The gastrointestinal tract houses millions of microbes, and thus has evolved several host defense mechanisms to keep them at bay, and prevent their entry into the host. One such mucosal surface ...defense is the secretion of secretory immunoglobulins (SIg). Secretion of SIg depends on the polymeric immunoglobulin receptor (pIgR), which transports polymeric Ig (IgA or IgM) from the basolateral surface of the epithelium to the apical side. Upon reaching the luminal side, a portion of pIgR, called secretory component (SC) is cleaved off to release Ig, forming SIg. Through antigen-specific and non-specific binding, SIg can modulate microbial communities and pathogenic microbes via several mechanisms: agglutination and exclusion from the epithelial surface, neutralization, or via host immunity and complement activation. Given the crucial role of SIg as a microbial scavenger, some pathogens also evolved ways to modulate and utilize pIgR and SIg to facilitate infection. This review will cover the regulation of the pIgR/SIg cycle, mechanisms of SIg-mediated mucosal protection as well as pathogen utilization of SIg.
...monkeys infected with genetically related recoviruses and bovine NoV also contain virus antigen-positive intestinal lamina propria cells 10,17. ...one question raised by our model is how NoVs ...cause gastroenteritis in the absence of enterocyte infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The cell tropism of human noroviruses and the development of an in vitro infection model remain elusive. Although susceptibility to individual human norovirus strains correlates with an individual’s ...histo-blood group antigen (HBGA) profile, the biological basis of this restriction is unknown. We demonstrate that human and mouse noroviruses infected B cells in vitro and likely in vivo. Human norovirus infection of B cells required the presence of HBGA-expressing enteric bacteria. Furthermore, mouse norovirus replication was reduced in vivo when the intestinal microbiota was depleted by means of oral antibiotic administration. Thus, we have identified B cells as a cellular target of noroviruses and enteric bacteria as a stimulatory factor for norovirus infection, leading to the development of an in vitro infection model for human noroviruses.
We describe a case of chronic coronavirus disease 2019 (COVID-19) in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing ...replication of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for at least 119 days. The patient had 3 admissions related to COVID-19 over a 4-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient's lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.
Noroviruses 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.
The gut microbiota, the collection of all bacterial members in the intestinal tract, plays a key role in health. Disruption of the indigenous microbiota by a variety of stressors, including ...antibiotic therapy and intestinal infections, is associated with multiple health problems. We sought to determine if infection with Norovirus disrupts the gut microbiota. Barcoded pyrosequencing of the 16S rRNA-encoding gene was used to characterize the stool microbiota in Norovirus-infected human patients (n = 38). While the microbiota in most infected patients (n = 31) resembled that seen in uninfected healthy controls, a minority of patients (n = 7) possessed a significantly altered microbiota characterized by reduced relative numbers of Bacteriodetes and a corresponding increase in Proteobacteria. In these patients, the increase in Proteobacteria was due to a single operational taxonomic unit (OTU) of Escherichia coli. We cultured E. coli from Norovirus-infected patients and characterized them using PCR-ribotyping and virulence factor analysis. Multiple ribotypes were encountered, but none possessed typical virulence factors commonly carried by enteropathogenic E. coli strains. Microbiota disruption and elevated Proteobacteria were not significantly correlated to patient age, gender, sampling time following illness onset, or overall gut inflammation. These results demonstrate that some patients have a disrupted microbiota following Norovirus infection, and therefore may be at elevated risk for long-term health complications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
About the Authors: Abimbola O. Kolawole Affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America ORCID logo ...http://orcid.org/0000-0001-8520-865X Christiane E. Wobus * E-mail: cwobus@umich.edu Affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America ORCID logo http://orcid.org/0000-0001-5286-0924 Introduction The historical lack of models recapitulating the complexity of the human intestinal epithelium has hindered studies into many aspects of human enteric virus biology. ...comparing animals from different species remains a confounding factor when trying to infer how findings may apply to human health. ...the development of human gastrointestinal organoids to study virus–host interactions marks a significant advance. ...our laboratory recently demonstrated that representative human astrovirus strains from all 3 clades infect 2D HIEs derived from all intestinal segments irrespective of cellular differentiation status 23. 2D, two-dimensional; HIE, human intestinal enteroid; HIO, human intestinal organoid; PSC, pluripotent stem cell. https://doi.org/10.1371/journal.ppat.1008212.g001 Gastrointestinal organoid infection models uncover human cell tropism for enteric viruses Multiple cell types contribute to the complexity of intestinal epithelium and its many functions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and ...translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.
Ferrate(VI) (FeVIO4 2, Fe(VI)) is an emerging oxidant/disinfectant to treat a wide range of contaminants and microbial pollutants in wastewater. This study describes the inactivation of murine ...norovirus (MNV) by Fe(VI) in phosphate buffer (PB) and secondary effluent wastewater (SEW). The decay of Fe(VI) had second-order kinetics in PB while Fe(VI) underwent an initial demand followed by first-order decay kinetics in SEW. The Chick–Watson inactivation kinetic model, based on integral CT (ICT) dose, well fitted the inactivation of MNV in both PB and SEW. In PB, the values of the inactivation rate constant (k d) decreased with an increase in pH, which was related to the reaction of protonated Fe(VI) species (HFeO4 –) with MNV. Higher k d was observed in SEW than in PB. The inactivation of indigenous fecal coliforms (FC) in SEW was also measured. A two-population double-exponential model that accounted for both dispersed and particle-associated FC well fitted the inactivation data with determined k d and particle-associated inactivation rate constant (k p). Results show that Fe(VI) was more effective in inactivating dispersed FC than MNV. The MNV inactivation results obtained herein, coupled with the detailed modeling, provide important information in designing an Fe(VI) wastewater disinfection process.
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