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Biology of Coronaviruses and Predicted Origin of SARS-CoV-2
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Giorgio Palù, Alberto Reale, Nicolas G. Bazan, Pritam Kumar Panda, Vladimir N. Uversky, Murat Seyran, Alaa A. A. Aljabali, Samendra P. Sherchan, Gajendra Kumar Azad, Wagner Baetas-da-Cruz, Parise Adadi, Murtaza M. Tambuwala, Bruce D. Uhal, Kazuo Takayama, Ángel Serrano-Aroca, Tarek Mohamed Abd El-Aziz, Adam M. Brufsky, Kenneth Lundstrom
The first step in the life cycle of SARS-CoV-2 is the initial attachment of the viral particle by the receptor-binding domain (RBD) in the S1 region to the ACE2 receptor on bronchial epithelial cells and alveolar pneumocytes to downregulate the receptor expression, which leads to severe acute respiratory failure (Figure 2.2) [41]. The virus tropism is determined by the location of the RBD and the target receptor. For example, the RBD is located at the N-terminus of the S protein in the murine hepatitis virus (MHV), but at the C-terminus of the S1 region in SARS-CoV. Furthermore, carcinoembryonic antigen-related adhesion molecule-1 (CEACAM1) is the receptor for MHV [42], while MERS-CoV targets dipeptidyl-peptidase 4 (DPP4) [43] and SARS-CoV, HCoVNL63, and SARS-CoV-2 attach to ACE2 [44].
Mucosal interactions with enteropathogenic bacteria
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nadine Cerf-Bensussan, Pamela Schnupf, Valérie Gaboriau-Routhiau, Philippe J. Sansonetti
Among the host factors that facilitate AIEC colonization is the abnormal ileal expression of CEACAM6, which has been observed in patients with ileal Crohn's disease. In contrast to CEACAM1, which is constitutively expressed on the apical cell surface of intestinal epithelial cells, CEACAM6 is an induced molecule. AIEC adhere to the brush border of primary ileal enterocytes isolated from patients with Crohn's disease, but not those from individuals without IBD, due to the abnormal expression of CEACAM6. Most AIEC strains associated with Crohn's disease ileal mucosa express type I pili variants that increase the interaction between AIEC and ileal epithelial cells. Increased expression of CEACAM6 can result from interferon-γ (IFN-γ) or TNF-α stimulation and also from infection with AIEC bacteria, indicating that AIEC can promote their own colonization in patients with Crohn's disease. The presence of AIEC bacteria and their ability to induce the secretion of pro-inflammatory cytokines by infected macrophages could lead to an amplification loop of colonization and inflammation. This has been confirmed in vivo with the LF82 strain of AIEC, but not nonpathogenic E. coli K-12, wherein LF82 persists in the gut of mice that transgenically express human CEACAMs and induces severe colitis.
Solithromycin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Solithromycin remained active against a range of intracellular organisms in in vitro intracellular studies (Lemaire et al., 2009; Mallegol et al., 2013). Five strains of N. gonorrhoeae (1 azithromycin-susceptible and 4 with azithromycin MICs ≥ 1 mg/l) were tested against varying solithromycin concentrations after incubation with HeLa cells expressing the CEACAM1 receptor (Mallegol et al., 2013). At 4 × and 1 × the MIC, loss of cell viability was demonstrated in 4 out of 5 isolates at 20 hours (Mallegol et al., 2013). One isolate, with azithromycin MIC 1 mg/l and solithromycin MIC 0.0625 mg/l, did not show any reduction in viability at 24 hours when exposed to solithromycin concentrations 4 × the MIC (Mallegol et al., 2013). No macrolide-resistant mutations were detected, however this isolate demonstrated an elevated intracellular fitness in comparison to other strains tested, which may explain the viability of the strain after solithromycin exposure in cell culture (Mallegol et al., 2013). Solithromycin was significantly more potent against S. aureus ATCC 25923 that had been phagocytosed by THP-1 macrophages versus telithromycin, clarithromycin, or azithromycin (Mallegol et al., 2013). For L. monocytogenes EGD and L. pneumonphila ATCC 33153 strains, solithromycin was 50- and 100-fold more potent than azithromycin when the organisms were phagocytosed by THP-1 macrophages (Mallegol et al., 2013).
