Dynamics Of Host-pathogen Interactions Research Articles

Variation in Cell Surface Hydrophobicity among Cryptococcus neoformans Strains Influences Interactions with Amoebas.

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that cause significant morbidity and mortality. Cell surface hydrophobicity (CSH) is a biophysical parameter that influences the adhesion of fungal cells or spores to biotic and abiotic surfaces. C. neoformans is encased by polysaccharide capsule that is highly hydrophilic and is a critical determinant of virulence. In this study, we report large differences in the CSH of some C. neoformans and C. gattii strains. The capsular polysaccharides of C. neoformans strains differ in repeating motifs and therefore vary in the number of hydroxyl groups, which, along with higher-order structure of the capsule, may contribute to the variation in hydrophobicity that we observed. We found that cell wall composition, in the context of chitin-chitosan content, does not influence CSH. For C. neoformans, CSH correlated with phagocytosis by natural soil predator Acanthamoeba castellanii Furthermore, capsular binding of the protective antibody (18B7), but not the nonprotective antibody (13F1), altered the CSH of C. neoformans strains. Variability in CSH could be an important characteristic in comparing the biological properties of cryptococcal strains.IMPORTANCE The interaction of a microbial cell with its environment is influenced by the biophysical properties of a cell. The affinity of the cell surface for water, defined by the cell surface hydrophobicity (CSH), is a biophysical parameter that varies among different strains of Cryptococcus neoformans The CSH influences the phagocytosis of the yeast by its natural predator in the soil, the amoeba. Studying variation in biophysical properties like CSH gives us insight into the dynamic host-predator interaction and host-pathogen interaction in a damage-response framework.

Vaginal Microbiota and HPV Infection: Novel Mechanistic Insights and Therapeutic Strategies.

Cervical cancer is a global public health concern. The complex interaction of genetic and environmental factors is critical for the progress of cervical cancer. Growing evidence suggests that microbes, human papillomavirus (HPV), and the immune system interact closely with each other to govern homeostasis of the vaginal environment and the health of the lower genital tract of females. Certain vaginal microbial strains may play either a protective or a pathogenic role in carcinogenesis of the cervix after HPV persistent infection. Probiotics can therefore present a putative therapeutic approach for cervical cancer. However, work in this field remains limited. Recent technological developments have allowed us to identify microbes and their products using culture-independent molecular detection techniques. In this review, we discuss the composition of the vaginal bacterial community, its commensal flora and the protective impact this has on the health of the female genital tract. This review will also describe critical immune factors in lower genital tract health and summarize the role of the vaginal microbiota in cervical carcinogenesis. Knowledge in this field has provided researchers with the clues and tools to propose the use of probiotics as a potential line of treatment for cervical cancer and has provided valuable insights into host–pathogen interaction dynamics within the female genital tract.

The Genetic Basis of Natural Variation in Drosophila melanogaster Immune Defense against Enterococcus faecalis.

Dissecting the genetic basis of natural variation in disease response in hosts provides insights into the coevolutionary dynamics of host-pathogen interactions. Here, a genome-wide association study of Drosophila melanogaster survival after infection with the Gram-positive entomopathogenic bacterium Enterococcus faecalis is reported. There was considerable variation in defense against E. faecalis infection among inbred lines of the Drosophila Genetics Reference Panel. We identified single nucleotide polymorphisms associated with six genes with a significant (p < 10−08, corresponding to a false discovery rate of 2.4%) association with survival, none of which were canonical immune genes. To validate the role of these genes in immune defense, their expression was knocked-down using RNAi and survival of infected hosts was followed, which confirmed a role for the genes krishah and S6k in immune defense. We further identified a putative role for the Bomanin gene BomBc1 (also known as IM23), in E. faecalis infection response. This study adds to the growing set of association studies for infection in Drosophila melanogaster and suggests that the genetic causes of variation in immune defense differ for different pathogens.

From the Cradle to the Grave of an Infection: Host-Pathogen Interaction Visualized by Intravital Microscopy.

