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Virulent microbes produce proteins that interact with host cell targets to promote pathogenesis. For example, virulent bacterial pathogens have proteins called effectors that are typically enzymes and are secreted into host cells. To detect and respond to the activities of effectors, diverse phyla of host organisms evolved effector-triggered immunity (ETI). In ETI, effectors are often sensed indirectly by detection of their virulence activities in host cells. ETI mechanisms can be complex and involve several classes of host proteins. Guards monitor the functional or physical integrity of another host protein, the guardee or decoy, and become activated to initiate an immune response when the guardee or decoy is modified or disrupted by an effector. A guardee typically has an intrinsic anti-pathogen function and is the intended target of an effector. A decoy structurally mimics a host protein that has intrinsic anti-pathogen activity and is unintentionally targeted by an effector. A decoy can be an individual protein, or a protein domain integrated into a guard. Here, we review the origins of ETI and focus on 5 mechanisms, in which the key steps of a pathway can include activation of a caspase by a RIPoptosome or inflammasome, formation of pores in the plasma membrane, release of cytokines and ending in cell death by pyroptosis. Survey of the 5 mechanisms, which have been shown to be host protective in mouse models of bacterial infection, reveal how distinct regulators of RIPoptosome or inflammasome pathways can act as guards or integrated decoys to trigger ETI. Common themes are highlighted and the limited mechanistic understanding of ETI bactericidal activity is discussed. [ABSTRACT FROM AUTHOR]

Caspase-1 and related proteases are key players in inflammation and innate immunity. Here, we characterize the evolutionary history of caspase-1 and its close relatives across 19 primates and 21 rodents, focusing on differences that may cause discrepancies between humans and animal studies. While caspase-1 has been retained in all these taxa, other members of the caspase-1 subfamily (caspase-4, caspase-5, caspase-11, and caspase-12 and CARD16, 17, and 18) each have unique evolutionary trajectories. Caspase-4 is found across simian primates, whereas we identified multiple pseudogenization and gene loss events in caspase-5, caspase-11, and the CARDs. Because caspase-4 and caspase-11 are both key players in the noncanonical inflammasome pathway, we expected that these proteins would be likely to evolve rapidly. Instead, we found that these two proteins are largely conserved, whereas caspase-4's close paralog, caspase-5, showed significant indications of positive selection, as did primate caspase-1. Caspase-12 is a nonfunctional pseudogene in humans. We find this extends across most primates, although many rodents and some primates retain an intact, and likely functional, caspase-12. In mouse laboratory lines, we found that 50% of common strains carry nonsynonymous variants that may impact the functions of caspase-11 and caspase-12 and therefore recommend specific strains to be used (and avoided). Finally, unlike rodents, primate caspases have undergone repeated rounds of gene conversion, duplication, and loss leading to a highly dynamic proinflammatory caspase repertoire. Thus, we uncovered many differences in the evolution of primate and rodent proinflammatory caspases and discuss the potential implications of this history for caspase gene functions. [ABSTRACT FROM AUTHOR]

Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond changes in the immune responses, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight the potential importance of considering prior microbial exposures when investigating vaccine responses. Author summary: Early-life viral infections can shape the host immune system and affect how it responds to vaccines. In this study, we introduced a series of viruses to young mice and then analyzed their immune systems before and after administering a vaccine for SARS-CoV-2, the virus responsible for COVID-19. We found that these early viral exposures caused significant changes in the immune system, influencing both the types and behaviors of immune cells and the levels of important signaling molecules. Interestingly, while these exposures increased some immune responses, they led to weaker antibody responses to vaccination. This suggests that early viral infections might reduce the effectiveness of vaccines later in life. Additionally, these viral exposures altered the composition of intestinal bacteria, which is known to influence immune health. Our findings highlight the importance of considering early-life infections when studying vaccine responses and immune development. [ABSTRACT FROM AUTHOR]

Zebrafish are popular research organisms selected for laboratory use due in part to widespread availability from the pet trade. Many contemporary colonies of laboratory zebrafish are maintained in aquaculture facilities that monitor and aim to curb infections that can negatively affect colony health and confound experiments. The impact of laboratory control on the microbial constituents associated with zebrafish in research environments compared to the pet trade are unclear. Diseases of unknown causes are common in both environments. We conducted a metatranscriptomic survey to broadly compare the zebrafish-associated microbes in pet trade and laboratory environments. We detected many microbes in animals from the pet trade that were not found in laboratory animals. Cohousing experiments revealed several transmissible microbes including a newly described non-enveloped, double-stranded RNA virus in the Birnaviridae family we name Rocky Mountain birnavirus (RMBV). Infections were detected in asymptomatic animals from the pet trade, but when transmitted to laboratory animals RMBV was associated with pronounced antiviral responses and hemorrhagic disease. These experiments highlight the pet trade as a distinct source of diverse microbes that associate with zebrafish and establish a paradigm for the discovery of newly described pathogenic viruses and other infectious microbes that can be developed for study in the laboratory. Zebrafish are a well-known model organism, but are laboratory conditions too clean to be physiologically relevant? In this study, zebrafish from the pet trade are shown to harbor many more microbes, which can be transmitted to experimentally tractable laboratory zebrafish for further study. Using this strategy, the authors identify the first zebrafish birnavirus, showing that it is pathogenic for laboratory zebrafish. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most globally devastating viruses threatening the swine industry worldwide. Substantial advancements have been achieved in recent years towards comprehending the pathogenesis of PRRSV infection and the host response, involving both innate and adaptive immune responses. Not only a multitude of host proteins actively participate in intricate interactions with viral proteins, but microRNAs (miRNAs) also play a pivotal role in the host response to PRRSV infection. If a PRRSV--host interaction at the protein level is conceptualized as the front line of the battle between pathogens and host cells, then their fight at the RNA level resembles the hidden front line. miRNAs are endogenous small non-coding RNAs of approximately 20--25 nucleotides (nt) that primarily regulate the degradation or translation inhibition of target genes by binding to the 3'-untranslated regions (UTRs). Insights into the roles played by viral proteins and miRNAs in the host response can enhance our comprehensive understanding of the pathogenesis of PRRSV infection. The intricate interplay between viral proteins and cellular targets during PRRSV infection has been extensively explored. This review predominantly centers on the contemporary understanding of the host response to PRRSV infection at the RNA level, in particular, focusing on the twenty-six miRNAs that affect viral replication and the innate immune response. [ABSTRACT FROM AUTHOR]

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell–mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T (TRM) cells constitute a distinct subset within the memory T cell population, serving as the vanguard against invading pathogens and antigens in peripheral non-lymphoid tissues, including the respiratory tract, intestines, and skin. Notably, TRM cells adapt to the specific microenvironment of each tissue, predominantly maintaining a sessile state with distinctive phenotypic and functional attributes. Their role is to ensure continuous immunological surveillance and protection. Recent findings have highlighted the pivotal contribution of TRM cells to the modulation of adaptive immune responses in allergic disorders such as allergic rhinitis, asthma, and dermatitis. A comprehensive understanding of the involvement of TRM cells in allergic diseases bears profound implications for allergy prevention and treatment. This review comprehensively explores the phenotypic characteristics, developmental mechanisms, and functional roles of TRM cells, focusing on their intricate relationship with allergic diseases. [ABSTRACT FROM AUTHOR]

Spring viremia of carp virus (SVCV) is a highly lethal virus in common carp (Cyprinus carpio) and other cyprinid fish species. The aim of the present study was to develop an in vivo therapeutic measure against SVCV using artificial microRNA (AmiRNA) targeting the SVCV P gene transcript. Three candidates of AmiRNAs (AmiR-P1, -P2, and -P3) were selected, and their ability to downregulate SVCV P gene transcript was analyzed by both synthesized AmiRNA mimics and AmiRNA-expressing vector system, in which AmiR-P3 showed the strongest inhibitory activity among the three candidates. To overcome in vivo limitation of miRNA mimics or plasmid-based miRNA expression systems, we rescued recombinant snakehead rhabdoviruses (SHRVs) expressing SVCV P gene–targeting AmiRNA (rSHRV-AmiR-P3) or control AmiRNA (rSHRV-AmiR-C) using reverse genetic technology. The successful expression of AmiR-P3 and AmiR-C in cells infected with the rescued viruses was verified by quantitative PCR. To evaluate the availability of rSHRV-AmiR-P3 for in vivo control of SVCV, zebrafish (Danio rerio) were (i) infected with either rSHRV-AmiR-C or rSHRV-AmiR-P3 followed by SVCV infection or (ii) infected with SVCV followed by either rSHRV-AmiR-C or rSHRV-AmiR-P3 infection. Fish infected with rSHRVs before and after SVCV infection showed significantly higher survival rates than fish infected with SVCV alone. There was no significant difference in survival rates between groups of fish infected with rSHRV-AmiR-C and rSHRV-AmiR-P3 before SVCV infection; however, fish infected with SVCV followed by infection with rSHRV-AmiR-P3 showed significantly higher survival rates than fish infected with rSHRV-AmiR-C. These results suggest that rSHRV-AmiR-P3 has therapeutic potential against SVCV in fish when administered after SVCV infection, and rSHRVs expressing artificial microRNAs targeting SVCV transcripts could be used as a tool to control SVCV infection in fish for a therapeutic purpose. [ABSTRACT FROM AUTHOR]

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology. This study describes an innate immune mechanism for sensing coronavirus and picornavirus infection by detecting the activity of virus-encoded proteases. Genetic variants among mammalian hosts affect which viruses can be sensed by this host 'tripwire' system, confirming its importance in the evolutionary arms race between viruses and the host immune response. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of mortality due to infectious diseases, only surpassed in 2020 by COVID-19. Despite the development in diagnostics, therapeutics, and evaluation of new vaccines for TB, this infectious disease remains uncontrollable due to the emergence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) TB, among other factors. The development in transcriptomics (RNomics) has enabled the study of gene expression in TB. It is considered that non-coding RNAs (ncRNAs) from host [microRNAs (miRNAs)] and Mtb [small RNAs (sRNAs)] are important elements in TB pathogenesis, immune resistance, and susceptibility. Many studies have shown the importance of host miRNAs in regulating immune response against Mtb via in vitro and in vivo mice models. The bacterial sRNAs play a major role in survival, adaptation, and virulence. Here, we review the characterization and function of host and bacteria ncRNAs in TB and their potential use in clinical applications as diagnostic, prognostic, and therapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Air pollution caused by SARS-CoV-2 and other viruses in human settlements will have a great impact on human health, but also a great risk of transmission. The transmission power of the virus can be represented by quanta number in the Wells-Riley model. In order to solve the problem of different dynamic transmission scenarios, only a single influencing factor is considered when predicting the infection rate, which leads to large differences in quanta calculated in the same space. In this paper, an analog model is established to define the indoor air cleaning index RL and the space ratio parameter. Based on infection data analysis and rule summary in animal experiments, factors affecting quanta in interpersonal communication were explored. Finally, by analogy, the factors affecting person-to-person transmission mainly include viral load of infected person, distance between individuals, etc., the more severe the symptoms, the closer the number of days of illness to the peak, and the closer the distance to the quanta. In summary, there are many factors that affect the infection rate of susceptible people in the human settlement environment. This study provides reference indicators for environmental governance under the COVID-19 epidemic, provides reference opinions for healthy interpersonal communication and human behavior, and provides some reference for accurately judging the trend of epidemic spread and responding to the epidemic. [ABSTRACT FROM AUTHOR]

The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the ab T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes--here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells--two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents. [ABSTRACT FROM AUTHOR]

Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. Most influenza virions cannot, when acting as individual particles, complete the entire viral life cycle. Nevertheless influenza is incredibly successful in the suppression of innate immune detection and the production of interferons, remaining undetected in >99% of cells in tissue-culture models of infection. Notably, the same variation that leads to replication failure can, by chance, inactivate the major innate immune antagonist in influenza A virus, NS1. What explains the observed rarity of interferon production in spite of the frequent loss of this, critical, antagonist? By studying how genetic and phenotypic variation in a viral population lacking NS1 correlates with interferon production, we have built a model of the "worst-case" failure from an improved understanding of the steps at which NS1 acts in the viral life cycle to prevent the triggering of an innate immune response. In doing so, we find that NS1 prevents the detection of de novo innate immune ligands, defective viral genomes, and viral export from the nucleus, although only generation of de novo ligands appears absolutely required for enhanced detection of virus in the absence of NS1. Due to this, the highest frequency of interferon production we observe (97% of infected cells) requires a high level of replication in the presence of defective viral genomes with NS1 bearing an inactivating mutation that does not impact its partner encoded on the same segment, NEP. This is incredibly unlikely to occur given the standard variation found within a viral population, and would generally require direct, artificial, intervention to achieve at an appreciable rate. Thus from our study, we procure at least a partial explanation for the seeming contradiction between high rates of replicative failure and the rarity of the interferon response to influenza infection. Author summary: The production of interferons in response to viral threat is a potent barrier to successful infection. Viruses like influenza A virus encode potent interferon antagonists, suppressing detection of viral replication such that only an incredibly small number of cells successfully produce interferons. Strikingly, even in the absence of its major interferon antagonist, NS1, influenza still only induces an interferon response in a minority of infected cells. Using a combination of single-cell RNAseq, flow cytometry, and classical bulk methods, we explored how heterogeneity, both genetic and phenotypic, in a virus lacking NS1, explains the observed rarity of the interferon response. In doing so, we find that, in the absence of NS1, viral replication is absolutely required to induce an interferon response, and that both active export and the presence of defective viral genomes can greatly enhance, but are not strictly required, for the detection of this virus. The confluence of events which we find maximizes the host response is incredibly unlikely to occur alongside the absence of the NS1 protein via the most common forms of genetic variation in the viral population, perhaps explaining, in part, how a virus with such a high error rate nevertheless has such a high rate of success at evading cell intrinsic innate immunity. [ABSTRACT FROM AUTHOR]

Background: Infectious Salmon Anaemia Virus (ISAV) is an Orthomixovirus that represents a large problem for salmonid aquaculture worldwide. Current prevention and treatment methods are only partially effective. Genetic selection and genome engineering have the potential to develop ISAV resistant salmon stocks. Both strategies can benefit from an improved understanding of the genomic regulation of ISAV pathogenesis. Here, we used single-cell RNA sequencing of an Atlantic salmon cell line to provide the first high dimensional insight into the transcriptional landscape that underpins host-virus interaction during early ISAV infection. Results: Salmon head kidney (SHK-1) cells were single-cell RNA sequenced at 24, 48 and 96 h post-ISAV challenge. At 24 h post infection, cells showed expression signatures consistent with viral entry, with genes such as PI3K, FAK or JNK being upregulated relative to uninfected cells. At 48 and 96 h, infected cells showed a clear anti-viral response, characterised by the expression of IFNA2 or IRF2. Uninfected bystander cells at 48 and 96 h also showed clear transcriptional differences, potentially suggesting paracrine signalling from infected cells. These bystander cells expressed pathways such as mRNA sensing, RNA degradation, ubiquitination or proteasome; and up-regulation of mitochondrial ribosome genes also seemed to play a role in the host response to the infection. Correlation between viral and host genes revealed novel genes potentially key for this fish-virus interaction. Conclusions: This study has increased our understanding of the cellular response of Atlantic salmon during ISAV infection and revealed host-virus interactions at the cellular level. Our results highlight various potential key genes in this host-virus interaction, which can be manipulated in future functional studies to increase the resistance of Atlantic salmon to ISAV. [ABSTRACT FROM AUTHOR]

Atlantic Bonefish (Albula vulpes) are economically important due to their popularity with recreational anglers. In the State of Florida, USA, bonefish population numbers declined by approximately 60% between the 1990s and 2015. Habitat loss, water quality impairment, chemical inputs, and other anthropogenic factors have been implicated as causes, but the role of pathogens has been largely overlooked, especially with respect to viruses. We used a metagenomic approach to identify and quantify viruses in the blood of 103 A. vulpes sampled throughout their Western Atlantic range, including populations in Florida that have experienced population declines and populations in Belize, Mexico, Puerto Rico, and The Bahamas that have remained apparently stable. We identified four viruses, all of which are members of families known to infect marine fishes (Flaviviridae, Iflaviridae, Narnaviridae, and Nodaviridae), but all of which were previously undescribed. Bonefish from Florida and Mexico had higher viral richness (numbers of distinct viruses per individual fish) than fish sampled from other areas, and bonefish from the Upper Florida Keys had the highest prevalence of viral infection (proportion of positive fish) than fish sampled from any other location. Bonefish from Florida also had markedly higher viral loads than fish sampled from any other area, both for a novel narnavirus and for all viruses combined. Bonefish viruses may be indicators of environmentally driven physiological and immunological compromise, causes of ill health, or both. [ABSTRACT FROM AUTHOR]

