scholarly journals Natural Secretory Immunoglobulins Enhance Norovirus Infection

2018 ◽  
Author(s):  
Holly Turula ◽  
Juliana Bragazzi-Cunha ◽  
Sadeesh Ramakrishnan ◽  
Carol Wilke ◽  
Mariam Gonzalez-Hernandez ◽  
...  
Keyword(s):  
Enteric Virus ◽  
Cell Types ◽  
Lymphoid Follicle ◽  
Enteric Pathogens ◽  
Intestinal Lumen ◽  
Economic Losses ◽  
M Cells ◽  
Murine Norovirus ◽  
Germ Free ◽  
Secretory Immunoglobulins

AbstractSecretory immunoglobulins (SIg) are a first line of mucosal defense by the host. They are secreted into the gut lumen via the polymeric immunoglobulin receptor (pIgR) where they bind to antigen and are transported back across the FAE via M cells. Noroviruses are highly prevalent, enteric pathogens that cause significant morbidity, mortality and economic losses worldwide. Murine norovirus (MNV) exploits microfold (M) cells to cross the lymphoid follicle-associated epithelium (FAE) and infect the underlying population of immune cells. However, whether natural, innate SIg can protect against norovirus infection remains unknown. To investigate the role of natural SIg during murine norovirus pathogenesis, we used pIgR-deficient animals, which lack SIg in the intestinal lumen. Contrary to other enteric pathogens, acute MNV replication was significantly reduced in the gastrointestinal tract of pIgR-deficient animals compared to controls, despite increased numbers of dendritic cells, macrophages, and B cells in the Peyer’s patch, established MNV target cell types. Also, natural SIg did not alter MNV FAE binding or FAE crossing into the lymphoid follicle. Instead, further analysis revealed enhanced baseline levels of the antiviral molecules interferon gamma (IFNɣ) and inducible nitric oxide synthase (iNOS) in the small intestine of naive pIgR-deficient animals compared to controls. Removing the microbiota equalized IFNɣ and iNOS transcript levels as well as MNV viral loads in germ-free pIgR KO mice compared to germ-free controls. These data are consistent with a model whereby SIg sensing reduces pro-inflammatory, antiviral molecules, which facilitates intestinal homeostasis but thereby promotes MNV infection. In conclusion, these findings demonstrate that natural SIg are not protective during norovirus infection in mice and represent another example of indirect modulation of enteric virus pathogenesis by the microbiota.

scholarly journals Natural Secretory Immunoglobulins Promote Enteric Viral Infections

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Holly Turula ◽  
Juliana Bragazzi Cunha ◽  
Bernardo A. Mainou ◽  
Sadeesh K. Ramakrishnan ◽  
Carol A. Wilke ◽  
...  
Keyword(s):  
Enteric Virus ◽  
Enteric Pathogens ◽  
Polymeric Immunoglobulin Receptor ◽  
Murine Norovirus ◽  
Virus Infections ◽  
Significant Morbidity ◽  
Immunoglobulin Receptor ◽  
Ifn Γ ◽  
Secretory Immunoglobulins

ABSTRACTNoroviruses are enteric pathogens causing significant morbidity, mortality, and economic losses worldwide. Secretory immunoglobulins (sIg) are a first line of mucosal defense against enteric pathogens. They are secreted into the intestinal lumen via the polymeric immunoglobulin receptor (pIgR), where they bind to antigens. However, whether natural sIg protect against norovirus infection remains unknown. To determine if natural sIg alter murine norovirus (MNV) pathogenesis, we infected pIgR knockout (KO) mice, which lack sIg in mucosal secretions. Acute MNV infection was significantly reduced in pIgR KO mice compared to controls, despite increased MNV target cells in the Peyer's patch. Natural sIg did not alter MNV binding to the follicle-associated epithelium (FAE) or crossing of the FAE into the lymphoid follicle. Instead, naive pIgR KO mice had enhanced levels of the antiviral inflammatory molecules interferon gamma (IFN-γ) and inducible nitric oxide synthase (iNOS) in the ileum compared to controls. Strikingly, depletion of the intestinal microbiota in pIgR KO and control mice resulted in comparable IFN-γ and iNOS levels, as well as MNV infectious titers. IFN-γ treatment of wild-type (WT) mice and neutralization of IFN-γ in pIgR KO mice modulated MNV titers, implicating the antiviral cytokine in the phenotype. Reduced gastrointestinal infection in pIgR KO mice was also observed with another enteric virus, reovirus. Collectively, our findings suggest that natural sIg are not protective during enteric virus infection, but rather, that sIg promote enteric viral infection through alterations in microbial immune responses.IMPORTANCEEnteric virus, such as norovirus, infections cause significant morbidity and mortality worldwide. However, direct antiviral infection prevention strategies are limited. Blocking host entry and initiation of infection provides an established avenue for intervention. Here, we investigated the role of the polymeric immunoglobulin receptor (pIgR)-secretory immunoglobulin (sIg) cycle during enteric virus infections. The innate immune functions of sIg (agglutination, immune exclusion, neutralization, and expulsion) were not required during control of acute murine norovirus (MNV) infection. Instead, lack of pIgR resulted in increased IFN-γ levels, which contributed to reduced MNV titers. Another enteric virus, reovirus, also showed decreased infection in pIgR KO mice. Collectively, our data point to a model in which sIg-mediated microbial sensing promotes norovirus and reovirus infection. These data provide the first evidence of the proviral role of natural sIg during enteric virus infections and provide another example of how intestinal bacterial communities indirectly influence MNV pathogenesis.

