SUMMARY Blood group antigens represent polymorphic traits inherited among individuals and populations. At present, there are 34 recognized human blood groups and hundreds of individual blood group antigens and alleles. Differences in blood group antigen expression can increase or decrease host susceptibility to many infections. Blood groups can play a direct role in infection by serving as receptors and/or coreceptors for microorganisms, parasites, and viruses. In addition, many blood group antigens facilitate intracellular uptake, signal transduction, or adhesion through the organization of membrane microdomains. Several blood groups can modify the innate immune response to infection. Several distinct phenotypes associated with increased host resistance to malaria are overrepresented in populations living in areas where malaria is endemic, as a result of evolutionary pressures. Microorganisms can also stimulate antibodies against blood group antigens, including ABO, T, and Kell. Finally, there is a symbiotic relationship between blood group expression and maturation of the gastrointestinal microbiome.

Blood Groups in Infection and Host Susceptibility

Analysis of enterovirus infection is difficult in animals because they express different virus receptors than humans, and static cell culture systems do not reproduce the physical complexity of the human intestinal epithelium. Here, using coxsackievirus B1 (CVB1) as a prototype enterovirus strain, we demonstrate that human enterovirus infection, replication and infectious virus production can be analyzed in vitro in a human Gut-on-a-Chip microfluidic device that supports culture of highly differentiated human villus intestinal epithelium under conditions of fluid flow and peristalsis-like motions. When CVB1 was introduced into the epithelium-lined intestinal lumen of the device, virions entered the epithelium, replicated inside the cells producing detectable cytopathic effects (CPEs), and both infectious virions and inflammatory cytokines were released in a polarized manner from the cell apex, as they could be detected in the effluent from the epithelial microchannel. When the virus was introduced via a basal route of infection (by inoculating virus into fluid flowing through a parallel lower 'vascular' channel separated from the epithelial channel by a porous membrane), significantly lower viral titers, decreased CPEs, and delayed caspase-3 activation were observed; however, cytokines continued to be secreted apically. The presence of continuous fluid flow through the epithelial lumen also resulted in production of a gradient of CPEs consistent with the flow direction. Thus, the human Gut-on-a-Chip may provide a suitable in vitro model for enteric virus infection and for investigating mechanisms of enterovirus pathogenesis.

/pdf/human-gut-on-a-chip-supports-polarized-infection-of-r0iy71v943.pdf

Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Guidelines for the use and interpretatoin of assays for monitoring autophagy

Abstract Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors. 

pdf/autophagy-regulator-of-cell-death-101vvp36b1.pdf

Autophagy: Regulator of cell death

Cell death is a common outcome of virus infection. In some cases, cell death curbs virus replication. In others, cell death enhances virus dissemination and contributes to tissue injury, exacerbating viral disease. Three forms of cell death are observed following virus infection-apoptosis, necroptosis, and pyroptosis. In this review, I describe the core machinery needed for each of these forms of cell death. Using representative viruses, I highlight how distinct stages of virus replication initiate signaling pathways that elicit these forms of cell death. I also discuss viral strategies to overcome the deleterious effects of cell death on virus propagation and the consequences of cell death for host physiology.

Viruses and the Diversity of Cell Death.

Enteroviruses invade their hosts by crossing the intestinal epithelium. We have examined the mechanism by which echovirus 1 (EV1) enters polarized intestinal epithelial cells (Caco-2). Virus binds to VLA-2 on the apical cell surface and moves rapidly to early endosomes. Using inhibitory drugs, dominant negative mutants, and small interfering RNAs (siRNAs) to block specific endocytic pathways, we found that virus entry requires dynamin GTPase and membrane cholesterol but is independent of both clathrin- and caveolin-mediated endocytosis. Instead, infection requires factors commonly associated with macropinocytosis, including amiloride-sensitive Na+/H+ exchange, protein kinase C, and C-terminal-binding protein-1 (CtBP1); furthermore, EV1 accumulates rapidly in intracellular vesicles with dextran, a fluid-phase marker. These results suggest a role for macropinocytosis in the process by which EV1 enters polarized cells to initiate infection.

