Bordetella pertussis is a Gram-negative, aerobic, pathogenic, encapsulated coccobacillus bacterium of the genus Bordetella. It is the causative agent of pertussis or whooping cough. Despite widespread vaccination, B. pertussis continues to cause illness and death worldwide due to declining immunity and pathogen adaptation. Its virulence factors include pertussis toxin, adenylate cyclase toxin, filamentous haemagglutinin, pertactin, pili, and tracheal cytotoxin.
B. pertussis is an obligate human pathogen and is transmitted through airborne droplets. The disease's incubation period averages 7–10 days, however the range is anywhere from 6–20 days. The bacterium attaches to the ciliated epithelial cells lining the respiratory tract using specialized surface proteins to remain in place. It then releases toxins that disrupt normal cellular functions and cause symptoms in its human host, the only known reservoir for B. pertussis.
The complete B. pertussis genome of 4,086,186 base pairs was published in 2003. This is smaller than the closely-related species B. bronchiseptica, with a genome of 5.2 million base pairs. On the other hand, similarly to B. bronchiseptica, B. pertussis can express a flagellum-like structure, although it is normally classified as nonmotile bacterium.
Taxonomy The genus Bordetella contains nine species: B. pertussis, B. parapertussis, B. bronchiseptica, B. avium, B. hinzii, B. holmesii, B. trematum, B. ansorpii, and B. petrii.
B. pertussis, B. parapertussis and B. bronchiseptica form a closely related phylogenetical group. B. parapertussis causes a disease similar to whooping cough in humans, and B. bronchiseptica infects a range of mammal hosts, including humans, and causes a spectrum of respiratory disorders.
Evolution The disease pertussis was first described by French physician Guillaume de Baillou after the epidemic of 1578. The disease may have been described earlier in a Korean medical textbook. The causative agent of pertussis was identified and isolated by Jules Bordet and Octave Gengou in 1906. It is believed that the genus Bordetella may have evolved from ancestors that could survive in the soil according to 16S rRNA gene sequencing data. 16S rRNA is a component of all bacteria that allows for the comparison of phyla within a sample. The expansion of human development into the agricultural field caused there to be an influx of human to soil contact. This increase not only created more advantageous environments for the ancestors of Bordetella not only to thrive in, but to spread to humans as well. B. pertussis is able to persist among infants and young children in spite of high vaccination rates. There have been global outbreaks within the past decade. In 2012, epidemic outbreaks in Canada, Australia, France, the UK, Japan, and the USA were prevalent. The cases of B. pertussis in Africa are seemingly unpublished, but on the rise as they primarily target infants and young children.
It was initially determined that B. pertussis is a monomorphic pathogen in which the majority of strains found had the same two types of alleles: ptxA1 or ptxA2. Modern developments in genome sequencing have allowed B. pertussis to be studied more allowing for the discovery of the ptxP region. Through studying the gene, there has been evidence of mutations within the gene that show missing genomes present on the DNA strand. A study by Bart et al. revealed that 25% of the genes on the Tohama I reference strain of the B. pertussis sequence were missing in comparison to the ancestral strains. These mutations were noted to be caused by an increase in intragenomic recombination with loss of DNA. Genes controlled by the BvgAS system have transformed B. pertussis into a much more contagious pathogen. In particular, strains with the ptxP3 allele, that developed through mutations in recent years, have an increased expression of toxins. Ultimately, this leads to higher acuteness of the disease when contracted. This has caused an upwards trend of most cases of B. pertussis being the ptxP3 strain, especially in developing countries. Since the 1990s, most cases in developed countries such as the United States have ptxP3 isolates rather than the ptxA1 causing it to become the more dominant strain. This can be seen post-COVID-19 with a surge in B.pertussis among older children in Asian countries, with a hot spot in Singapore. The most recent evolution of the ptxP3 is MS-MT28 strain that has been identified in vaccinated older children in Singapore. However, this strain not only belongs to the ptxP3 lineage but also to the ptxA1. New discoveries found 98% of ptxA1 and 50% of ptxP3 strands being MRBP, these lineages are the foundations of where this new MS-MT28 evolved from. The core of MS-MT28 is the MT28 clone which was spread to China in 2007 from Europe. It is inferred that Europe is the birth place of this clone, MT28, in 2003 that eventually spread all around the world, ending up in China in 2007. Based on this study, it was concluded that the rising rapid rates of cases in older children in Singapore and other parts of China post-COVID-19 could be based on the children integrating back with society after a prolonged lockdown period. These cases arose very quickly and did not have high hospitalization rates, which was unprecedented.
Growth requirements Bordetella pertussis prefers aerobic conditions in pH range of 7.0–7.5, optimal to thrive in the human body. The max pH level for their growth was at a pH level of 8.0. The minimum pH range for minimal growth was at pH 6.0-6.5. The bacteria are not able to reproduce at pH levels lower than 5.0.
In addition, Bordetella pertussis favors a temperature range of 35 °C to 37 °C. This species is a strict aerobe and its nutritional requirements are meticulous in its requirement for nicotinamide supplement. Due to B. Pertussis's specialized media requirements, antimicrobial testing is limited, which can lead to underreporting in clinical settings. It has been identified that the growth of the bacteria is hindered in the presence of fatty acids, peroxide media, metal ions, and sulfides.
As a strict aerobe, the bacterium requires oxygen to grow and sustain. Such aerobes undergo cellular respiration to metabolize substances using oxygen. In such respiration, the terminal electron acceptor for the electron transport chain is oxygen. The organism is oxidase positive, but urease, nitrate reductase, and citrate negative.
B. pertussis is not exclusively an extracellular pathogen, meaning that it not only grows outside the cell, it can efficiently adapt to an internal environment. It also lowers the level of its BvgAS two-component system, which leads to an expression of virulence genes and an avirulent phenotype. In addition, it can adjust the central and energy metabolism, cell wall reinforcement, maintenance of appropriate redox and metal homeostasis, and repair of damaged macromolecules. Studies have also shown mutants lacking cysteine dioxygenase genes displaying attenuated cytotoxicity toward THP-1 cells, which highlights the role of sulphur metabolism in host-pathogen interactions.
Metabolism B. pertussis presents unique challenges and opportunities for metabolic modeling, especially given its reemergence as a pathogen. Elevated glutamate levels were found to slow growth due to oxidative stress, revealing a complex relationship. This effect is compounded by observations suggesting that a small starting population could amplify oxidative stress through quorum sensing, a phenomenon deserving further investigation.
When B. pertussis is in a balanced medium of lactate and glutamate that does not accumulate ammonium, a partially faulty citric acid cycle in B. pertussis and its ability to synthesize and break down β-hydroxybutyrate is observed. Cultivating B. pertussis in this medium resulted in some production of polyhydroxybutyrate but no excretion of β-hydroxybutyrate, indicating a more efficient conversion of carbon into biomass compared to existing media formulations.
In biofilm conditions, B. pertussis cells exhibited increased toxin levels alongside reduced expression of certain proteins, indicating a metabolic shift towards utilizing the full tricarboxylic acid (TCA) cycle over the glyoxylate shunt. These changes correlated with heightened polyhydroxybutyrate accumulation and superoxide dismutase activity, potentially contributing to prolonged survival in biofilms. The interplay between protein expression and metabolic responses highlights the intricate mechanisms influencing B. pertussis growth and adaptation. Despite a less negative energy profile compared to host tissues like the human respiratory system, B. pertussis efficiently couples biosynthesis with catabolism, sustaining robust growth even after extended incubation periods.
B. pertussis cannot use sugars as a carbon source, so amino acids are used, the main and efficient one being glutamate. Glutamate goes through the TCA cycle once converted by glutamate dehydrogenase. It can also be used for other pathways such as gluconeogenesis.
Host species Humans are the only host species of B. pertussis. B. pertussis is able to survive intracellularly in the phagocytic cell of a mammal. B. pertussis releases proteins to aid in metabolism, stress response, iron uptake, and regulation, which permit for the bacteria's resilience to survive. Depending on the host cell, B. pertussis is able to survive in human macrophages and epithelial cells for three days. B. pertussis can gain iron from its host proteins which is a way it adapts metabolically. In iron starved conditions, B. pertussis adapts by increasing iron regulating systems such as the Bhu system which promotes heme later on in infection. Iron is acquired through the production of siderophores or from heme. If iron starved, this could cause the pathogen to be metabolically stressed.
Outbreaks of whooping cough have been observed among chimpanzees in a zoo, and wild gorillas; in both cases, it is considered likely that the infection was acquired as a result of close contact with humans. Several zoos have a long-standing custom of vaccinating their primates against whooping cough.
Research shows that some primate species are highly sensitive to B. pertussis, and developed a clinical whooping cough in high incidence when exposed to low inoculation doses. Whether the bacteria spread naturally in wild animal populations has not been confirmed satisfactorily by laboratory diagnosis. In research settings, baboons have been used as a model of the infection although it is not known whether the pathology in baboons is the same as in humans.Cherry, J.D. The History of Pertussis (Whooping Cough); 1906–2015: Facts, Myths, and Misconceptions. Curr Epidemiol Rep 2, 120–130 (2015). https://doi.org/10.1007/s40471-015-0041-9
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