Rapid bursts of cellular proliferative, biosynthetic, and secretory activities by leukocytes require considerable metabolic resources that are especially important during periods of infection and ...inflammation 2, 3. Because immune cells have negligible intracellular nutrient stores and rely on aerobic glycolysis for activation and proliferation, they are particularly dependent on the uptake of metabolic substrates 2-6. ...even though B. pertussis is best known for its actions on the respiratory tract, this pathogen also acts at several other host sites, including spleen and blood; both sites play direct roles in mobilizing the host immune response during different phases of infection 31. ...analogous to PTX action in pancreatic beta cells, it is possible that ACT also acts on beta cells to increase cAMP, activate PKA, and thus significantly elevate insulin secretion. Clinical implications Despite numerous differences between B. pertussis and P. falciparum, they share the ability to cause profound disturbances in host metabolism during infection. Because hypoglycemia is often associated as a marker for disease severity, we propose that P. falciparum and B. pertussis induction of hypoglycemia serve as model systems to answer fundamental questions concerning how pathogen manipulation of metabolism can affect infection, pathogenesis, and the host immune response.
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Recent reemergence of pertussis (whooping cough) in highly vaccinated populations and rapid expansion of Bordetella pertussis strains lacking pertactin (PRN), a common acellular vaccine antigen, have ...raised the specter of vaccine-driven evolution and potential return of what was once the major killer of children. The discovery that most circulating B. pertussis strains in the United States have acquired new and independent disruptive mutations in PRN is compelling evidence of strong selective pressure. However, the other 4 antigens included in acellular vaccines do not appear to be selected against so rapidly. We consider 3 aspects of PRN that distinguish it from other vaccine antigens, which might, individually or collectively, explain why only this antigen is being precipitously eliminated. An understanding of the increase in PRN-deficient strains should provide useful information for the current search for new protective antigens and provide broader lessons for the design of improved subunit vaccines.
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Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu ...vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn's response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus
and to the newborn via milk. But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring's response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach.
The neonatal immune system is generally viewed as deficient compared to adults, often attributed to its incomplete development. This view is reinforced by the extraordinary sensitivity and ...susceptibility of neonates to certain pathogens. Examination of the basis for this susceptibility has characterized neonatal immunity as skewed strongly toward anti-inflammatory responses, which are interpreted as the lack of full development of the strong inflammatory responses observed in adults. Here we examine the alternative explanation that neonatal immune responses are generally complete in healthy newborns but evolved and adapted to very different functions than adult immunity. Adult immunity is primarily aimed at controlling pathogens that invade the holobiont, with substantial competition and protection conferred by resident microbiota. Rather than simply repelling new invaders, the immediate and critical challenge of the neonatal immune system during the sudden transition from near sterility to microbe-rich world is the assimilation of a complex microbiota to generate a stable and healthy holobiont. This alternative view of the role of the neonatal immune system both explains its strong anti-inflammatory bias and provides a different perspective on its other unique aspects. Here we discuss recent work exploring the initial contact of newborns with microbes and their interactions with neonatal immune responses, contrasting these alternative perspectives. Understanding how the need to rapidly acquire a highly complex and rich microbiota of commensals affects interactions between the neonatal immune system and both commensals and pathogens will allow more targeted and effective collaboration with this system to quickly achieve a more disease-resistant holobiont.
About the Authors: Kalyan K. Dewan * E-mail: kaldew@uga.edu Affiliation: Department of Infectious Disease, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of ...America ORCID logo http://orcid.org/0000-0001-9847-0286 Eric T. Harvill Affiliation: Department of Infectious Disease, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America ORCID logo http://orcid.org/0000-0001-8893-2133 Citation: Dewan KK, Harvill ET (2019) Did new transmission cycles in anthropogenic, dense, host populations encourage the emergence and speciation of pathogenic Bordetella? The authors have declared that no competing interests exist. ...the advent of vaccines in the mid 1950s, whooping cough (pertussis) was among the most prevalent and deadly diseases for children in the United States 1, 2 and still remains a worldwide problem, particularly for developing countries 3. Alternately, it can associate with predatory amoeba to expand in numbers and disperse in the environment via their complex life cycle. https://doi.org/10.1371/journal.ppat.1007600.g001 Anthropogenic sources of dense host populations favor closed life cycles The remarkable ability to subvert phagocytic amoebae of the environment is likely to involve many different molecular “tools” that could contribute to the ability to cause opportunistic infections in mammals. ...despite the genome reduction and the loss of its environmental existence, the master regulator of the Bvg system controlling the switch from the Bvg+ to the Bvg− phase, and corresponding transcriptional response of Bvg− phase genes in environmental temperatures remains conserved among the human restricted classical species.