Echovirus 1 entry into polarized Caco-2 cells depends on dynamin, cholesterol, and cellular factors associated with macropinocytosis

Enteroviruses invade the host by crossing the intestinal mucosa, which is lined by polarized epithelium. A number of enteroviruses, including echoviruses (EV) and group B coxsackieviruses (CVB), initiate infection by attaching to decay-accelerating factor (DAF), a molecule that is highly expressed on the apical surface of polarized epithelial cells. We previously observed that entry of DAF-binding CVB3 into polarized intestinal epithelial cells occurs by an unusual endocytic mechanism that requires caveolin but does not involve clathrin or dynamin. Here we examined the entry of a DAF-binding echovirus, EV7. We found that drugs, small interfering RNAs (siRNAs), and dominant negative mutants that target factors required for clathrin-mediated endocytosis, including clathrin and dynamin, inhibited both EV7 infection and internalization of virions from the cell surface. Once virus had entered the cell, it colocalized with markers of early endosomes (EEA1) and then late endosomes (LAMP-2). Inhibition of endosomal maturation—with siRNAs or dominant negative mutants targeting Rab5 and Rab7—inhibited infection and prevented release of viral RNA into the cell. These results indicate that EV7 is internalized by clathrin-mediated endocytosis and then moves to early and late endosomes before releasing its RNA. Trafficking through endosomes is known to be important for viruses that depend on low pH or endosomal cathepsin proteases to complete the entry process. However, we found that EV7 infection required neither low pH nor cathepsins. IMPORTANCE The results demonstrate that echovirus 7 (EV7), after binding to decay-accelerating factor (DAF) on the cell surface, enters cells by clathrin-mediated endocytosis; this entry mechanism differs markedly from that of another DAF-binding enterovirus, coxsackievirus B3 (CVB3). Thus, after attachment to the same cell surface receptor, these closely related viruses enter the same cells by different mechanisms. The cellular cues required for release of viral RNA from the enterovirus capsid (“uncoating”) remain poorly defined. We found that EV7 moved to late endosomes and that release of RNA depended on endosomal maturation; nonetheless, EV7 did not depend on the endosomal factors implicated in uncoating and entry by other viruses. The results suggest either that an unidentified endosomal factor is essential for uncoating of EV7 or that trafficking through the endosome is an essential step in a pathway that leads to another intracellular organelle where uncoating is completed.

Echovirus 7 Entry into Polarized Intestinal Epithelial Cells Requires Clathrin and Rab7

Echovirus 7 enters polarized Caco-2 intestinal epithelial cells by a clathrin-mediated endocytic process and then moves through the endosomal system before releasing its genome into the cytoplasm. We examined the possible role in virus entry of core components of the autophagy machinery. We found that depletion of Beclin-1, Atg12, Atg14, Atg16, or LC3 with specific small interfering RNAs inhibited echovirus 7 infection upstream of uncoating but had little or no effect on virus attachment to the cell surface. These data indicate that multiple autophagy-related proteins are important for one or more events that occur after the virus has bound its receptor on the cell surface but before RNA is released from the virus capsid. Although we have not determined the mechanism by which each protein contributes to virus entry, we found that stable depletion of Atg16L1 interfered with virus internalization from the cell surface rather than with intracellular trafficking. Autophagy gene products may thus participate in the endocytic process that moves virus into polarized Caco-2 cells.

Echovirus 7 entry into polarized Caco-2 intestinal epithelial cells involves core components of the autophagy machinery

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

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Echovirus 1 entry into polarized Caco-2 cells depends on dynamin, cholesterol, and cellular factors associated with macropinocytosis

Echovirus 7 Entry into Polarized Intestinal Epithelial Cells Requires Clathrin and Rab7

Echovirus 7 entry into polarized Caco-2 intestinal epithelial cells involves core components of the autophagy machinery

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells