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Host-Pathogen Interactions - Top 30 Publications

Differential responses of Helicoverpa armigera C-type immunlectin genes to the endoparasitoid Campoletis chlorideae.

The C-type lectins mediate nonself recognition in insects. The previous studies focused on host immunlectin response to bacterial infection; however, the molecular basis of immunlectin reactions to endoparasitoids has not been elucidated. The present study investigated the effect of parasitization by Campoletis chlorideae on hemagglutination activity (HA; defined as the ability of lectin to agglutinate erythrocytes or other cells), and transcriptional expression of C-type immunlectin genes in the larval host, Helicoverpa armigera. Parasitization induced four- to eightfold higher HA in the parasitized larvae, compared to nonparasitized larvae at days 2 and 6 postparasitization (PP), however inhibited HA at other days PP. Eight C-type lectins were differentially expressed in different host developmental stages, from feeding to wandering stage. The mRNA levels of HaCTL1, HaCTL3, HaCTL4, and HaCTL5 were upregulated and HaCTL2 and HaCTL7 were downregulated. Tissue analysis showed that HaCTLs were mainly expressed in fat body or hemocytes, while HaCTL5 was highly expressed in testes. The effects of parasitization on the lectin expression patterns differed. Lectins except HaCTL6 or HaCTL5 were significantly down- or upregulated in parasitized larvae at day 4 or 6 PP compared with that of nonparasitized larvae. We infer from our results that C-type immunlectins are involved in host-parasitoid interactions, and parasitization alter host immunlectin levels both in inhibiting and promoting host immune defenses to endoparasitoids. These immunlectin genes indicated an altered physiological status of the host insect, depending on developmental stage, tissue, and parasitization.

The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. According to official reports from 121 countries across five WHO regions, there were 213 899 newly diagnosed cases in 2014. Although leprosy affects the skin and peripheral nerves, it can present across a spectrum of clinical and histopathological forms that are strongly influenced by the immune response of the infected individuals. These forms comprise the extremes of tuberculoid leprosy (TT), with a M. leprae-specific Th1, but also a Th17, response that limits M. leprae multiplication, through to lepromatous leprosy (LL), with M. leprae-specific Th2 and T regulatory responses that do not control M. leprae replication but rather allow bacterial dissemination. The interpolar borderline clinical forms present with similar, but less extreme, immune biases. Acute inflammatory episodes, known as leprosy reactions, are complications that may occur before, during or after treatment, and cause further neurological damages that can cause irreversible chronic disabilities. This review discusses the innate and adaptive immune responses, and their interactions, that are known to affect pathogenesis and influence the clinical outcome of leprosy.

Biology and Systematics of Echinococcus.

The biology of Echinococcus, the causative agent of echinococcosis (hydatid disease) is reviewed with emphasis on the developmental biology of the adult and metacestode stages of the parasite. Major advances include determining the origin, structure and functional activities of the laminated layer and its relationship with the germinal layer; and the isolation, in vitro establishment and characterization of the multipotential germinal cells. Future challenges are to identify the mechanisms that provide Echinococcus with its unique developmental plasticity and the nature of activities at the parasite-host interface, particularly in the definitive host. The revised taxonomy of Echinococcus is presented and the solid nomenclature it provides will be essential in understanding the epidemiology of echinococcosis.

Echinococcus-Host Interactions at Cellular and Molecular Levels.

The potentially lethal zoonotic diseases alveolar and cystic echinococcosis are caused by the metacestode larval stages of the tapeworms Echinococcus multilocularis and Echinococcus granulosus, respectively. In both cases, metacestode growth and proliferation occurs within the inner organs of mammalian hosts, which is associated with complex molecular host-parasite interactions that regulate nutrient uptake by the parasite as well as metacestode persistence and development. Using in vitro cultivation systems for parasite larvae, and informed by recently released, comprehensive genome and transcriptome data for both parasites, these molecular host-parasite interactions have been subject to significant research during recent years. In this review, we discuss progress in this field, with emphasis on parasite development and proliferation. We review host-parasite interaction mechanisms that occur early during an infection, when the invading oncosphere stage undergoes a metamorphosis towards the metacestode, and outline the decisive role of parasite stem cells during this process. We also discuss special features of metacestode morphology, and how this parasite stage takes up nutrients from the host, utilizing newly evolved or expanded gene families. We comprehensively review mechanisms of host-parasite cross-communication via evolutionarily conserved signalling systems and how the parasite signalling systems might be exploited for the development of novel chemotherapeutics. Finally, we point to an urgent need for the development of functional genomic techniques in this parasite, which will be imperative for hypothesis-driven analyses into Echinococcus stem cell biology, developmental mechanisms and immunomodulatory activities, which are all highly relevant for the development of anti-infective measures.

Transmissible gastroenteritis virus does not suppress IFN-β induction but is sensitive to IFN in IPEC-J2 cells.

Coronaviruses tend to efficiently evade innate immune sensing. Alpha-coronaviruses interfere with the type I interferon (IFN) response in various ways, ensuring the limited activation of IFN responses. Transmissible gastroenteritis virus (TGEV), an Alphacoronavirus genera virus, is an important pathogen that mainly infects piglet, but little is known about the activation of the host immune response. We show that TGEV induces a delayed activation of the IFN response in intestinal epithelial cells. Briefly, IFN-β expression induced by TGEV infection is delayed with respect to that induced by poly(I:C) transfection. In addition, some of the IFN-stimulated genes (ISGs) were up-regulated in the early infection stage without obvious expression of IFN-β. Moreover, we show that activation of IFN responses induced by poly(I:C) could inhibit viral replication in the early infection stage, but failed in the late infection stage in IPEC-J2 cells. Finally, the activation of IFN responses induced by TGEV infection cannot inhibit viral replication. Taken together, this study provides a preliminary analysis of an interaction between TGEV and IFN-β responses of intestinal epithelial cells.

Streptococcus suis small RNA rss04 contributes to the induction of meningitis by regulating capsule synthesis and by inducing biofilm formation in a mouse infection model.

Streptococcus suis (SS) is an important pathogen for pigs, and it is also considered as a zoonotic agent for humans. Meningitis is one of the most common features of the infection caused by SS, but little is known about the mechanisms of SS meningitis. Recent studies have revealed that small RNAs (sRNAs) have emerged as key regulators of the virulence in several bacteria. In the previous study, we reported that SS sRNA rss04 was up-regulated in pig cerebrospinal fluid and contributes to SS virulence in a zebrafish infection model. Here, we show that rss04 facilitates SS invasion of mouse brain and lung in vivo. Label-free quantitation mass spectrometry analysis revealed that rss04 regulates transcriptional regulator CcpA and several virulence factors including LuxS. Transmission electron microscope and Dot-blot analyses indicated that rss04 represses capsular polysaccharide (CPS) production, which in turn facilitates SS adherence and invasion of mouse brain microvascular endothelial cells bEnd.3 in vitro and activates the mRNA expression of TLR2, CCL2, IL-6 and TNF-α in mouse brain in vivo at 12h post-infection. In addition, rss04 positively regulates SS biofilm formation. Survival analysis of infected mice showed that biofilm state in brain contributes to SS virulence by intracranial subarachnoidal route of infection. Together, our data reveal that SS sRNA rss04 contributes to the induction of meningitis by regulating the CPS synthesis and by inducing biofilm formation, thereby increasing the virulence in a mouse infection model. To our knowledge, rss04 represents the first bacterial sRNA that plays definitive roles in bacterial meningitis.

Characterization of the interaction of African swine fever virus with monocytes and derived macrophage subsets.

African swine fever (ASF) is a devastating disease for which there is no vaccine available. The ASF virus (ASFV) primarily infects cells of the myeloid lineage and this tropism is thought to be crucial for disease pathogenesis. A detailed in vitro characterization of the interactions of a virulent Sardinian isolate (22653/14) and a tissue culture adapted avirulent strain (BA71V) of ASFV with porcine monocytes, un-activated (moMΦ), classically (moM1) and alternatively (moM2) activated monocyte-derived macrophages was conducted in an attempt to better understand this relationship. Using a multiplicity-of-infection (MOI) of 1, both viruses were able to infect monocytes and macrophage subsets, but BA71V presented a reduced ability to infect moM1 compared to 22653/14, with higher expression of early compared to late proteins. Using an MOI of 0.01, only 22653/14 was able to replicate in all the macrophage subsets, with initially lowest in moM1 and moM2. No differences were observed in the expression of CD163 between ASFV infected and uninfected bystander cells. ASFV down-regulated CD16 expression but did not modulate MHC class II levels in monocytes and macrophage subsets. BA71V-infected but not 22653/14-infected moMΦ and moM2 presented with a reduced expression of MHC class I compared to the mock-infected controls. Higher levels of IL-18, IL1-β and IL-1α were released from moM1 after infection with BA71V compared to 22653/14 or mock-infected control. These results revealed differences between these ASFV strains, suggesting that virulent isolates have evolved mechanisms to counteract activated macrophages responses, promoting their survival, dissemination in the host and so ASF pathogenesis.

Effects of Mycoplasma hyopneumoniae on porcine nasal cavity dendritic cells.

Mycoplasma hyopneumoniae (Mhp) is the primary etiological agent responsible for swine enzootic pneumonia (EP), a disease that cause tremendous economic losses all over the swine industry. Dendritic cells (DCs), the most effective antigen-presenting cells, are widely distributed beneath respiratory epithelium. DCs uptake and present antigens to T cells, to initiate protective immune responses or generate immune-mediated pathology in different infections. In this study, we investigated the changes in the different DCs subpopulations, T cells and SIgA positive cells counts in porcine nasal cavity after long time Mhp infection. We further evaluated the role of porcine DCs in Mhp exposure. Our results showed that the number of SLA-II-DR(+)SWC3a(+)DCs, SLA-II-DR(+)CD11b(+) DCs, T cells, SIgA positive cells in nasal cavity were decreased after Mhp 28 days infection in vivo experiment. The antigen presenting ability of DCs were inhibited by Mhp exposure. DCs couldn't activate T-cell proliferation by down-regulating the antigen presenting molecule CD1a expression and promoting high level of IL-10 production. Further more, the expression levels of IL-12 and IFN-γ in DCs were decreased, suggesting that DCs favour for Th2 immune response development after Mhp exposure in vitro. Taken together, Mhp infection impairs the immune function which allows the persistence of Mhp and cause predispose pigs to secondary infections. The decline of DCs presentation ability is the reason why dysfunction and persistence in Mhp infection. These findings are benefit for exploring the pathogenic mechanisms of Mhp in pigs.

Evolution of bopA Gene in Burkholderia: A Case of Convergent Evolution as a Mechanism for Bacterial Autophagy Evasion.

Autophagy is an important defense mechanism targeting intracellular bacteria to restrict their survival and growth. On the other hand, several intracellular pathogens have developed an antiautophagy mechanism to facilitate their own replication or intracellular survival. Up to now, no information about the origin or evolution of the antiautophagic genes in bacteria is available. BopA is an effector protein secreted by Burkholderia pseudomallei via the type three secretion system, and it has been shown to play a pivotal role in their escape from autophagy.  The evolutionary origin of bopA was examined in this work. Sequence similarity searches for BopA showed that no homolog of BopA was detected in eukaryotes. However, eukaryotic linear motifs were detected in BopA. The phylogenetic tree of the BopA proteins in our analysis is congruent with the species phylogeny derived from housekeeping genes. Moreover, there was no obvious difference in GC content values of bopA gene and their respective genomes. Integrated information on the taxonomic distribution, phylogenetic relationships, and GC content of the bopA gene of Burkholderia revealed that this gene was acquired via convergent evolution, not from eukaryotic host through horizontal gene transfer (HGT) event. This work has, for the first time, characterized the evolutionary mechanism of bacterial evasion of autophagy. The results of this study clearly demonstrated the role of convergent evolution in the evolution of how bacteria evade autophagy.

A cysteine protease from Spirometra erinaceieuropaei plerocercoid is a critical factor for host tissue invasion and migration.

Sparganosis in humans caused by the plerocercoid larvae of Spirometra erinaceieuropaei is found worldwide, especially in Eastern Asia and the Far East. Previous studies have suggested that dissolution of plerocercoid body, plerocercoid invasion of host tissue, and migration are important processes for sparganosis progression. However, the mechanisms underlying these processes have yet to be determined. Here, we demonstrated the enzymatic property and involvement of a native 23kDa cysteine protease (Se23kCP), purified from plerocercoids, in sparganosis pathogenesis. Se23kCP is mature protease consisting of 216 amino acids and has a high sequence similarity with cathepsin L in various organisms. Se23kCP conjugated with N-glycans, which have a core fucose residue. Both cysteine and serine protease-specific activities were determined in Se23kCP and their optimal pHs were found to be different, indicating that Se23kCP has a wide range of substrate specificity. Se23kCP was secreted from tegumental vacuoles of the plerocercoid to host subcutaneous tissues and degraded human structural proteins, such as collagen and fibronectin. In addition, the plerocercoid body was lysed by Se23kCP, which facilitated larval invasion of host tissue. Our findings suggest that Se23kCP induces host tissue invasion and migration, and might be an essential molecule for sparganosis onset and progression.

High level methicillin resistance correlates with reduced Staphylococcus aureus endothelial cell damage.

There has been controversy about the intrinsic virulence of methicillin-resistant Staphylococcus aureus (MRSA) as compared to methicillin-susceptible S. aureus (MSSA). To address this discrepancy, the intrinsic virulence of 42 MRSA and 40 MSSA clinical isolates was assessed by testing endothelial cell (EC) damage, a surrogate marker for virulence in blood stream infections. Since these clinical isolates represent a heterogeneous group, well characterized S. aureus laboratory strains with SCCmec loss- and gain-of-function mutations were used in addition. The clinical MRSA isolates carrying typical hospital acquired SCCmec types (I, II or III) induced significantly less damage (47.8%) as compared to isolates with other SCCmec types (62.3%, p=0.03) and MSSA isolates (64.2%, p<0.01). There was a strong inverse correlation between high-level oxacillin resistance and low EC damage induction (R(2)=0.4464, p<0.001). High-level oxacillin resistant strains (MIC >32μ/ml) grew significantly slower as compared to isolates with low-level resistance (p=0.047). The level of EC damage positively correlated with α- and δ-toxin production (p<0.0001 and p<0.05, respectively) but not with β-toxin production. Invasive MRSA isolates (n=21, 56.3%) were significantly less cytotoxic as compared to invasive MSSA isolates (n=20, 68.0%, p<0.05). There was no difference between EC damage induced by superficial versus invasive isolates in either MRSA or MSSA strains. Our data suggest that the intrinsic virulence of MRSA is similar or even reduced as compared to MSSA strains but is linked to the level of methicillin resistance.

Cell-Density Dependence of Host-Defense Peptide Activity and Selectivity in the Presence of Host Cells.

Host-defense peptides (HDPs) are promising compounds against multidrug-resistant microbes. In vitro, their bactericidal and toxic concentrations are significantly different, but this might be due to the use of separate assays, with different cell densities. For experiments with a single cell type, the cell-density dependence of the active concentration of the DNS-PMAP23 HDP could be predicted based on the water/cell-membrane partition equilibrium and exhibited a lower bound at low cell counts. On the basis of these data, in the simultaneous presence of both bacteria and an excess of human cells, one would expect no significant toxicity, but also inhibition of the bactericidal activity due to peptide sequestration by host cells. However, this inhibition did not take place in assays with mixed cell populations, showing that for the HDP esculentin-1a(1-21)NH2, a range of bactericidal, nontoxic concentrations exists and confirming the effective selectivity of HDPs. Mixed-cell assays might be necessary to effectively asses HDP selectivity.

Virology: A parasite's parasite saves host's neighbours.

The activation of the IFNβ induction/signaling pathway in porcine alveolar macrophages by porcine reproductive and respiratory syndrome virus is variable.

It has been recognized that the expression of type I interferon (IFNα/β) may be suppressed during infection with porcine reproductive, respiratory syndrome virus (PRRSV). This causes profound negative effects on both the innate and adaptive immunity of the host resulting in persistence of infection.

The induction of the collagen capsule synthesis by Trichinella spiralis is closely related to protease-activated receptor 2.

The muscle-stage larvae of the parasite Trichinella spiralis have the ability to survive within host muscle tissue by virtue of the formation a nurse cell-parasite complex, which is surrounded by collagen. The formation of the complex is initiated by excretory-secretory (ES) proteins produced by the parasite. To determine the mechanisms underlying collagen capsule formation, we investigated the expression levels of several types of collagen genes and TGF-βI signaling-related genes (Smad2 and Smad3) in muscle cells. Synthesis of type I, IV, and VI collagen, which are major constituents of the collagen capsule, significantly increased during T. spiralis infection. In addition, we found that expression of the protease-activated receptor 2 (PAR2) gene was significantly increased during this period. Expression levels of the collagen genes and TGF-βI, Smad2, and Smad3 were induced by ES proteins and a PAR2 agonist, whereas their enhanced expression levels were reduced by a PAR2 antagonist and serine protease inhibitors. To evaluate the involvement of PAR2 during T. spiralis infection in vivo, we infected wild-type and PAR2 knockout (KO) mice with T. spiralis. Expression levels of type I, IV, and VI collagen genes and TGF-βI signaling-related genes (Smad2 and Smad3) were also decreased in the PAR2 KO mice. Phosphorylation of Smad2/3, which was increased by T. spiralis infection, was significantly diminished in the PAR2 KO mice. In conclusion, ES proteins containing serine protease most likely activate collagen synthesis via PAR2 and TGF-βI signaling, and this event could influence collagen capsule formation.

Borrelia burgdorferi – morphological structure and motility as adaptation for transmission and survival in the habitat of a tick-vertebrate setup

Lyme borreliosis is a multisystem chronic disease caused by Borrelia burgdorferi sensu lato (s.l.) spirochete transmitted by Ixodes. This bacterium has a remarkable ability to survive in tick-vertebrate setup. Its infection causes diagnostic and clinical difficulties. It was distinguished as a separate disease entity over 30 years ago. Observations made by Steere et al. proved to be a milestone since they found correlation between the occurrence of skin and joint lesions with tick bites. Further studies showed that the disease affects not only joints and skin, but also nervous and circulatory systems. Shortly afterwards, an etiological factor was identified – spirochete isolated by W. Burgdorfer (from ticks) as well as Steer and Benach (from blood). Research conducted by other authors confirmed that the spirochete named after its discoverer (Borrelia burgdorferi) is a common etiological factor for disease entities classified as Lyme borreliosis. The high incidence of Lyme borreliosis among the residents of endemic areas, along with diagnostic and therapeutic difficulties, make it a serious academic, clinical and social problem. The present article elaborates on bacterium structure and selected mechanisms facilitating the colonisation of particular hosts. Knowledge of those processes might be useful in understanding complex pathogenesis of lesions occurring in Lyme disease.

Bacteria establish an aqueous living space in plants crucial for virulence.

High humidity has a strong influence on the development of numerous diseases affecting the above-ground parts of plants (the phyllosphere) in crop fields and natural ecosystems, but the molecular basis of this humidity effect is not understood. Previous studies have emphasized immune suppression as a key step in bacterial pathogenesis. Here we show that humidity-dependent, pathogen-driven establishment of an aqueous intercellular space (apoplast) is another important step in bacterial infection of the phyllosphere. Bacterial effectors, such as Pseudomonas syringae HopM1, induce establishment of the aqueous apoplast and are sufficient to transform non-pathogenic P. syringae strains into virulent pathogens in immunodeficient Arabidopsis thaliana under high humidity. Arabidopsis quadruple mutants simultaneously defective in a host target (AtMIN7) of HopM1 and in pattern-triggered immunity could not only be used to reconstitute the basic features of bacterial infection, but also exhibited humidity-dependent dyshomeostasis of the endophytic commensal bacterial community in the phyllosphere. These results highlight a new conceptual framework for understanding diverse phyllosphere-bacterial interactions.

Role of non-motile microtubule-associated proteins in virus trafficking.

Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellular transport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAP1 and MAP2 families, and microtubule plus-end tracking proteins (+TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on non-motile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.

Viruses of parasites as actors in the parasite-host relationship: A "ménage à trois".

The complex parasite-host relationship involves multiple mechanisms. Moreover, parasites infected by viruses modify this relationship adding more complexity to the system that now comprises three partners. Viruses infecting parasites were described several decades ago. However, until recently little was known about the viruses involved and their impact on the resulting disease caused to the hosts. To clarify this situation, we have concentrated on parasitic diseases caused to humans and on how virus-infected parasites could alter the symptoms inflicted on the human host. It is clear that the effect caused to the human host depends on the virus and on the parasite it has infected. Consequently, the review is divided as follows: Viruses with a possible effect on the virulence of the parasite. This section reviews pertinent articles showing that infection of parasites by viruses might increase the detrimental effect of the tandem virus-parasite on the human host (hypervirulence) or decrease virulence of the parasite (hypovirulence). Parasites as vectors affecting the transmission of viruses. In some cases, the virus-infected parasite might facilitate the transfer of the virus to the human host. Parasites harboring viruses with unidentified effects on their host. In spite of recently renewed interest in parasites in connection with their viruses, there still remains a number of cases in which the effect of the virus of a given parasite on the human host remains ambiguous. The triangular relationship between the virus, the parasite and the host, and the modulation of the pathogenicity and virulence of the parasites by viruses should be taken into account in the rationale of fighting against parasites.

Host transcriptomic responses to pneumonic plague reveal that Yersinia pestis inhibits both the initial adaptive and innate immune responses in mice.

Pneumonic plague is the most deadly form of infection caused by Yersinia pestis and can progress extremely fast. However, our understanding on the host transcriptomic response to pneumonic plague is insufficient. Here, we used RNA-sequencing technology to analyze transcriptomic responses in mice infected with fully virulent strain 201 or EV76, a live attenuated vaccine strain lacking the pigmentation locus. Approximately 600 differentially expressed genes (DEGs) were detected in lungs from both 201- and EV76-infected mice at 12h post-infection (hpi). DEGs in lungs of 201-infected mice exceeded 2000 at 48hpi, accompanied by sustained large numbers of DEGs in the liver and spleen; however, limited numbers of DEGs were detected in those organs of EV-infected mice. Remarkably, DEGs in lungs were significantly enriched in critical immune responses pathways in EV76-infected but not 201-infected mice, including antigen processing and presentation, T cell receptor signaling among others. Pathological and bacterial load analyses confirmed the rapid systemic dissemination of 201-infection and the confined EV76-infection in lungs. Our results suggest that fully virulent Y. pestis inhibits both the innate and adaptive immune responses that are substantially stimulated in a self-limited infection, which update our holistic views on the transcriptomic response to pneumonic plague.

The immunopathogenesis of staphylococcal skin infections - A review.

Staphylococcus aureus and S. pseudintermedius are the major causes of bacterial skin disease in humans and dogs. These organisms can exist as commensals on the skin, but they can also cause severe or even devastating infections. The immune system has evolved mechanisms to deal with pathogenic microorganisms and has strategies to combat bacteria of this type. What emerges is a delicate "peace" between the opposing sides, but this balance can be disrupted leading to a full blown "war". In the ferocious battle that ensues, both sides attempt to get the upper hand, using strategies that are comparable to those used by modern day armies. In this review article, the complex interactions between the immune system and the organisms are described using such military analogies. The process is described in a sequential manner, starting with the invasion itself, and progressing to the eventual battlezone in which there are heavy casualties on both sides. By the end, the appearance of a simple pustule on the skin surface will take on a whole new meaning.

Functions of Exosomes and Microbial Extracellular Vesicles in Allergy and Contact and Delayed-Type Hypersensitivity.

Extracellular vesicles, such as exosomes, are newly recognized intercellular conveyors of functional molecular mechanisms. Notably, they transfer RNAs and proteins between different cells that can then participate in the complex pathogenesis of allergic and related hypersensitivity responses and disease mechanisms, as described herein. This review highlights this important new appreciation of the in vivo participation of such extracellular vesicles in the interactions between allergy-mediating cells. We take into account paracrine epigenetic exchanges mediated by surrounding stromal cells and the endocrine receipt of exosomes from distant cells via the circulation. Exosomes are natural ancient nanoparticles of life. They are made by all cells and in some form by all species down to fungi and bacteria, and are present in all fluids. Besides a new focus on their role in the transmission of genetic regulation, exosome transfer of allergens was recently shown to induce allergic inflammation. Importantly, regulatory and tolerogenic exosomes can potently inhibit allergy and hypersensitivity responses, usually acting nonspecifically, but can also proceed in an antigen-specific manner due to the coating of the exosome surface with antibodies. Deep analysis of processes mediated by exosomes should result in the development of early diagnostic biomarkers, as well as allergen-specific, preventive and therapeutic strategies. These will likely significantly diminish the risks of current allergen-specific parenteral desensitization procedures, and of the use of systemic immunosuppressive drugs. Since extracellular vesicles are physiological, they can be fashioned for the specific delivery of therapeutic molecular instructions through easily tolerated, noninvasive routes, such as oral ingestion, nasal administration, and perhaps even inhalation.

Density-dependent effects of Caligus rogercresseyi infestation on the immune responses of Salmo salar.

Sea lice infestations are a particular concern in the salmonid aquaculture industry due to damaging effects on fish growth, disease/infection susceptibility, and survival. Despite the impacts of sea lice parasitism, few studies have determined corresponding physiological thresholds, or the quantity of sea lice that can trigger measurable effects in the host immune response. The present study evaluated the mRNA expressions of immune-related genes in Salmo salar (Atlantic salmon) under infestation challenges with contrasting loads of the sea louse Caligus rogercresseyi. Specifically, two groups of S. salar were infected with either 35 (i.e. low parasitic load) or 100 (i.e. high parasitic load) copepodids per fish. At 14 days post-infestation, the mRNA levels of immune-related genes (e.g. related to oxidative stress, pro- and inflammatory responses, and the adaptive TH1/TH2 pathways) were assessed through RT-qPCR. Significant differences were found in relation to parasitic load, suggesting density-dependent effects that activated the S. salar immune system. Higher parasitic load promoted strong inflammatory and oxidative stress responses that were correlated with the TH1 immune response. This study highlights the molecular signatures for distinct parasitic loads, providing new perspectives towards fully understanding parasite-host interactions.

Proteomics progresses in microbial physiology and clinical antimicrobial therapy.

Clinical microbial identification plays an important role in optimizing the management of infectious diseases and provides diagnostic and therapeutic support for clinical management. Microbial proteomic research is aimed at identifying proteins associated with microbial activity, which has facilitated the discovery of microbial physiology changes and host-pathogen interactions during bacterial infection and antimicrobial therapy. Here, we summarize proteomic-driven progresses of host-microbial pathogen interactions at multiple levels, mass spectrometry-based microbial proteome identification for clinical diagnosis, and antimicrobial therapy. Proteomic technique progresses pave new ways towards effective prevention and drug discovery for microbial-induced infectious diseases.

Effects of soybean resistance on variability in life history traits of the higher trophic level parasitoid Meteorus pulchricornis (Hymenoptera: Braconidae).

To extrapolate the influence of plant cultivars varying in resistance levels to hosts on parasitoid life history traits, we estimated variation in parasitoid developmental and reproductive performances as a function of resistance in soybean cultivars, which were randomly chosen from a line of resistant genotypes. Our study showed that the parasitoid Meteorus pulchricornis varied widely in offspring survival and lifetime fecundity, but varied slightly in development time and adult body size, in response to the soybean cultivars that varied in resistance to the host Spodoptera litura. Furthermore, the variability in survival and lifetime fecundity was different between attacking the 2nd and the 4th instar host larvae, varying more in survival but less in lifetime fecundity when attacking the 4th than 2nd instar larvae. Our study provides further evidence supporting that plant resistance to herbivorous hosts have variable effects on different life history traits of higher trophic level parasitoids.

The assessment of host and bacterial proteins in sputum from active pulmonary tuberculosis.

Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis. The protein composition of sputum may reflect the immune status of the lung. This study aimed to evaluate the protein profiles in spontaneous sputum samples from patients with active pulmonary TB. Sputum samples were collected from patients with pulmonary TB and healthy controls. Western blotting was used to analyze the amount of interleukin 10 (IL-10), interferon-gamma (IFN-γ), IL-25, IL-17, perforin-1, urease, albumin, transferrin, lactoferrin, adenosine deaminase (also known as adenosine aminohydrolase, or ADA), ADA-2, granzyme B, granulysin, and caspase-1 in sputum. Results of detection of IL-10, IFN-γ, perforin-1, urease, ADA2, and caspase-1, showed relatively high specificity in distinguishing patients with TB from healthy controls, although sensitivities varied from 13.3% to 66.1%. By defining a positive result as the detection of any two proteins in sputum samples, combined use of transferrin and urease as markers increased sensitivity to 73.2% and specificity to 71.1%. Furthermore, we observed that the concentration of transferrin was proportional to the number of acid-fast bacilli detected in sputum specimens. Detection of sputum transferrin and urease was highly associated with pulmonary TB infection. In addition, a high concentration of transferrin detected in sputum might correlate with active TB infection. This data on sputum proteins in patients with TB may aid in the development of biomarkers to assess the severity of pulmonary TB.

Propionibacterium acnes inhibits FOXM1 and induces cell cycle alterations in human primary prostate cells.

Propionibacterium acnes has been detected in diseased human prostate tissue, and cell culture experiments suggest that the bacterium can establish a low-grade inflammation. Here, we investigated its impact on human primary prostate epithelial cells. Microarray analysis confirmed the inflammation-inducing capability of P. acnes but also showed deregulation of genes involved in the cell cycle. qPCR experiments showed that viable P. acnes downregulates a master regulator of cell cycle progression, FOXM1. Flow cytometry experiments revealed that P. acnes increases the number of cells in S-phase. We tested the hypothesis that a P. acnes-produced berninamycin-like thiopeptide is responsible for this effect, since it is related to the FOXM1 inhibitor siomycin. The thiopeptide biosynthesis gene cluster was strongly expressed; it is present in subtype IB of P. acnes, but absent from type IA, which is most abundant on human skin. A knock-out mutant lacking the gene encoding the berninamycin-like peptide precursor was unable to downregulate FOXM1 and to halt the cell cycle. Our study reveals a novel host cell-interacting activity of P. acnes.

Differential compartmentalization of Streptococcus pyogenes virulence factors and host protein binding properties as a mechanism for host adaptation.

Streptococcus pyogenes is an important human pathogen responsible for substantial morbidity and mortality worldwide. Although S. pyogenes is a strictly human pathogen with no other known animal reservoir, several murine infection models exist to explore different aspects of the bacterial pathogenesis. Inoculating mice with wild-type S. pyogenes strains can result in the generation of new bacterial phenotypes that are hypervirulent compared to the original inoculum. In this study, we used a serial mass spectrometry based proteomics strategy to investigate if these hypervirulent strains have an altered distribution of virulence proteins across the intracellular, surface associated and secreted bacterial compartments and if any change in compartmentalization can alter the protein-protein interaction network between bacteria and host proteins. Quantitative analysis of the S. pyogenes surface and secreted proteomes revealed that animal passaged strains are associated with significantly higher amount of virulence factors on the bacterial surface and in the media. This altered virulence factor compartmentalization results in increased binding of several mouse plasma proteins to the bacterial surface, a trend that was consistent for mouse plasma from several different mouse strains. In general, both the wild-type strain and animal passaged strain were capable of binding high amounts of human plasma proteins. However, compared to the non-passaged strains, the animal passaged strains displayed an increased ability to bind mouse plasma proteins, in particular for M protein binders, indicating that the increased affinity for mouse blood plasma proteins is a consequence of host adaptation of this pathogen to a new host. In conclusion, plotting the total amount of virulence factors against the total amount of plasma proteins associated to the bacterial surface could clearly separate out animal passaged strains from wild type strains indicating a virulence model that could predict the virulence of a S. pyogenes strain in mice and which could be used to identify key aspects of this bacteria's pathogenesis.

Local activation of coagulation factor XIII reduces systemic complications and improves the survival of mice after Streptococcus pyogenes M1 skin infection.

Coagulation is a mechanism for wound healing after injury. Several recent studies delineate an additional role of the intrinsic pathway of coagulation, also known as the contact system, in the early innate immune response against bacterial infections. In this study, we investigated the role of factor XIII (FXIII), which is activated upon coagulation induction, during Streptococcus pyogenes-mediated skin and soft tissue infections. FXIII has previously been shown to be responsible for the immobilization of bacteria within a fibrin network which may prevent systemic bacterial dissemination. In order to investigate if the FXIII-mediated entrapment of S. pyogenes also influences the disease outcome we used a murine S. pyogenes M1 skin and soft tissue infection model. Here, we demonstrate that a lack of FXIII leads to prolonged clotting times, increased signs of inflammation, and elevated bacterial dissemination. Moreover, FXIII-deficient mice show an impaired survival when compared with wildtype animals. Additionally, local reconstitution of FXIII-deficient mice with a human FXIII-concentrate (Fibrogammin(®)P) could reduce the systemic complications, suggesting a protective role for FXIII during early S. pyogenes skin infection. FXIII therefore might be a possible therapeutically application to support the early innate immune response during skin infections caused by S. pyogenes.

The human immune system's response to carcinogenic and other infectious agents transmitted by mosquito vectors.

It has been hypothesised that mosquitoes [Diptera: Culicidae] may play more of a role in certain cancers than is currently appreciated. Research links 33 infectious agents to cancer, 27 of which have a presence in mosquitoes, and that, in addition, mosquito saliva downregulates the immune system. The objective of this paper is to review the literature on the immune system and cancer-causing infectious agents, particularly those present in mosquitoes, with a view to establishing whether such infectious agents can, in the long run, defeat the immune system or be defeated by it. Many of the viruses, bacteria and parasites recognised by the International Agency for Research on Cancer (IARC) as carcinogenic and suspected by others as being involved in cancer have evolved numerous complex ways of avoiding, suppressing or altering the immune system's responses. These features, coupled with the multiplicity and variety of serious infectious agents carried by some species of mosquitoes and the adverse effects on the immune system of mosquito saliva, suggest that post-mosquito bite the immune system is likely to be overwhelmed. In such a situation, immunisation strategies offer little chance of cancer prevention, unless a single or limited number of critical infectious agents can be isolated from the 'mosquito' cocktail. If that proves to be impossible cancer prevention will, therefore, if the hypothesis proves to be correct, rest on the twin strategies of environmentally controlling the mosquito population and humans avoiding being bitten. The latter strategy will involve determining the factors that demark those being bitten from those that are not.