During infections, interactions between host immune cells and the pathogen occur in distinct anatomical locations and along defined time scales. This can best be assessed in the physiological context of an infection in the living tissue. Consequently, intravital imaging has enabled us to dissect the critical phases and events throughout an infection in real time in living tissues. Specifically, advances in visualizing specific cell types and individual pathogens permitted tracking the early events of tissue invasion of the pathogen, cellular interactions involved in the induction of the immune response as well the events implicated in clearance of the infection. In this respect, two vantage points have evolved since the initial employment of this technique in the field of infection biology. On the one hand, strategies acquired by the pathogen to establish within the host and circumvent or evade the immune defenses have been elucidated. On the other hand, analyzing infections from the immune system's perspective has led to insights into the dynamic cellular interactions that are involved in the initial recognition of the pathogen, immune induction as well as effector function delivery and immunopathology. Furthermore, an increasing interest in probing functional parameters in vivo has emerged, such as the analysis of pathogen reactivity to stress conditions imposed by the host organism in order to mediate clearance upon pathogen encounter. Here, we give an overview on recent intravital microscopy findings of host-pathogen interactions along the course of an infection, from both the immune system's and pathogen's perspectives. We also discuss recent developments and future perspectives in extracting intravital information beyond the localization of pathogens and their interaction with immune cells. Such reporter systems on the pathogen's physiological state and immune cell functions may prove useful in dissecting the functional dynamics of host-pathogen interactions. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

The intracellular pathogen concept.

The intracellular pathogen concept classifies pathogenic microbes on the basis of their site of replication and dependence on host cells. This concept played a fundamental role in establishing the field of cellular microbiology, founded in part by Dr. Pascale Cossart, whose seminal contributions are honored in this issue of Molecular Microbiology. The recognition that microbes can access and replicate in privileged compartments within host cells has led to many new and fruitful lines of investigation into the biology of the cell and mechanisms of cell-mediated immunity. However, like any scientific concept, the intracellular pathogen concept can become a dogma that constrains thinking and oversimplifies complex and dynamic host-pathogen interactions. Growing evidence has blurred the distinction between "intracellular" and "extracellular" pathogens and demonstrated that many pathogens can exist both within and outside of cells. Although the intracellular pathogen concept remains useful, it should not be viewed as a rigid classification of pathogenic microbes, which exhibit remarkable variation and complexity in their behavior in the host.

Fluorescence Biosensor for Real-Time Interaction Dynamics of Host Proteins with HIV-1 Capsid Tubes.

The human immunodeficiency virus 1 (HIV-1) capsid serves as a binding platform for proteins and small molecules from the host cell that regulate various steps in the virus life cycle. However, there are currently no quantitative methods that use assembled capsid lattices to measure host-pathogen interaction dynamics. Here we developed a single-molecule fluorescence biosensor using self-assembled capsid tubes as biorecognition elements and imaged capsid binders using total internal reflection fluorescence microscopy in a microfluidic setup. The method is highly sensitive in its ability to observe and quantify binding, to obtain dissociation constants, and to extract kinetics with an extended application of using more complex analytes that can accelerate characterization of novel capsid binders.

Restoration of cytosolic calcium inhibits Mycobacterium tuberculosis intracellular growth: Theoretical evidence and experimental observation

Mycobacterium tuberculosis (Mtb) is a highly successful intracellular pathogen because of its ability to modulate host’s anti-microbial pathways. Phagocytosis acts as the first line of defence against microbial infection. However, Mtb inhibits Phosphatidylinositol 3-phosphate (PI3P) oscillations which is required for phagolysosomal fusion. Here we attempted to understand the mechanisms by which Mtb eliminates phagosome-lysosome fusion. To address this, we built a four dimensional ordinary differential equation model and explored the contribution of PI3P during Mtb phagocytosis. Using this model, we identified some sensitive parameters that influence the dynamics of host-pathogen interactions. We observed that PI3P dynamics can be controlled by regulating the intracellular calcium oscillations. Some plausible methods to restore PI3P oscillations are ER flux rate, recruitment rate of proteins, like Rab GTPase, and cooperativity coefficient of calcium dependent consumption of calmodulin. Further, we investigated whether modulation of these pathways is a potential therapeutic intervention strategy. Here we showed that RyR2 agonist caffeine stimulated calcium influx and inhibited growth of intracellular Mtb in macrophages. Taken together, we demonstrate that modulation of host calcium level is a plausible strategy for killing of intracellular Mtb.