Co-expression of vimentin and cytokeratins in M cells of rabbit intestinal lymphoid follicle-associated epithelium

1992 ◽  
Vol 24 (1) ◽  
pp. 33-39 ◽  
Author(s):  
Mark A. Jepson ◽  
Caroline M. Mason ◽  
Mark K. Bennett ◽  
Nicholas L. Simmons ◽  
Barry H. Hirst
Keyword(s):  
Lymphoid Follicle ◽  
M Cells ◽  
Follicle Associated Epithelium

scholarly journals Single-cell transcriptomics reveals immune response of intestinal cell types to viral infection

2020 ◽  
Author(s):  
Sergio Triana ◽  
Megan L. Stanifer ◽  
Mohammed Shahraz ◽  
Markus Mukenhirn ◽  
Carmon Kee ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Cell ◽  
Cell Lineage ◽  
Enteric Virus ◽  
Cell Types ◽  
Intestinal Cell ◽  
Intestinal Epithelial ◽  
Proliferating Cells ◽  
Interferon Stimulated Genes ◽  
Human Intestinal Epithelium

AbstractHuman intestinal epithelial cells form a primary barrier protecting us from pathogens, yet only limited knowledge is available about individual contribution of each cell type to mounting an immune response against infection. Here, we developed a pipeline combining single-cell RNA-Seq and highly-multiplex RNA imaging and applied it to human intestinal organoids infected with human astrovirus, a model human enteric virus. We found that interferon controls the infection and that astrovirus infects all major cell types and lineages with a preferential infection of proliferating cells. Intriguingly, each intestinal epithelial cell lineage has a unique basal expression of interferon-stimulated genes and, upon astrovirus infection, undergoes an antiviral transcriptional reprogramming by upregulating distinct sets of interferon-stimulated genes. These findings suggest that in the human intestinal epithelium, each cell lineage plays a unique role in resolving virus infection. Our pipeline can be applicable to other organoids and viruses, opening new avenues to unravel roles of individual cell types in viral pathogenesis.

scholarly journals The Dual Tropism of Noroviruses

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Christiane E. Wobus
Keyword(s):  
Epithelial Cells ◽  
Rna Viruses ◽  
Intestinal Epithelial Cells ◽  
Mammalian Species ◽  
Cell Types ◽  
Economic Losses ◽  
Cell Tropism ◽  
Intestinal Epithelial ◽  
Complex Cell ◽  
Significant Morbidity

ABSTRACTNoroviruses are highly prevalent enteric RNA viruses. Human noroviruses (HuNoVs) cause significant morbidity, mortality, and economic losses worldwide. Infections also occur in other mammalian species, including mice. Despite the discovery of the first norovirus in 1972, the viral tropism has long remained an enigma. A long-held assumption was that these viruses infect intestinal epithelial cells. Recent data support a more complex cell tropism of epithelial and nonepithelial cell types.

scholarly journals CD300lf conditional knockout mouse reveals strain-specific cellular tropism for murine norovirus

2020 ◽  
Author(s):  
Vincent R. Graziano ◽  
Mia Madel Alfajaro ◽  
Cameron O. Schmitz ◽  
Renata B. Filler ◽  
Madison S. Strine ◽  
...  
Keyword(s):  
Knockout Mouse ◽  
Cell Types ◽  
Conditional Knockout ◽  
Cell Tropism ◽  
Murine Norovirus ◽  
Conditional Knockout Mouse ◽  
Tuft Cells ◽  
Cellular Tropism ◽  
Myelomonocytic Cells