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Infection and inflammation of the middle ears that characterizes acute and chronic otitis media (OM), is a major reason for doctor visits and antibiotic prescription, particularly among children. ...Nasopharyngeal pathogens that are commonly associated with OM in humans do not naturally colonize the middle ears of rodents, and experimental models in most cases involve directly injecting large numbers of human pathogens into the middle ear bullae of rodents, where they induce a short-lived acute inflammation but fail to persist. Here we report that Bordetella pseudohinzii, a respiratory pathogen of mice, naturally, efficiently and rapidly ascends the eustachian tubes to colonize the middle ears, causing acute and chronic histopathological changes with progressive decrease in hearing acuity that closely mimics otitis media in humans. Laboratory mice experimentally inoculated intranasally with very low numbers of bacteria consistently have their middle ears colonized and subsequently transmit the bacterium to cage mates. Taking advantage of the specifically engineered and well characterized immune deficiencies available in mice we conducted experiments to uncover different roles of T and B cells in controlling bacterial numbers in the middle ear during chronic OM. The iconic mouse model provides significant advantages for elucidating aspects of host-pathogen interactions in otitis media that are currently not possible using other animal models. This natural model of otitis media permits the study of transmission between hosts, efficient early colonization of the respiratory tract, ascension of the eustachian tube, as well as colonization, pathogenesis and persistence in the middle ear. It also allows the combination of the powerful tools of mouse molecular immunology and bacterial genetics to determine the mechanistic basis for these important processes.
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Multiple lines of evidence suggest that Bordetella species have a significant life stage outside of the mammalian respiratory tract that has yet to be defined. The Bordetella virulence gene (BvgAS) ...two-component system, a paradigm for a global virulence regulon, controls the expression of many "virulence factors" expressed in the Bvg positive (Bvg+) phase that are necessary for successful respiratory tract infection. A similarly large set of highly conserved genes are expressed under Bvg negative (Bvg-) phase growth conditions; however, these appear to be primarily expressed outside of the host and are thus hypothesized to be important in an undefined extrahost reservoir. Here, we show that Bvg- phase genes are involved in the ability of Bordetella bronchiseptica to grow and disseminate via the complex life cycle of the amoeba Dictyostelium discoideum. Unlike bacteria that serve as an amoeba food source, B. bronchiseptica evades amoeba predation, survives within the amoeba for extended periods of time, incorporates itself into the amoeba sori, and disseminates along with the amoeba. Remarkably, B. bronchiseptica continues to be transferred with the amoeba for months, through multiple life cycles of amoebae grown on the lawns of other bacteria, thus demonstrating a stable relationship that allows B. bronchiseptica to expand and disperse geographically via the D. discoideum life cycle. Furthermore, B. bronchiseptica within the sori can efficiently infect mice, indicating that amoebae may represent an environmental vector within which pathogenic bordetellae expand and disseminate to encounter new mammalian hosts. These data identify amoebae as potential environmental reservoirs as well as amplifying and disseminating vectors for B. bronchiseptica and reveal an important role for the Bvg- phase in these interactions.
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Halophilic prokaryotes are adapted to thrive in extreme conditions of salinity. Identification and analysis of distinct macromolecular characteristics of halophiles provide insight into the factors ...responsible for their adaptation to high-salt environments. The current report presents an extensive and systematic comparative analysis of genome and proteome composition of halophilic and non-halophilic microorganisms, with a view to identify such macromolecular signatures of haloadaptation.
Comparative analysis of the genomes and proteomes of halophiles and non-halophiles reveals some common trends in halophiles that transcend the boundary of phylogenetic relationship and the genomic GC-content of the species. At the protein level, halophilic species are characterized by low hydrophobicity, over-representation of acidic residues, especially Asp, under-representation of Cys, lower propensities for helix formation and higher propensities for coil structure. At the DNA level, the dinucleotide abundance profiles of halophilic genomes bear some common characteristics, which are quite distinct from those of non-halophiles, and hence may be regarded as specific genomic signatures for salt-adaptation. The synonymous codon usage in halophiles also exhibits similar patterns regardless of their long-term evolutionary history.
The generality of molecular signatures for environmental adaptation of extreme salt-loving organisms, demonstrated in the present study, advocates the convergent evolution of halophilic species towards specific genome and amino acid composition, irrespective of their varying GC-bias and widely disparate taxonomic positions. The adapted features of halophiles seem to be related to physical principles governing DNA and protein stability, in response to the extreme environmental conditions under which they thrive.
B. parapertussis is a whooping cough etiological agent with the ability to evade the immune response induced by pertussis vaccines. We previously demonstrated that in the absence of opsonic ...antibodies B. parapertussis hampers phagocytosis by neutrophils and macrophages and, when phagocytosed, blocks intracellular killing by interfering with phagolysosomal fusion. But neutrophils can kill and/or immobilize extracellular bacteria through non-phagocytic mechanisms such as degranulation and neutrophil extracellular traps (NETs). In this study we demonstrated that B. parapertussis also has the ability to circumvent these two neutrophil extracellular bactericidal activities. The lack of neutrophil degranulation was found dependent on the O antigen that targets the bacteria to cell lipid rafts, eventually avoiding the fusion of nascent phagosomes with specific and azurophilic granules. IgG opsonization overcame this inhibition of neutrophil degranulation. We further observed that B. parapertussis did not induce NETs release in resting neutrophils and inhibited NETs formation in response to phorbol myristate acetate (PMA) stimulation by a mechanism dependent on adenylate cyclase toxin (CyaA)-mediated inhibition of reactive oxygen species (ROS) generation. Thus, B. parapertussis modulates neutrophil bactericidal activity through two different mechanisms, one related to the lack of proper NETs-inducer stimuli and the other one related to an active inhibitory mechanism. Together with previous results these data suggest that B. parapertussis has the ability to subvert the main neutrophil bactericidal functions, inhibiting efficient clearance in non-immune hosts.
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