A bilayer tissue culture model of the bovine alveolus

The epithelial lining of the lung is often the first point of interaction between the host and inhaled pathogens, allergens and medications. Epithelial cells are therefore the main focus of studies which aim to shed light on host-pathogen interactions, to dissect the mechanisms of local host immunity and study toxicology. If these studies are not to be conducted exclusively in vivo, it is imperative that in vitro models are developed with a high in vitro-in vivo correlation. We describe here a co-culture bilayer model of the bovine alveolus, designed to overcome some of the limitations encountered with mono-culture and live animal models. Our system includes bovine pulmonary arterial endothelial cells (BPAECs) seeded onto a permeable membrane in 24 well Transwell format. The BPAECs are overlaid with immortalised bovine alveolar type II epithelial cells and the bilayer cultured at air-liquid interface for 14 days before use; in our case to study host-mycobacterial interactions. Characterisation of novel cell lines and the bilayer model have provided compelling evidence that immortalised bovine alveolar type II cells are an authentic substitute for primary alveolar type II cells and their culture as a bilayer in conjunction with BPAECs provides a physiologically relevant in vitro model of the bovine alveolus. The bilayer model may be used to study dynamic intracellular and extracellular host-pathogen interactions, using proteomics, genomics, live cell imaging, in-cell ELISA and confocal microscopy. The model presented in this article enables other researchers to establish an in vitro model of the bovine alveolus that is easy to set up, malleable and serves as a comparable alternative to in vivo models, whilst allowing study of early host-pathogen interactions, currently not feasible in vivo. The model therefore achieves one of the 3Rs objectives in that it replaces the use of animals in research of bovine respiratory diseases.

Pseudomonas aeruginosa Protease IV Exacerbates Pneumococcal Pneumonia and Systemic Disease.

Pneumonia is a pulmonary disease affecting people of all ages and is consistently a leading cause of childhood mortality and adult hospitalizations. Streptococcus pneumoniae and Pseudomonas aeruginosa are major lung pathogens commonly associated with community-acquired and nosocomial pneumonia. Additionally, mixed lung infections involving these bacterial pathogens are increasing in prevalence and are frequently more severe than single infections. The cooperative interactions of these two pathogens that impact pulmonary disease severity are understudied. A major secreted virulence factor of P.aeruginosa, protease IV (PIV), cleaves interleukin 22 (IL-22), a cytokine essential for maintaining innate mucosal defenses against extracellular pathogens. Here, we investigate the ability of PIV to augment the virulence of a pneumococcal strain with limited virulence, S.pneumoniae EF3030, in a C57BL/6 murine model of pneumonia. We demonstrate that pulmonary coinfection involving P.aeruginosa 103-29 and S.pneumoniae EF3030 results in pneumococcal bacteremia that is abrogated during pneumococcal coinfection with a PIV-deficient strain. Furthermore, intratracheal administration of exogenous PIV and EF3030 resulted in abundant immune cell infiltration into the lung with large abscess formation, as well as severe bacteremia leading to 100% mortality. Heat-inactivated PIV did not worsen pneumonia or reliably induce bacteremia, suggesting that the specific activity of PIV is required. Our studies also show that PIV depletes IL-22 in vivo Moreover, PIV-mediated enhancement of pneumonia and disease severity was dependent on the expression of pneumolysin (Ply), a prominent virulence factor of S.pneumoniae Altogether, we reveal that PIV and Ply additively potentiate pneumonia in a murine model of lung infection.IMPORTANCES.pneumoniae remains the leading cause of bacterial pneumonia despite widespread use of pneumococcal vaccines, forcing the necessity for appropriate treatment to control pneumococcal infections. Coinfections involving S.pneumoniae with other bacterial pathogens threaten antibiotic treatment strategies and disease outcomes. Currently, there is not an effective treatment for alveolar-capillary barrier dysfunction that precedes bacteremia. An understanding of the dynamics of host-pathogen interactions during single and mixed pulmonary infections could elucidate proper treatment strategies needed to prevent or reduce invasive disease. Antibiotic treatment decreases bacterial burden in the lung but also increases acute pathology due to cytotoxins released via antibiotic-induced bacterial lysis. Therefore, targeted therapeutics that inhibit or counteract the effects of bacterial proteases and toxins are needed in order to limit pathology and disease progression. This study identifies the cooperative effect of PIV and Ply, products of separate lung pathogens that additively alter the lung environment and facilitate invasive disease.

Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages

Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host-pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNγ (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb-induced differentially expressed genes revealed various terms, related to host-protection and inflammation, enriched in up-regulated genes. On the other hand, terms related to dis-regulation of cellular functions were enriched in down-regulated genes. Differential expression analysis revealed known as well as novel transcription factor genes in Mtb infection, many of them significantly down-regulated. IFNγ or IL-4/IL-13 pre-stimulation induce additional differentially expressed genes in Mtb-infected macrophages. Cluster analysis uncovered significant numbers, prolonging their expressional changes. Furthermore, Mtb infection augmented cytokine-mediated M1 and M2 pre-activations. In addition, we identified unique transcriptional features of Mtb-mediated differentially expressed lncRNAs. In summary we provide a comprehensive in depth gene expression/regulation profile in Mtb-infected macrophages, an important step forward for a better understanding of host-pathogen interaction dynamics in Mtb infection.

Co-evolutionary interactions between host resistance and pathogen avirulence genes in rice-Magnaporthe oryzae pathosystem

Rice and Magnaporthe oryzae constitutes an ideal pathosystem for studying host-pathogen interaction in cereals crops. There are two alternative hypotheses, viz. Arms race and Trench warfare, which explain the co-evolutionary dynamics of hosts and pathogens which are under continuous confrontation. Arms race proposes that both R- and Avr- genes of host and pathogen, respectively, undergo positive selection. Alternatively, trench warfare suggests that either R- or Avr- gene in the pathosystem is under balanced selection intending to stabilize the genetic advantage gained over the opposition. Here, we made an attempt to test the above-stated hypotheses in rice-M. oryzae pathosystem at loci of three R-Avr gene pairs, Piz-t-AvrPiz-t, Pi54-AvrPi54 and Pita-AvrPita using allele mining approach. Allele mining is an efficient way to capture allelic variants existing in the population and to study the selective forces imposed on the variants during evolution. Results of nucleotide diversity, neutrality statistics and phylogenetic analyses reveal that Piz-t, Pi54 and AvrPita are diversified and under positive selection at their corresponding loci, while their counterparts, AvrPiz-t, AvrPi54 and Pita are conserved and under balancing selection, in nature. These results imply that rice-M. oryzae populations are engaged in a trench warfare at least at the three R/Avr loci studied. It is a maiden attempt to study the co-evolution of three R-Avr gene pairs in this pathosystem. Knowledge gained from this study will help in understanding the evolutionary dynamics of host-pathogen interaction in a better way and will also aid in developing new durable blast resistant rice varieties in future.

Self-clearance of Pestivirus in a Pyrenean Chamois ( Rupicapra pyrenaica) Population.

Understanding the dynamics of host-pathogen interaction is key to the management of epidemics. A pestivirus belonging to the border disease virus group 4 emerged around 2001 in Pyrenean chamois ( Rupicapra pyrenaica) in Spain and France. The virus had significant demographic impact in some populations, but it was less harmful and more endemic in other places. The determinants of these local variations are still unclear. Here, we documented empirical evidence of self-clearance of the virus in a chamois population in France. This population has regularly been counted, and chamois were trapped and harvested each year, providing unique demographic and epidemiologic surveys of the population since 1984 and 1994, respectively. The virus was detected using direct (PCR) and indirect (antibody) testing. We showed that virus transmission declined in 2011-12 and likely ceased in 2013, leading to a decline in antibody prevalence since 2014. Self-clearance may be due to limited exchanges with other populations, decrease in population size after an epizootic, and herd immunity. The age structure of captured animals shifted to younger age classes after virus self-clearance, suggesting a return to a colonizing population structure. The possible consequences of virus re-entry are discussed. This observation suggests that pestivirus dynamics occurs at the scale of the metapopulation of Pyrenean chamois. Local self-clearance and re-emergence may help explain the variation of virus dynamics at the local scale.

A novel method for genome-wide profiling of dynamic host-pathogen interactions using 3\u2032 end enriched RNA-seq

Marek’s disease is a contagious lymphoproliferative disease of chickens and typical model of viral oncogenesis. Mapping changes or different states over the course of infection for both host and pathogen would provide important insights into dynamic host-pathogen interactions. Here we introduced 3′ end enriched RNA-seq as a novel method to study host-pathogen interactions in chicken embryo fibroblasts cells challenged with Marek’s disease virus. The method allowed accurate profiling of gene expression and alternative polyadenylation sites for host and pathogen simultaneously. We totally identified 476 differentially expressed genes and 437 APA switching genes in host, including switching in tandem 3′ UTRs and switching between coding region and 3′ UTR. Most of these genes were related to innate immunity, apoptosis and metabolism, but two sets of genes overlapped a little, suggesting two complementary mechanisms in gene regulation during MDV infection. In summary, our results provided a relatively comprehensive insight into dynamic host-pathogen interactions in regulation of gene transcription during infection of Marek’s disease virus and suggested that 3′ end enriched RNA-seq was a promising method to investigate global host-pathogen interactions.

Predicting the Potential for Natural Recovery of Atlantic Salmon (Salmo salar L.) Populations following the Introduction of Gyrodactylus salaris Malmberg, 1957 (Monogenea).

Gyrodactylus salaris (Monogenea, Platyhelminthes) is a notifiable freshwater pathogen responsible for causing catastrophic damage to wild Atlantic salmon stocks, most notably in Norway. In some strains of Baltic salmon (e.g., from the river Neva) however, the impact is greatly reduced due to some form of innate resistance that regulates parasite numbers, resulting in fewer host mortalities. Gyrodactylus salaris is known from 17 European states; its status in a further 35 states remains unknown; the UK, the Republic of Ireland and certain watersheds in Finland are free of the parasite. Thus, the parasite poses a serious threat if it emerges in Atlantic salmon rearing regions throughout Europe. At present, infections are generally controlled via extreme measures such as the treatment of entire river catchments with the biocide rotenone, in order to remove all hosts, before restocking with the original genetic stock. The use of rotenone in this way in EU countries is unlikely as it would be in contravention of the Water Framework Directive. Not only are such treatments economically and environmentally costly, they also eradicate the potential for any host/parasite evolutionary process to occur. Based on previous studies, UK salmon stocks have been shown to be highly susceptible to infection, analogous to Norwegian stocks. The present study investigates the impact of a G. salaris outbreak within a naïve salmon population in order to determine long-term consequences of infection and the likelihood of coexistence. Simulation of the salmon/ G. salaris system was carried out via a deterministic mathematical modelling approach to examine the dynamics of host-pathogen interactions. Results indicated that in order for highly susceptible Atlantic strains to evolve a resistance, both a moderate-strong deceleratingly costly trade-off on birth rate and a lower overall cost of the immune response are required. The present study provides insights into the potential long term impact of G. salaris if introduced into G. salaris-free territories and suggests that in the absence of external controls salmon populations are likely to recover to high densities nearing 90% of that observed pre-infection.

Model of Host-Pathogen Interaction Dynamics Links In Vivo Optical Imaging and Immune Responses.

ABSTRACTTracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions.

Hijacking Host Cell Highways: Manipulation of the Host Actin Cytoskeleton by Obligate Intracellular Bacterial Pathogens

Intracellular bacterial pathogens replicate within eukaryotic cells and display unique adaptations that support key infection events including invasion, replication, immune evasion, and dissemination. From invasion to dissemination, all stages of the intracellular bacterial life cycle share the same three-dimensional cytosolic space containing the host cytoskeleton. For successful infection and replication, many pathogens hijack the cytoskeleton using effector proteins introduced into the host cytosol by specialized secretion systems. A subset of effectors contains eukaryotic-like motifs that mimic host proteins to exploit signaling and modify specific cytoskeletal components such as actin and microtubules. Cytoskeletal rearrangement promotes numerous events that are beneficial to the pathogen, including internalization of bacteria, structural support for bacteria-containing vacuoles, altered vesicular trafficking, actin-dependent bacterial movement, and pathogen dissemination. This review highlights a diverse group of obligate intracellular bacterial pathogens that manipulate the host cytoskeleton to thrive within eukaryotic cells and discusses underlying molecular mechanisms that promote these dynamic host-pathogen interactions.

Host-Bacterial Interactions in Post-treatment Apical Periodontitis: A Metaproteome Analysis

IntroductionThis study evaluated the bacterial and human metaproteome of root apexes and the matched inflammatory lesions from teeth with post-treatment apical periodontitis. MethodsRoot apexes and matched inflammatory lesions from root canal–treated teeth with apical periodontitis were obtained during periradicular surgery. All root canal fillings were rated as adequate on the basis of radiographs and cone-beam computed tomography. The specimens were cryopulverized and subjected to metaproteomic analysis for human and bacterial proteins by using a mass spectrometry platform that is based on nanoflow liquid chromatography coupled with linear ion trap quadrupole Velos Orbitrap. ResultsThe metaproteome analyses revealed the presence of viable and metabolically active human and bacterial cells in both apexes and lesions. Several bacterial proteins of interest for pathogenicity and therapeutics were identified in both apexes and lesions, including proteins related to antibiotic resistance, proteolytic function, stress response, adhesion, and virulence. Many human proteins related to immune defense mechanisms were also detected in both root apex and lesion specimens, including immunoglobulins, complement system, and proteins linked to T-cell and B-cell activation, neutrophil microbicidal processes, antigen recognition/presentation, bone resorption, and protection against tissue damage. ConclusionsOccurrence of host defense factors from the innate and adaptive immune responses and bacterial virulence, survival, and resistance proteins in matched root apexes/periradicular inflammatory lesions indicates a complex and dynamic host-pathogen interaction in teeth with post-treatment apical periodontitis.

Commentary: Advancement of Knowledge of Brucella Over the Past 50 Years.