Plant-infecting viruses of the genus Nepovirus (subfamily Comovirinae, family Secoviridae, order Picornavirales) are bipartite positive-strand RNA viruses with each genomic RNA encoding a single large polyprotein. The RNA1-encoded 3C-like protease cleaves the RNA1 polyprotein at five sites and the RNA2 polyprotein at two or three sites, depending on the nepovirus. The specificity of nepovirus 3C-like proteases is notoriously diverse, making the prediction of cleavage sites difficult. In this study, the position of nepovirus cleavage sites was systematically re-evaluated using alignments of the RNA1 and RNA2 polyproteins, phylogenetic relationships of the proteases, and sequence logos to examine specific preferences for the P6 to P1' positions of the cleavage sites. Based on these analyses, the positions of previously elusive cleavage sites, notably the 2a-MP cleavage sites of subgroup B nepoviruses, are now proposed. Distinct nepovirus protease clades were identified, each with different cleavage site specificities, mostly determined by the nature of the amino acid at the P1 and P1' positions of the cleavage sites, as well as the P2 and P4 positions. The results will assist the prediction of cleavage sites for new nepoviruses and help refine the taxonomy of nepoviruses. An improved understanding of the specificity of nepovirus 3C-like proteases can also be used to investigate the cleavage of plant proteins by nepovirus proteases and to understand their adaptation to a broad range of hosts. [ABSTRACT FROM AUTHOR]

CD4+ and CD8+ T lymphocytes mediate most of the adaptive immune response against tumors. Naïve T lymphocytes specific for tumor antigens are primed in lymph nodes by dendritic cells. Upon activation, antigen-specific T cells proliferate and differentiate into effector cells that migrate out of peripheral blood into tumor sites in an attempt to eliminate cancer cells. After accomplishing their function, most effector T cells die in the tissue, while a small fraction of antigen-specific T cells persist as long-lived memory cells, circulating between peripheral blood and lymphoid tissues, to generate enhanced immune responses when re-encountering the same antigen. A subset of memory T cells, called resident memory T (TRM) cells, stably resides in non-lymphoid peripheral tissues and may provide rapid immunity independently of T cells recruited from blood. Being adapted to the tissue microenvironment, TRM cells are potentially endowed with the best features to protect against the reemergence of cancer cells. However, when tumors give clinical manifestation, it means that tumor cells have evaded immune surveillance, including that of TRM cells. Here, we review the current knowledge as to how TRM cells are generated during an immune response and then maintained in non-lymphoid tissues. We then focus on what is known about the role of CD4+ and CD8+ TRM cells in antitumor immunity and their possible contribution to the efficacy of immunotherapy. Finally, we highlight some open questions in the field and discuss how new technologies may help in addressing them. [ABSTRACT FROM AUTHOR]

JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune‐compromised individuals. The most notable of these JCPyV‐associated CNS diseases is the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML). PML, an AIDS‐defining disease in the pre‐cART epoch, has emerged as a life‐threatening complication in patients receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain hematological malignancies. Among the rapidly expanding list of PML‐associated biologics, natalizumab (Tysabri®) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal, the only therapeutic option for PML, is often complicated by a high‐mortality cerebral inflammatory reaction. No anti‐JCPyV agents are available. Lack of a tractable animal model of polyomavirus‐induced central nervous system (CNS) disease is an acknowledged bottleneck to elucidating PML pathogenesis, immunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus replication in tissue culture, and uncovering early events that presage JCPyV‐associated neuropathology. The natural virus–host mouse polyomavirus (MuPyV) model has recently been developed to explore mechanisms of polyomavirus‐associated CNS disease. In this review, we will cover the benefits of using the MuPyV model to answer fundamental questions about innate and adaptive immune control of JCPyV, the impact of immunomodulation on JCPyV pathogenesis, and how this MuPyV CNS infection model will help improve criteria for identifying patients at risk for JCPyV‐associated CNS diseases before the development of irreversible lesions. [ABSTRACT FROM AUTHOR]

Regulation of immunity throughout an organism is critical for host defense. Previous studies in the nematode Caenorhabditis elegans have described an "ON/OFF" immune switch comprised of the antagonistic paralogs PALS-25 and PALS-22, which regulate resistance against intestinal and epidermal pathogens. Here, we identify and characterize a PALS-25 gain-of-function mutant protein with a premature stop (Q293*), which we find is freed from physical repression by its negative regulator, the PALS-22 protein. PALS-25(Q293*) activates two related gene expression programs, the Oomycete Recognition Response (ORR) against natural pathogens of the epidermis, and the Intracellular Pathogen Response (IPR) against natural intracellular pathogens of the intestine. A subset of ORR/IPR genes is upregulated in pals-25(Q293*) mutants, and they are resistant to oomycete infection in the epidermis, and microsporidia and virus infection in the intestine, but without compromising growth. Surprisingly, we find that activation of PALS-25 seems to primarily stimulate the downstream bZIP transcription factor ZIP-1 in the epidermis, with upregulation of gene expression in both the epidermis and in the intestine. Interestingly, we find that PALS-22/25-regulated epidermal-to-intestinal signaling promotes resistance to the N. parisii intestinal pathogen, demonstrating cross-tissue protective immune induction from one epithelial tissue to another in C. elegans. Author summary: Multicellular organisms need to monitor the health and function of multiple tissues simultaneously to respond appropriately to pathogen infection. Here, we study an ON/OFF switch in the roundworm C. elegans that controls immune responses to diverse natural pathogens of the skin and gut. We show a physical association between the 'ON switch' protein PALS-25 and the 'OFF switch' protein PALS-22, and that this association is disrupted in a mutant, activated form of PALS-25. When either PALS-22 is lost, or PALS-25 is activated, a downstream immune regulator ZIP-1 is activated more prominently in the skin than in the gut. Excitingly, our findings show that skin-specific loss of PALS-22 or skin-specific activation of PALS-25 can induce immune responses in the worm gut. These findings highlight the coordination of immune responses across different tissues that are commonly infected by microbial pathogens. [ABSTRACT FROM AUTHOR]

The green seaweed Ulva is important from ecological and economic perspectives, but the identification of species is often problematic. Here we assessed and discussed different perspectives to establish a stable taxonomic framework for Ulva, which will benefit both ecological and applied research. We evaluated (1) the performance of commonly used DNA-barcode markers (ITS rDNA, rbcL, and tufA) using species delimitation methods (PTP and GMYC), (2) the usage of species names in the literature, and (3) the geographic coverage of genetic data to identify poorly sampled regions. Species delimitation employing the tufA gene was the most consistent across methods. Not surprisingly, DNA-based species delimitation was often in disagreement with traditional morphology-based species definitions. Biological species concepts, where tested, proved to be generally narrower than DNA-based species delimitation. Although the use of molecular markers has greatly improved our view of Ulva diversity, the names associated with DNA sequences in public databases are often unreliable, complicating species identification. Recently, sequencing type materials has considerably reduced the gap between DNA sequence data and Linnaean names, but our knowledge on Ulva diversity remains inadequate, especially in tropical regions. Perspectives for Ulva taxonomy include the consistent use of multiple DNA-barcode markers assisted by species delimitation methods, applications of genomic data, and crossing experiments. To arrive at a stable nomenclature, we outline the benefits and shortcomings of adhering to the rules and practices of the International Code of Nomenclature for algae, fungi, and plants, for example, by sequencing name-bearing types and discuss alternative approaches. [ABSTRACT FROM AUTHOR]

Reporter viruses provide powerful tools for both basic and applied virology studies, however, the creation and exploitation of reporter influenza A viruses (IAVs) have been hindered by the limited tolerance of the segmented genome to exogenous modifications. Interestingly, our previous study has demonstrated the underlying mechanism that foreign insertions reduce the replication/transcription capacity of the modified segment, impairing the delicate balance among the multiple segments during IAV infection. In the present study, we developed a "balance compensation" strategy by incorporating additional compensatory mutations during initial construction of recombinant IAVs to expand the tolerance of IAV genome. As a proof of concept, promoter-enhancing mutations were introduced within the modified segment to rectify the segments imbalance of a reporter influenza PR8-NS-Gluc virus, while directed optimization of the recombinant IAV was successfully achieved. Further, we generated recombinant IAVs expressing a much larger firefly luciferase (Fluc) by coupling with a much stronger compensatory enhancement, and established robust Fluc-based live-imaging mouse models of IAV infection. Our strategy feasibly expands the tolerance for foreign gene insertions in the segmented IAV genome, which opens up better opportunities to develop more versatile reporter IAVs as well as live attenuated influenza virus-based vaccines for other important human pathogens. Author summary: Foreign nucleotide insertions often interfere with the replication/transcription of the modified segment of IAV genome, impairing the delicate balance of the segmented genome during IAV. In general the larger the insertion is, the more the balance is impaired. The limited tolerance of IAV genome greatly restricts the creation and application of recombinant IAVs. In this study, we developed a "balance compensation" strategy to expand the tolerance of IAV genome. In coupled with appropriate compensatory enhancement during initial construction, recombinant IAVs harboring much larger foreign insertions are successfully generated and maintain genetically stable, facilitating their use as powerful tools, e.g., the reporter IAVs and live-attenuated influenza virus-vectored vaccines. [ABSTRACT FROM AUTHOR]

The advent of technologies that can characterize the phenotypes, functions and fates of individual cells has revealed extensive and often unexpected levels of diversity between cells that are nominally of the same subset. CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), are no exception. Investigations of individual CD8+ T cells both in vitro and in vivo have highlighted the heterogeneity of cellular responses at the levels of activation, differentiation and function. This review takes a broad perspective on the topic of heterogeneity, outlining different forms of variation that arise during a CD8+ T cell response. Specific attention is paid to the impact of T cell receptor (TCR) stimulation strength on heterogeneity. In particular, this review endeavors to highlight connections between variation at different cellular stages, presenting known mechanisms and key open questions about how variation between cells can arise and propagate. [ABSTRACT FROM AUTHOR]

Although many studies have observed genome-wide host transposon expression alteration during viral infection, the mechanisms of induction and the impact on the host remain unclear. Utilizing recently published influenza A virus (IAV) time series data and ENCODE functional genomics data, we characterized virus induced host differentially expressed transposons (virus-induced-TE) by investigating genome-wide spatial and functional relevance between the virus-induced-TEs and epigenomic markers (e.g. histone modification and chromatin remodelers). We found that a significant fraction of virus-induced-TEs are derived from host enhancer regions, where CHD4 binding and/or H3K27ac occupancy is high or H3K9me3 occupancy is low. By overlapping virus-induced-TEs to human enhancer RNAs (eRNAs), we discovered that a proportion of virus-induced-TEs are either eRNAs or part of enhancer RNAs. Upon further analysis of the eRNA targeted genes, we found that the virus-induced-TE related eRNA targets are overrepresented in differentially expressed host genes of IAV infected samples. Our results suggest that changing chromatin accessibility from repressive to permissive in the transposon docked enhancer regions to regulate host downstream gene expression is potentially one of the virus and host cell interaction mechanisms, where transposons are likely important regulatory genomic elements. Our study provides a new insight into the mechanisms of virus-host interaction and may lead to novel strategies for prevention and therapeutics of IAV and other virus infectious diseases. [ABSTRACT FROM AUTHOR]

Many pathogens encode proteases that serve to antagonize the host immune system. In particular, viruses with a positive-sense single-stranded RNA genome [(+)ssRNA], including picornaviruses, flaviviruses, and coronaviruses, encode proteases that are not only required for processing viral polyproteins into functional units but also manipulate crucial host cellular processes through their proteolytic activity. Because these proteases must cleave numerous polyprotein sites as well as diverse host targets, evolution of these viral proteases is expected to be highly constrained. However, despite this strong evolutionary constraint, mounting evidence suggests that viral proteases such as picornavirus 3C, flavivirus NS3, and coronavirus 3CL, are engaged in molecular 'arms races' with their targeted host factors, resulting in host- and virus-specific determinants of protease cleavage. In cases where protease-mediated cleavage results in host immune inactivation, recurrent host gene evolution can result in avoidance of cleavage by viral proteases. In other cases, such as recently described examples in NLRP1 and CARD8, hosts have evolved 'tripwire' sequences that mimic protease cleavage sites and activate an immune response upon cleavage. In both cases, host evolution may be responsible for driving viral protease evolution, helping explain why viral proteases and polyprotein sites are divergent among related viruses despite such strong evolutionary constraint. Importantly, these evolutionary conflicts result in diverse protease-host interactions even within closely related host and viral species, thereby contributing to host range, zoonotic potential, and pathogenicity of viral infection. Such examples highlight the importance of examining viral protease-host interactions through an evolutionary lens. [ABSTRACT FROM AUTHOR]

Cell culture-derived defective interfering particles (DIPs) are considered for antiviral therapy due to their ability to inhibit influenza A virus (IAV) production. DIPs contain a large internal deletion in one of their eight viral RNAs (vRNAs) rendering them replication-incompetent. However, they can propagate alongside their homologous standard virus (STV) during infection in a competition for cellular and viral resources. So far, experimental and modeling studies for IAV have focused on either the intracellular or the cell population level when investigating the interaction of STVs and DIPs. To examine these levels simultaneously, we conducted a series of experiments using highly different multiplicities of infections for STVs and DIPs to characterize virus replication in Madin-Darby Canine Kidney suspension cells. At several time points post infection, we quantified virus titers, viable cell concentration, virus-induced apoptosis using imaging flow cytometry, and intracellular levels of vRNA and viral mRNA using real-time reverse transcription qPCR. Based on the obtained data, we developed a mathematical multiscale model of STV and DIP co-infection that describes dynamics closely for all scenarios with a single set of parameters. We show that applying high DIP concentrations can shut down STV propagation completely and prevent virus-induced apoptosis. Interestingly, the three observed viral mRNAs (full-length segment 1 and 5, defective interfering segment 1) accumulated to vastly different levels suggesting the interplay between an internal regulation mechanism and a growth advantage for shorter viral RNAs. Furthermore, model simulations predict that the concentration of DIPs should be at least 10000 times higher than that of STVs to prevent the spread of IAV. Ultimately, the model presented here supports a comprehensive understanding of the interactions between STVs and DIPs during co-infection providing an ideal platform for the prediction and optimization of vaccine manufacturing as well as DIP production for therapeutic use. Author summary: Influenza viruses replicate inside their hosts after infection. Along with the release of wild-type standard virus (STV), they can also generate specific kinds of particles that have deletions in their genome. These so-called "defective interfering particles" (DIPs) are unable to replicate on their own. However, during co-infection with STV they can interfere with the viral life cycle suppressing STV production and instead release a large number of progeny DIPs. Recent studies have shown promising results regarding their potential as antiviral agents. To characterize the interactions between STVs and DIPs during co-infections, we infected animal cell cultures using 12 different multiplicities of infection for STVs and DIPs, respectively. We measured intra- and extracellular infection dynamics and show that STV replication can be suppressed completely using high amounts of DIPs. Then, we developed a mathematical model that describes co-infection dynamics closely using a single set of parameters. We used this model to predict optimal dosing ratios for DIPs to suppress STV infections and for cell culture-derived production of DIPs for antiviral therapy. [ABSTRACT FROM AUTHOR]

To produce artificial microRNA (amiR)-mediated self-inhibitory viral hemorrhagic septicemia virus (VHSV), we inserted VHSV P gene-targeting amiR sequence (amiR-P) or control amiR sequence (amiR-C) between N and P genes of VHSV genome, and rescued recombinant VHSVs (rVHSV-A-amiR-P and rVHSV-A-amiR-C) using reverse genetic technology. The growth of rVHSV-A-amiR-P was significantly retarded compared to the control virus, rVHSV-A-amiR-C, due to the production of self P gene transcript-attacking microRNAs in infected cells. To enhance the replication of rVHSV-A-amiR-P, we generated the Dicer gene-knockout epithelioma papulosum cyprini (EPC-ΔDicer) cells using a CRISPR/Cas9 system, and evaluated the effect of Dicer knockout on the titer of rVHSV-A-amiR-P. The replication of rVHSV-A-amiR-C in EPC-ΔDicer cells was not different from that in control EPC cells, while the copy number of rVHSV-A-amiR-P was increasingly risen up in EPC-ΔDicer cells compared to that in control EPC cells, and the final viral titer of rVHSV-A-amiR-P was enhanced by culture in EPC-ΔDicer cells. These results indicate that VHSV can be attenuated by the equipment of self-mRNA-targeting microRNA sequence in the genome, and the titer of artificial miRNA-expressing attenuated recombinant VHSVs can be enhanced by the knockout of Dicer gene in EPC cells. [ABSTRACT FROM AUTHOR]

CD8 positive, tissue resident memory T cells (TRM) are a specialized subset of CD8 memory T cells that surveil tissues and provide critical first-line protection against tumors and pathogen re-infection. Recently, much effort has been dedicated to understanding the function, phenotype and development of TRM. A myriad of signals is involved in the development and maintenance of resident memory T cells in tissue. Much of the initial research focused on the roles tissue-derived signals play in the development of TRM, including TGFß and IL-33 which are critical for the upregulation of CD69 and CD103. However, more recent data suggest further roles for antigenic and pro-inflammatory cytokines. This review will focus on the interplay of pro-inflammatory, tissue and antigenic signals in the establishment of resident memory T cells. [ABSTRACT FROM AUTHOR]

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status. [ABSTRACT FROM AUTHOR]

Resident memory CD8+ T (TRM) cells are a lymphocyte lineage distinct from circulating memory CD8+ T cells. TRM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8+ TRM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional networks and inhibitory checkpoint receptors control TRM differentiation and response. Additionally, extrinsic stimuli such as cytokines, cognate antigen, fatty acids, and damage signals regulate TRM formation, maintenance, and expansion. In this review, we will summarize knowledge of CD8+ TRM generation and highlight mechanisms that regulate the persistence and responses of heterogeneous TRM populations in different tissues and distinct microenvironments. [ABSTRACT FROM AUTHOR]

Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRM are transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRM are governed by a contextual milieu that balances TRM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRM phenotype and function, and discuss the contribution of TRM to promoting protective immune responses in situ while maintaining tissue homeostasis. [ABSTRACT FROM AUTHOR]

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis. Author summary: SARS-CoV-2 infects the respiratory tract, targeting cells of the diverse airway epithelium. Infection outcomes depend on several factors that may vary in this heterogenous population including viral tropism, antiviral immunity, and response to antiviral therapies like remdesivir. We found that SARS-CoV-2 infects an array of airway epithelial cells, relying on the host protease TMPRSS2 for entry. Ciliated epithelial cells were the dominant target, and remdesivir blocked viral replication across multiple cell types. We uncovered cellular heterogeneity in early antiviral immunity to SARS-CoV-2 and identified cell type-specific ISGs associated with either high levels of viral replication or protection from infection. [ABSTRACT FROM AUTHOR]

The green algal genus Ulva is widely distributed around all continents. Plants with both distromatic or monostromatic thalli now form a single taxon based on ITS rDNA and rbcL gene sequencing. Ulva is known to occupy several ecological niches including freshwater and marine (intertidal and subtidal) habitats, attributed to its tolerance to key determinants such as light, temperature, and salinity. The genus is perceived as model system to study life cycle, morphogenesis and development from simple to complex multicellularity. The life cycle is isomorphic and biphasic type, knowledge of which is important in developing viable cultivation techniques. The culture of Ulva is by photo-bioreactor, land-based, and open-sea farming producing about 1500 t dry annum−1 biomass. The understanding of scientific basis for eutrophication-driven green tide events is of paramount importance for coastal ecosystem management. Studies related to cross-kingdom cross-talk between Ulva and surrounding microbes have been recently undertaken through high-throughput techniques to understand their role in growth, development, and morphogenesis. Several regional species are rich in vital nutrients and thus qualify in the functional food sector, and recent research is poised to develop a bio-refinery model for complete utilization of feedstock. Ulva spp. are also used as a feed source in aquaculture and for environmental bioremediation. [ABSTRACT FROM AUTHOR]

Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection. Author summary: Influenza A virus (IAV) is a respiratory virus that can infect multiple cell types in the lung. It is not known how individual cell types contribute to the innate immune response. Additionally, it is not known how distinct stages of early IAV replication are detected by infected cells. To address these questions, we use a combination of viruses that can replicate but not spread and viruses that can only undergo the very first steps of replication. These tools allow us to identify and analyze infected cells during the earliest stages of virus replication. We uncover distinct responses to different stages of IAV replication in vitro and in vivo. Additionally, we identify universal and cell type-specific antiviral responses in vivo. Altogether, our data suggest that both replication stage and the cell type infected contribute to antiviral gene activation during IAV infection. [ABSTRACT FROM AUTHOR]

Viral infection outcomes are governed by the complex and dynamic interplay between the infecting virus population and the host response. It is increasingly clear that both viral and host cell populations are highly heterogeneous, but little is known about how this heterogeneity influences infection dynamics or viral pathogenicity. To dissect the interactions between influenza A virus (IAV) and host cell heterogeneity, we examined the combined host and viral transcriptomes of thousands of individual cells, each infected with a single IAV virion. We observed complex patterns of viral gene expression and the existence of multiple distinct host transcriptional responses to infection at the single cell level. We show that human H1N1 and H3N2 strains differ significantly in patterns of both viral and host anti-viral gene transcriptional heterogeneity at the single cell level. Our analyses also reveal that semi-infectious particles that fail to express the viral NS can play a dominant role in triggering the innate anti-viral response to infection. Altogether, these data reveal how patterns of viral population heterogeneity can serve as a major determinant of antiviral gene activation. Author summary: The combination of the enormous diversity of viral populations, underlying heterogeneity within host cells, and random chance mean that no two infected cells look exactly the same. The role that single cell heterogeneity plays in determining infection outcomes remains very poorly understood. Here, we describe an approach that allowed us to quantify both viral and host gene expression in thousands of influenza A virus infected cells. We observed an enormous degree of heterogeneity in both viral and host gene expression between individual infected cells. We found that virions that fail to express the viral NS gene can be major drivers of host antiviral immune activation. Comparison of antiviral gene expression patterns between H1N1 and H3N2 infection revealed surprising differences in single cell patterns of innate immune activation. Altogether, these studies identify patterns of single cell heterogeneity in both host and viral gene expression as a significant driver of infection outcomes. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles secreted by cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighboring or distant cells. While a role for exosomes in antimicrobial defense has recently emerged, currently very little is known regarding the nature and functional relevance of exosomes generated in vivo , particularly during an active viral infection. Here, we characterized exosomes released into the airways during influenza virus infection. We show that these vesicles dynamically change in protein composition over the course of infection, increasing expression of host proteins with known anti-influenza activity, and viral proteins with the potential to trigger host immune responses. We show that exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigen that can be utilized by antigen presenting cells to drive the induction of a cellular immune response. Moreover, we show that attachment factors for influenza virus, namely α2,3 and α2,6-linked sialic acids, are present on the surface of airway exosomes and these vesicles have the ability to neutralize influenza virus, thereby preventing the virus from binding and entering target cells. These data reveal a novel role for airway exosomes in the antiviral innate immune defense against influenza virus infection. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes recent literature defining tissue-resident memory T cells (TRM) and discusses implications for HIV pathogenesis, vaccines, and eradication efforts. Recent Findings: Investigations using animal models and human tissues have identified a TRM transcriptional profile and elucidated signals within the tissue microenvironment leading to TRM development and maintenance. TRM are major contributors to host response in infectious diseases and cancer; in addition, TRM contribute to pathogenic inflammation in a variety of settings. Although TRM are daunting to study in HIV infection, recent work has helped define their molecular signatures and effector functions and tested strategies for their mobilization. Summary: Exclusive reliance on blood sampling to gain an understanding of host immunity overlooks the contribution of TRM, which differ in significant ways from their counterparts in circulation. It is hoped that greater understanding of these cells will lead to novel approaches to prevent and/or eradicate HIV infection. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is a seasonal pathogen with the potential to cause devastating pandemics. IAV infects multiple epithelial cell subsets in the respiratory tract, eliciting damage to the lungs. Clearance of IAV is primarily dependent on CD8+ T cells, which must balance control of the infection with immunopathology. Using a virus expressing Cre recombinase to permanently label infected cells in a Cre-inducible reporter mouse, we previously discovered infected club cells that survive both lytic virus replication and CD8+ T cell-mediated clearance. In this study, we demonstrate that ciliated epithelial cells, type I and type II alveolar cells can also become survivor cells. Survivor cells are stable in the lung long-term and demonstrate enhanced proliferation compared to uninfected cells. When we investigated how survivor cells evade CD8+ T cell killing we observed that survivor cells upregulated the inhibitory ligand PD-L1, but survivor cells did not use PD-L1 to evade CD8+ T cell killing. Instead our data suggest that survivor cells are not inherently resistant to CD8+ T cell killing, but instead no longer present IAV antigen and cannot be detected by CD8+ T cells. Finally, we evaluate the failure of CD8+ T cells to kill these previously infected cells. This work demonstrates that additional cell types can survive IAV infection and that these cells robustly proliferate and are stable long term. By sparing previously infected cells, the adaptive immune system may be minimizing pathology associated with IAV infection. [ABSTRACT FROM AUTHOR]