Noroviruses are a leading cause of gastrointestinal infection in humans and mice. Understanding human norovirus (HuNoV) cell tropism has important implications for our understanding of viral pathogenesis. Murine norovirus (MNoV) is extensively used as a surrogate model for HuNoV. We previously identified CD300lf as the receptor for MNoV. Here, we generated a Cd300lf conditional knockout (CD300lfF/F) mouse to elucidate the cell tropism of persistent and non-persistent strains of murine norovirus. Using this mouse model, we demonstrate that CD300lf expression on intestinal epithelial cells (IECs), and on tuft cells in particular, is essential for transmission of the persistent MNoV strain CR6 (MNoVCR6) in vivo. In contrast, the non-persistent MNoV strain CW3 (MNoVCW3) does not require CD300lf expression on IECs for infection. However, deletion of CD300lf in myelomonocytic cells (LysM Cre+) partially reduces CW3 viral load in lymphoid and intestinal tissues. Disruption of CD300lf expression on B cells (CD19 Cre), neutrophils (Mrp8 Cre), and dendritic cells (CD11c Cre) did not affect MNoVCW3 viral RNA levels. Finally, we show that the transcription factor STAT1, which is critical for the innate immune response, partially restricts the cell tropism of MNoVCW3 to LysM+ cells. Taken together, these data demonstrate that CD300lf expression on tuft cells is essential for MNoVCR6, that myelomonocytic cells are a major, but not exclusive, target cell of MNoVCW3, and that STAT1 signaling restricts the cellular tropism of MNoVCW3. This provides the first genetic system to study the cell type-specific role of CD300lf in norovirus pathogenesis. IMPORTANCE Human noroviruses (HuNoVs) are a leading cause of gastroenteritis resulting in up to 200,000 deaths each year. The receptor and cell tropism of HuNoV in immunocompetent humans are unclear. We use murine norovirus (MNoV) as a model for HuNoV. We recently identified CD300lf as the sole physiologic receptor for MNoV. Here, we leverage this finding to generate a Cd300lf conditional knockout mouse to decipher the contributions of specific cell types to MNoV infection. We demonstrate that persistent MNoVCR6 requires CD300lf expression on tuft cells. In contrast, multiple CD300lf+ cell types, dominated by myelomonocytic cells, are sufficient for non-persistent MNoVCW3 infection. CD300lf expression on epithelial cells, B cells, neutrophils, and dendritic cells is not critical for MNoVCW3 infection. Mortality associated with MNoVCW3 strain in Stat1-/- mice does not require CD300lf expression on LysM+ cells, highlighting that both CD300lf receptor expression and innate immunity regulate MNoV cell tropism in vivo.

scholarly journals Transmural heterogeneity of action potentials andI to1 in myocytes isolated from the human right ventricle

1998 ◽  
Vol 275 (2) ◽  
pp. H369-H377 ◽  
Author(s):  
Gui-Rong Li ◽  
Jianlin Feng ◽  
Lixia Yue ◽  
Michel Carrier
Keyword(s):  
Right Ventricle ◽  
Cardiac Electrophysiology ◽  
Cell Types ◽  
M Cells ◽  
Limited Information ◽  
Human Right ◽  
Dependent Inactivation ◽  
Significant Difference ◽  
The Right ◽  
Transmural Heterogeneity

Limited information is available about transmural heterogeneity in cardiac electrophysiology in man. The present study was designed to evaluate heterogeneity of cardiac action potential (AP), transient outward K+ current ( I to1) and inwardly rectifying K+ current ( I K1) in human right ventricle. AP and membrane currents were recorded using whole cell current- and voltage-clamp techniques in myocytes isolated from subepicardial, midmyocardial, and subendocardial layers of the right ventricle of explanted failing human hearts. AP morphology differed among the regional cell types. AP duration (APD) at 0.5–2 Hz was longer in midmyocardial cells (M cells) than in subepicardial and subendocardial cells. At room temperature, observed I to1, on step to +60 mV, was significantly greater in subepicardial (6.9 ± 0.8 pA/pF) and M cells (6.0 ± 1.1 pA/pF) than in subendocardial cells (2.2 ± 0.7 pA/pF, P < 0.01). Slower recovery of I to1 was observed in subendocardial cells. The half-inactivation voltage of I to1 was more negative in subendocardial cells than in M and subepicardial cells. At 36°C, the density of I to1 increased, the time-dependent inactivation and reactivation accelerated, and the frequency-dependent reduction attenuated in all regional cell types. No significant difference was observed in I K1 density among the regional cell types. The results indicate that M cells in humans, as in canines, show the greatest APD and that a gradient of I to1 density is present in the transmural ventricular wall. Therefore, the human right ventricle shows significant transmural heterogeneity in AP morphology and I to1properties.

scholarly journals Human intestinal M cells exhibit enterocyte-like intermediate filaments

