bar plot showing MaAsLin2 coefficients for families with corrected p-values < 0.05. Coefficients are equivalent to log2(fold change) over time; negative coefficients indicate decline in relative abundance and positive coefficients indicate increase in relative abundance. p-values corrected using Benjamini–Hochberg procedure shown. (d) Principal coordinate analysis showing Bray–Curtis distance by sex and pregnancy status at endpoint in the May cohort. Ellipses denote significant (kmeans, p < 0.05) clusters. Points colored by sex and pregnancy status.
Metabolomics analysis of May cohort bats (N = 9). Metabolites were detected by mass spectrometry of intestinal samples collected during necropsy. (a) sPLSDA showing bat intestinal metabolomes by sex (female, N = 5 and male, N = 4) based on differences in relative metabolite abundance. Points colored by sex. (b) Loadings of sPLSDA analysis of metabolite differences according to sex. Metabolites greater than or equal to 25% of the maximum absolute loading value are colored according to the direction in which they contribute to intergroup differences and labeled with metabolite name. Metabolites less than 25% of the maximum absolute loading value are shown in gray and unlabeled. (c) Correlation plot showing R values and p-values (shown for significance 0.1 and under) for Pearson correlation between metabolites (columns) and bacterial genera (rows). Positive R values in orange; negative R values in purple. Large p-values in white; small p-values in black. Metabolites organized and labelled by family. Asterisk (*) denotes an abbreviation for the Burkholderia–Caballeronia–Paraburkholderia family.
Sex differences and individual variability in the captive Jamaican fruit bat (Artibeus jamaicensis) intestinal microbiome and metabolome

February 2024

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97 Reads

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3 Citations

The intestinal microbiome plays an important role in mammalian health, disease, and immune function. In light of this function, recent studies have aimed to characterize the microbiomes of various bat species, which are noteworthy for their roles as reservoir hosts for several viruses known to be highly pathogenic in other mammals. Despite ongoing bat microbiome research, its role in immune function and disease, especially the effects of changes in the microbiome on host health, remains nebulous. Here, we describe a novel methodology to investigate the intestinal microbiome of captive Jamaican fruit bats (Artibeus jamaicensis). We observed a high degree of individual variation in addition to sex- and cohort-linked differences. The intestinal microbiome was correlated with intestinal metabolite composition, possibly contributing to differences in immune status. This work provides a basis for future infection and field studies to examine in detail the role of the intestinal microbiome in antiviral immunity.


The intracellular growth of the vacuolar pathogen Legionella pneumophila is dependent on the acyl chain composition of host membranes

November 2023

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23 Reads

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1 Citation

Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires disease. As a prototypical vacuolar pathogen L. pneumophila establishes a unique endoplasmic reticulum (ER)—derived organelle within which bacterial replication takes place. Bacteria—derived proteins are deposited in the host cytosol and in the lumen of the pathogen—occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of the Legionella —containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes — such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously from de novo synthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis and L. pneumophila intracellular replication. Using saturated fatty acids as well as cis— and trans— isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidification L. pneumophila intracellular replication was significantly reduced. Palmitoleic acid — a C16:1 monounsaturated fatty acid — that promotes membrane disorder when enriched in GPLs significantly increased bacterial replication within human and murine macrophages but not in axenic growth assays. Lipidome analysis of infected macrophages showed that treatment with exogenous palmitoleic acid resulted in membrane acyl chain reprogramming in a manner that promotes membrane disorder and live—cell imaging revealed that the consequences of increasing membrane disorder impinge on several LCV homeostasis parameters. Collectively, we provide experimental evidence that L. pneumophila replication within its intracellular niche is a function of the lipid bilayer disorder and hydrophobic thickness.


Citations (64)


... To avoid a pyroptotic cell death response triggered by cytosolic delivery of flagellin 78 , which can convolute data interpretation in infection-based growth assays, we used a flagellin clean deletion mutant. We engineered two distinct L. pneumophila Philadelphia-1 derived strains-Lp01 and JR32-to bioluminescence by inserting the LuxR operon (luxC luxD luxA luxB luxE) from Photorhabdus luminescens on the bacterial chromosome under the constitutive IcmR promoter using two different genetic approaches 79,80 (Supplementary Fig. 1a). For both strains the bioluminescence output increased exponentially during logarithmic growth in axenic cultures and peaked as the bacteria entered stationary phase ( Supplementary Fig. 1b, c) 79,80 . ...

Reference:

Iron-depleting nutritional immunity controls extracellular bacterial replication in Legionella pneumophila infections
The intracellular growth of the vacuolar pathogen Legionella pneumophila is dependent on the acyl chain composition of host membranes

Frontiers in Bacteriology

... Alpha diversity analyses revealed significant differences between sexes and among male reproductive stages (active and inactive). Previous analyses of the microbiota of phyllostomid bats, comparing sexes and reproductive conditions within sexes, have generally shown that both reproductive males and females harbor the most diverse bacterial communities [8,48]. However, in our study, reproductively active males exhibited a more diverse fecal microbiota compared to both females and inactive males. ...

Sex differences and individual variability in the captive Jamaican fruit bat (Artibeus jamaicensis) intestinal microbiome and metabolome

... While these results seem controversial, given that BHB has been demonstrated to cause hyperacetylation in some contexts by inhibiting HDACs, recent work has identified a non-canonical function for HDACs. This research demonstrated that Class I HDACs unexpectedly catalyze protein lysine modification with BHB [42]. Thus, the reduction in transcription may be a regulatory mechanism to avoid excessive Kbhb accumulation. ...

Reversible histone deacetylase activity catalyzes lysine acylation

... This could be due to the failure of newer vaccine formulations in engaging an immune response that is like infection, or it could be their inability to engage both the innate and adaptive arms of the immune system. A recent study showed that depending on the route of infection, F. tularensis has different, specific metabolic niches [98]. This could mean that there is no one answer to vaccinating against F. tularensis and that having multiple types of vaccines available is ideal for combatting different routes of infection. ...

Route of Francisella tularensis infection informs spatiotemporal metabolic reprogramming and inflammation in mice

... This hypothesis would for instance accommodate the observation that PRNP transcripts are induced upon long-term ( Supplementary Fig. S3) but not short-term (Supplementary Fig. S2F,G) TGFβ exposure. Our data further highlight a PrP C -dependent regulation of EGFR expression and signalling, recalling that previously described in neuroblastoma cells [50] and neural and dental pulp stem cells [26,51,52]. Because PrP C and EGFR co-localize in LUAD cells (Fig. 5I), as well as in other cancerous and non-cancerous cells [40,50], we speculate that PrP C modulates the dynamics of EGFR signalling, as already suggested over a decade ago in the study by Solis et al. [53]. ...

A PrP EGFR signaling axis controls neural stem cell senescence through modulating cellular energy pathways

Journal of Biological Chemistry

... In silico screening for treatment candidates with activity against CoV-2 followed by in vitro testing for activity against OC43 has resulted in the identification of several drugs that may be useful in treating COVID-19, including the antipsychotic lurasidone, the antimicrobial atovaquone, and the antivirals elbasvir and pibrentasvir (Milani et al., 2021;von Beck et al., 2023). In some cases, the drug candidate was further tested in vivo against CoV-2 using mouse models to confirm its efficacy (von Beck et al., 2023;Ojha et al., 2023;Ordonez et al., 2022). For example, the phytochemical sulforaphane was shown to inhibit both CoV-2 and OC43 in vitro, and oral treatment ameliorated disease in K18-hACE2 mice infected with CoV-2 (Ordonez et al., 2022). ...

Effective inhibition of HCoV-OC43 and SARS-CoV-2 by phytochemicals in vitro and in vivo
  • Citing Article
  • June 2023

International Journal of Antimicrobial Agents

... Neuronal bursts and raster plots were analyzed and generated by MEAnalyzer [23]. Oscillatory powers and peak frequency of delta (0.5-4 Hz) and gamma oscillations were analyzed by MAT-LAB (R2021a) as described previously [24]. ...

Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction

... In contrast, the mutagenic nucleoside N 4hydroxycytidine (NHC) is far more potent in vitro where it is possible to show a clear relationship between antiviral activity and mutation load in the viral genome, and its antiviral activity has been shown against a diverse group of RNA viruses [18][19][20][21][22]. The 5'-isopropyl ester prodrug of NHC, molnupiravir (MOV), is active in in vivo models for treating respiratory virus infections and is being used to treat SARS-CoV-2 in humans [23][24][25][26][27][28][29][30]. ...

Combined molnupiravir-nirmatrelvir treatment improves effect on SARS-CoV-2 in Macaques

JCI Insight

... [1][2][3][4] Small molecule therapeutics that can inhibit the RNA dependent polymerase (RdRp) and Main protease (Mpro) are clinically approved and had a big impact on reducing COVID-19 mortality. [5][6][7][8] The success of these small molecule drugs has created a tremendous interest in developing inhibitors against other proteins from SCoV-2 that are also essential for viral replication. 9,10 The papain-like protease (PLpro) from SCoV-2 is an essential protein for viral replication and an attractive target for developing small-molecule drugs. ...

Combined Molnupiravir and Nirmatrelvir Treatment Improves the Inhibitory Effect on SARS-CoV-2 in Rhesus Macaques

... The arginine deiminase system produces ornithine (BB_0842) (49), which is the peptidoglycan crosslinking diamino acid (50,51). Again, matching recent experimental data, two glycerol-3-phos phate dehydrogenases were predicted: one using NADH as a cofactor (BB_0368) (52) and one using FADH (BB_0243) (53). ...

Riboflavin salvage by Borrelia burgdorferi supports carbon metabolism and is essential for survival in the tick vector

Molecular Microbiology