Brucella ceti, a cetacean and zoonotic pathogen displaying a marked neurotropism in striped dolphins (Stenella coeruleoalba), appears to be the ancestor and a close relative of B. abortus, infecting cattle, as well as of B. melitensis, infecting sheep and goat (1). In addition to the elegant mechanisms and strategies utilized by Brucella genus members for entering and surviving into host cells, which are clearly explained in the aforementioned review article (2), the interaction between bacterial Hsp60 – a member of the GroEL family of chaperonins – and cellular prion protein (PrPC) has been reported to play a crucial role in B. abortus infection of murine, bone marrow-derived macrophages, with no evidence of microbial colonization and replication in cells from PrPC-deficient mice (3, 4). As “top predators,” cetaceans may accumulate within their tissues high concentrations of immunotoxic and neurotoxic “persistent organic pollutants” (POPs) like dioxins and dioxin-like compounds (DLCs) (5, 6), which have been demonstrated to exert pro-apoptotic activity on human neuronal cells (7). As a consequence, following dioxin-induced apoptosis, PrPC overexpression is likely to occur on host cell membrane, given the anti-apoptotic role of PrPC, which is consistently expressed on brain cells (8). Based upon the aforementioned model, the heavy (cerebral and extra-neural) tissue loads of lipophylic dioxins and DLCs commonly detected in stranded dolphins (5, 6) could elicit PrPC overexpression on behalf of brain cells, resulting at its turn in an amplified colonization and replication activity of B. ceti inside these cells. The recently characterized expression patterns of PrPC within the cerebral parenchyma as well as in secondary lymphoid tissues from wild dolphins (9), which resemble those previously reported in terrestrial mammals (8), provide additional support for such hypothesis, thereby making biologically plausible the occurrence of “neurobrucellosis,” a neurological disease condition frequently observed in B. ceti-affected striped dolphins (1). Indeed, high levels of dioxins and DLCs have been recently found in tissues from B. ceti meningoencephalitis-affected striped dolphins beached along the Ionian Sea coast of Italy (Antonio Petrella and Pasquale Troiano, personal communication). In this respect, it should be also emphasized that significant differences have been recently reported in the endo-cerebral expression levels of 5-lipoxygenase (5-LOX), a neurodegeneration biomarker (10), between infectious encephalitis/meningoencephalitis-affected and -unaffected striped dolphins, with the most consistent intensity of expression of the aforementioned enzyme having been detected in a B. ceti-infected individual (11). This appears to be a remarkable finding, provided that such an extensive neuroinflammatory and neurodegenerative lesions’ pattern could have acted synergistically with the high tissue concentrations of dioxins and DLCs found in this dolphin (Antonio Petrella and Pasquale Troiano, personal communication), thereby leading to PrPC overexpression, with subsequent putative increase of B. ceti colonization and replication inside brain cells. In conclusion, based upon the strong impact exerted by B. ceti infection on the health and conservation status of free-ranging cetaceans all across the globe, associated with the proven zoonotic capability of this microorganism (1, 5, 12), the study of the infection’s neuropathogenesis, including the strategies adopted by B. ceti in crossing the blood–brain barrier from striped dolphins, would deserve adequate attention. Particular emphasis should be additionally placed on the study of the infection’s epidemiology and of the evolutionary genetics of B. ceti, also in comparison with all the other known Brucella genus members, as well as on the study of host–pathogen interaction dynamics, with special reference to the “host related” (PrPC expression levels and patterns) and to the “environment related” (POPs, dioxins, DLCs, etc.) drivers and modulators of such complex interplay.

Within- and between-host mathematical modeling of Mycobacterium avium subspecies paratuberculosis (MAP) infections as a tool to study the dynamics of host-pathogen interactions in bovine paratuberculosis

Paratuberculosis is a chronic intestinal infection of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP). Although a small proportion of animals are able to clear the infection, the majority of exposed animals will become chronically infected for life. Substantial economic losses to the dairy industry are a result of the clinical manifestation of the disease; however, production losses and increased morbidity in subclinically affected animals are also important factors. Only a small fraction (approximately 10%) of chronically infected animals will develop a fatal progressive form of the disease. The progressive form of clinical paratuberculosis is characterized by chronic intractable diarrhea in cattle and weight loss, production losses and severe emaciation leading to death since no treatment is available. A schematic representation of current views regarding the dynamics and pathogenesis of paratuberculosis is depicted in Fig. 1. This special issue of Veterinary Research is a compilation of work that explores and connects the dynamics of MAP-host interaction biology at multiple levels. The aim of this work is to highlight the potential of mathematical modelling techniques in exploring knowledge gaps and alternative explanations for observations made in data from experimental and field studies, which may ultimately lead to a better understanding of this complex infection.

Mass spectrometry-based proteomic approaches to study pathogenic bacteria-host interactions.

Elucidation of molecular mechanisms underlying host-pathogen interactions is important for control and treatment of infectious diseases worldwide. Within the last decade, mass spectrometry (MS)-based proteomics has become a powerful and effective approach to better understand complex and dynamic host-pathogen interactions at the protein level. Herein we will review the recent progress in proteomic analyses towards bacterial infection of their mammalian host with a particular focus on enteric pathogens. Large-scale studies of dynamic proteomic alterations during infection will be discussed from the perspective of both pathogenic bacteria and host cells.