Gut ◽  
1998 ◽  
Vol 42 (1) ◽  
pp. 54-62 ◽  
Author(s):  
T Kucharzik ◽  
N Lügering ◽  
K W Schmid ◽  
M A Schmidt ◽  
R Stoll ◽  
...  
Keyword(s):  
Animal Models ◽  
Intermediate Filaments ◽  
Cell Types ◽  
Immunogold Electron Microscopy ◽  
M Cells ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells ◽  
Species Specific ◽  
Human Appendix ◽  
Absorptive Enterocytes

Background—The derivation and ultrastructural composition of M cells covering the lymphoid follicles of Peyer’s patches is still unknown. Results from different animal models have shown that there are species specific differences in the composition of intermediate filaments between M cells and neighbouring enterocytes. Little is known, however, about intermediate filaments of human M cells.Aims—To compare components of the cytoskeleton of human M cells with those of adjacent absorptive enterocytes.Methods—The expression and localisation of different cytokeratins, vimentin, and desmin in M cells was determined on follicle associated epithelia of human appendix using immunohistochemistry and immunogold electron microscopy.Results—Cytokeratins specific for human intestinal epithelial cells such as cytokeratins 8, 18, 19, and 20 were expressed in both absorptive enterocytes and M cells with no differences in intensity and cellular distribution between both cell types. Vimentin and desmin, tissue specific markers of either mesenchymal or myogenic cells, as well as other cytokeratins were not detectable in enterocytes or M cells.Conclusion—This is the first study on the structure of intermediate filaments in human intestinal M cells. Our results show that in contrast to several animal models, human M cells apparently do not differ from adjacent enterocytes in the composition of their intermediate filament cytoskeleton. The presence of enterocyte like cytokeratins and the absence of other cytokeratins as well as of vimentin and desmin supports the hypothesis of an epithelial origin of human intestinal M cells and suggests that M cells may derive from differentiated enterocytes.

scholarly journals Gut-associated Lymphoid Tissue in the Large Intestine of Calves. II. Electron Microscopy

1988 ◽  
Vol 25 (6) ◽  
pp. 509-515 ◽  
Author(s):  
E. M. Liebler ◽  
J. F. Pohlenz ◽  
N. F. Cheville
Keyword(s):  
Electron Microscopy ◽  
Large Intestine ◽  
Lymphoid Tissue ◽  
Cell Types ◽  
Goblet Cells ◽  
M Cells ◽  
Muscularis Mucosae ◽  
Transmission Electron ◽  
Luminal Side ◽  
Follicle Associated Epithelium

Scanning electron microscopy of lymphoid tissue in the large intestine of three germfree calves (age 3, 6, and 7 days) revealed two different units: propria nodules and lymphoglandular complexes (LGC). Propria nodules had lymphoid tissue predominantly in lamina propria and were covered by distinct follicle-associated epithelium which lacked goblet cells; nodules were surrounded by wide crypts, which were also lined by follicle-associated epithelium towards the luminal side. Lymphoglandular complexes had lymphoid follicles in the tunica submucosa; epithelial diverticulae extended through the muscularis mucosae branching into the lymphoid nodule. In centers of lymphoglandular complexes, protrusions of lymphoid tissue were covered with distinct follicle-associated epithelium. By transmission electron microscopy cells compatible with M cells in the small intestine of calves and cells with characteristics of both enteroabsorptive and M cells were found. Follicle-associated epithelium of propria nodules and lymphoglandular complexes differed only in the relative frequency of cell types.

scholarly journals Human Intestinal M Cells Display the Sialyl Lewis A Antigen

1999 ◽  
Vol 67 (2) ◽  
pp. 946-953 ◽  
Author(s):  
Paul J. Giannasca ◽  
Karen T. Giannasca ◽  
Alan M. Leichtner ◽  
Marian R. Neutra
Keyword(s):  
Cell Types ◽  
M Cells ◽  
Intestinal Epithelial ◽  
M Cell ◽  
Sialyl Lewis ◽  
Normal Individuals ◽  
Sialyl Lewis A ◽  
Inflammatory Bowel ◽  
Small Subpopulation ◽  
Lewis A

ABSTRACT The biochemical features that distinguish human M cells from other intestinal epithelial cell types are important for understanding microbial pathogenesis and for targeting vaccines to the mucosal immune system. We applied a large panel of carbohydrate-specific monoclonal antibodies and lectins to Peyer’s patch and cecum biopsy specimens from three normal individuals and a patient with inflammatory bowel disease. The results show that human M-cell glycosylation patterns are distinct from those of other species examined and that human M cells preferentially display the sialyl Lewis A antigen. This carbohydrate epitope is also present in a small subpopulation of enterocytes in the follicle-associated epithelium and in goblet cell mucins.

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