CEACAM1 regulates CD8+ T cell immunity and protects from severe pathology during Citrobacter rodentium induced colitis
Published in Gut Microbes, 2020
Julia Zöller, Jana-Fabienne Ebel, Vishal Khairnar, Verena Schmitt, Robert Klopfleisch, Jana Meiners, Virginia Seiffart, Wiebke Hansen, Jan Buer, Bernhard B. Singer, Karl S. Lang, Astrid M. Westendorf
In humans, CEACAM1 is the target of several Gram-negative commensal and pathogenic bacteria that inhabit the mucosal surfaces. In particular, pathogenic Neisseria, Haemophilus influenzae, Moraxella catarrhalis, Helicobacter pylori, Escherichia coli and Fusobacterium spp. strains have been found to associate via a highly specific protein-protein interaction with CEACAM1.2,39-42 Although the CEACAM-binding bacteria differ in their pathogenic potential, they share the same ecological niche. Thus, it is likely that CEACAM-binding promotes colonization of the mucosa. Interestingly, colons of Ceacam1−/− mice are much stronger colonized with C. rodentium compared to CEACAM1 sufficient WT mice, especially in the early phase of infection. Our fluorescence analysis revealed an enhanced accumulation of C. rodentium at the epithelial cells. However, we observed that, in contrast to other Gram-negative bacteria, C. rodentium is not binding to CEACAM1 and therefore CEACAM1 is not involved in the attachment of C. rodentium to intestinal epithelial cells.
The Helicobacter pylori HopQ outermembrane protein inhibits immune cell activities
Published in OncoImmunology, 2019
Chamutal Gur, Naseem Maalouf, Markus Gerhard, Bernhard B. Singer, Johanna Emgård, Violeta Temper, Tzahi Neuman, Ofer Mandelboim, Gilad Bachrach
Recently, the outer membrane protein HopQ was shown to be involved in helicobacter-mediated pathogenicity. It was demonstrated that HopQ interacts with various members of the CEACAM family expressed on the gastric epithelium specifically during gastritis and gastric cancer.8–10 It was further demonstrated that this interaction facilitates the translocation of the CagA protein into the gastric cells.8,11 CEACAM1 serves also as an inhibitory receptor on various immune cell subsets.12,13 It was shown in the past that binding of Opa (Opacity-associated proteins) proteins of pathogenic Neisseria strains to CEACAM1 impairs normal maturation of immature dendritic cells, suppresses lymphocyte responses to activating stimuli, and also hinders phagocytic engulfment of the bacteria.13
Fusobacterium spp. target human CEACAM1 via the trimeric autotransporter adhesin CbpF
Published in Journal of Oral Microbiology, 2019
Matthew L. Brewer, David Dymock, R. Leo Brady, Bernhard B. Singer, Mumtaz Virji, Darryl J. Hill
The protein produced (from 2B3) was able to bind CEACAM1-Fc in a dose-dependent manner up to 2 μg ml−1 both by ELISA (Figure 8) and by immunodotblotting (not shown). This recombinant protein was able to bind CEACAM1 in both monomeric and trimeric forms; however, increased binding was apparent to the trimeric form of the protein (Figure S9). Whilst the current study has focussed on CEACAM1, CbpF also has the ability to bind to CEA (Figure S10), albeit to a varying degree with the group I protein displaying significantly less binding compared to group II CbpF, about 50% as well. Moreover, the CbpF from group II displayed significantly higher binding to CEACAM1-Fc than group I CbpF, though the difference was not as great, about 75%. Neither class of CbpF showed the ability to bind other CEACAM constructs including CEACAM3-Fc, CEACAM6-Fc, CEACAM8-Fc, or murine CEACAM1b (mCEACAM1b-Fc; Figure 9).