As an important regulator of gene expression in eukaryotes, microRNAs (miRNAs) have been subject to extensive research to understand their pleiotropic roles in development and pathological processes. Here, we review strategies that have been developed to map microRNA‐target interactions and the most effective methods to attribute post‐transcriptional gene regulation through miRNA‐mediated silencing. We further discuss the importance of the biological context for silencing. The tiny ribonucleic acid (RNA) molecules called microRNAs play an essential role in the maintenance of cells as demonstrated by several studies focusing on a plethora of human diseases. In this review, we discuss about strategies used to identify the molecular targets of those RNA molecules as well as describe the importance of studying their roles in their natural biological context. [ABSTRACT FROM AUTHOR]

Influenza is a major health burden worldwide and is caused by influenza viruses that are enveloped and negative stranded RNA viruses. Little progress has been achieved in targeted intervention, either at a population level or at an individual level (to treat the cause), due to the toxicity of drugs and ineffective vaccines against influenza viruses. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in gene expression, cell differentiation, and tissue development and have been shown to silence viral replication in a sequence-specific manner. Investigation of these small endogenous nucleotides may lead to new therapeutics against influenza virus infection. Here, we describe our current understanding of the role of miRNAs in host defense response against influenza virus, as well as their potential and limitation as new therapeutic approaches. [ABSTRACT FROM AUTHOR]

This paper deals with the existence of solutions for a class of partial integral equations via Hadamard s fractional integral under the Pettis integrability assumption, by applying some techniques of measure of weak noncompactness. [ABSTRACT FROM AUTHOR]

Background The Indo-Pacific region has the largest number of seagrass species worldwide and this region is considered as the origin of the Hydrocharitaceae. Halophila ovalis and its closely-related species belonging to the Hydrocharitaceae are well-known as a complex taxonomic challenge mainly due to their high morphological plasticity. The relationship of genetic differentiation and geographic barriers of H. ovalis radiation was not much studied in this region. Are there misidentifications between H. ovalis and its closely related species? Does any taxonomic uncertainty among different populations of H. ovalis persist? Is there any genetic differentiation among populations in the Western Pacific and the Eastern Indian Ocean, which are separated by the Thai-Malay peninsula? Genetic markers can be used to characterize and identify individuals or species and will be used to answer these questions. Results Phylogenetic analyses of the nuclear ribosomal internal transcribed spacer region based on materials collected from 17 populations in the Western Pacific and the Eastern Indian Ocean showed that some specimens identified as H. ovalis belonged to the H. major clade, also supported by morphological data. Evolutionary divergence between the two clades is between 0.033 and 0.038, much higher than the evolutionary divergence among H. ovalis populations. Eight haplotypes were found; none of the haplotypes from the Western Pacific is found in India and vice versa. Analysis of genetic diversity based on microsatellite analysis revealed that the genetic diversity in the Western Pacific is higher than in the Eastern Indian Ocean. The unrooted neighbor-joining tree among 14 populations from the Western Pacific and the Eastern Indian Ocean showed six groups. The Mantel test results revealed a significant correlation between genetic and geographic distances among populations. Results from band-based and allele frequency-based approaches from Amplified Fragment Length Polymorphism showed that all samples collected from both sides of the Thai-Malay peninsula were clustered into two clades: Gulf of Thailand and Andaman Sea. Conclusions Our study documented the new records of H. major for Malaysia and Myanmar. The study also revealed that the Thai-Malay peninsula is a geographic barrier between H. ovalis populations in the Western Pacific and the Eastern Indian Ocean. [ABSTRACT FROM AUTHOR]

In order to keep subscribers up-to-date with the latest developments in their field, this current awareness service is provided by John Wiley & Sons and contains newly-published material on yeasts. Each bibliography is divided into 10 sections. 1 Reviews; 2 General; 3 Biochemistry; 4 Biotechnology; 5 Cell Biology; 6 Gene Expression; 7 Genetics; 8 Physiology; 9 Medical Mycology; 10 Recombinant DNA Technology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted. (7 weeks journals - search completed 11th. Feb. 2009) [ABSTRACT FROM AUTHOR]