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Amuategi Aulestiarte, Jone Alonso Estrada, Rocio Ostolaza Etxabe, Helena

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[Whooping cough: a close look]

Whooping cough is a contagious respiratory infection caused by Bordetella pertussis that can be fatal to certain populations. Although global immunization campaigns have helped to alleviate the situation, increases are recorded every 3-5 years. Osakidetza reported an outbreak in Gipuzkoa in June 2023. In this review, we have addressed the disease, the bacteria and its virulence factors.

Amuategi Aulestiarte, Jone Alonso Estrada, Rocio Ostolaza Etxabe, Helena

EU ES FR
EN CA GA

in 2019, lower respiratory infections killed 2.4 million people worldwide [38], with children under 5 years of age and older being the most affected [43]. These infections are usually caused by viruses and/or pathogenic bacteria, such as pneumonia, which accounts for nearly half of all deaths [29, 43]. Moreover, we cannot fail to mention the viruses of the Coronaviridae family, which are responsible for the common cold and SARS, MERS and/or COVID-19 diseases. In this review, however, we have had pertussis caused by Bordetella pertussis.

The return of an old disease

Whooping cough or whooping cough is a rare disease. However, the sound of the infected person breathing between one cough event and the next is well underestimated. Although it may initially resemble a typical cough, the symptoms may last for weeks or months. It can cause shortness of breath, sudden cough episodes, and fever, among other things. Apnea in newborn children is also common. Failure to overcome the disease in its early stages can lead to death in the most severe cases, with 90% of patients dying from pneumonia [23].

This infection still makes many children sick and die in the world, but it has to be prevented by vaccines [16]. According to the latest report published by the World Health Organization (WHO), before vaccines against whooping cough became available, it was one of the most common childhood diseases. in the 1950s and 1960s, large-scale vaccination campaigns led to a 90% drop in incidence and mortality, at least in industrialised countries (WHO, 2021).

Each country may have its own immunization campaign. For example, the website of the European Centre for Disease Control and Prevention (ECDC) contains information on European programmes. However, at this time, it is most common to receive a triple vaccine against diphtheria, tetanus and whooping cough. It is taken during childhood in three doses. Worldwide immunization coverage for this vaccine in 2021 was 81%, the lowest since 2008 [35].

As has already been pointed out, vaccines received in childhood are most often accompanied by very mild symptoms in adults. In addition, vaccinations received by mothers during pregnancy have also helped to prevent hospitalization and infant death. In this case, the mother will pass the antibodies produced to the child through the placenta, thus providing protection [23].

Whooping cough is caused by a bacteria called Bordetella pertussis, which can become contaminated by contact with airway secretions or salivary droplets. It was first identified, isolated and planted by Jules Bordet and Octave Gengou in 1906 [4]. Thanks to this and other findings related to immunity, Bordet was awarded the Nobel Prize in Medicine and Physiology in 1919.

Schematic illustration of Bordetella pertussis and its virulence factors. I'm talking about Arg. Created by Biorender.com.

Although the disease has been known for a long time, we are now unable to overcome it, as the number of infected increases every 3-5 years. It is currently a problem of public health services in a number of countries. For example, the whole of Europe has been in a state of epi-demia since 2011 (ECDC), while in our country, Osakidetza reported an outbreak in Europe in June 2023.

Indeed, it has been a few years since the WHO expressed its concern and recognized that the disease is on the rise globally. Unlike other respiratory infections, outbreaks in this case are not uniform, i.e. they are not associated with specific sites and/or seasons. Several epidemiological studies have indicated that the increase is likely to be associated with loss of immunity [22, 20, 34]. In other words, immunity against whooping cough is provisional and therefore has an expiry date. It is estimated that natural immunity lasts up to 3.5-30 years, and that acquired through vaccines lasts 4-14 years. Once the disease has passed, it is very common to get infected again. However, the severity of symptoms is linked to the time elapsed from the moment immunity was acquired [46].

Through the cell membranes

B. pertussis has a specific affinity for human airway mucosa. That means you have the ability to stick to it. In order to invade and reside in the upper and lower airways, it uses several virulence factors. Some help it adhere to host cells, while others use them to damage the epithelial layer and evade the immune system. If the reader would like more information on these virulence factors, we invite you to read the relevant reviews [15, 9].

The list of molecules used by this bacterium for attack is long. Among them is the pore-forming toxin Adenylate Cyclase, a protein that attacks the cells of the immune system. Thus, it weakens human defenses and the bacteria can easily spread in the body [25, 7].

Pore-forming toxins can no doubt be described as biological perforators, since they form aqueous channels leading from one side of the membrane to the other [8, 30]. Biological membranes are robust and dynamic scaffolds for maintaining cell integrity and architecture. They are composed of lipids, proteins and sugars that separate the internal and external environment of the cells [45]. They also regulate what can enter or leave the cell. Therefore, their deterioration can lead to cell death [3, 24, 47]. In all the vital kingdoms we can find some organism that produces some kind of pore-forming toxin: they can be pathogenic bacteria, nematodes, fungi, parasitic protozoa, frogs, plants and more developed organisms [19]. However, the molecular mechanisms by which all of these toxins attack cells are similar.

[Action of porous proteins in the cell membrane]. I'm talking about Arg. Created by Biorender.com.

Adenylate cyclase toxin, like other pore forming proteins, has a very special effect. Initially, when the bacterium is produced and secreted into the external environment, it is usually soluble in water and has hydrophobic regions hidden. In contrast, when it encounters the host cell, it changes in appearance: it visualizes these regions that were protected from water and it is inserted into the membrane [8, 17, 32, 42]. Then, in order to be able to form the pore, several proteins are bound, forming a more complex structure. This is how colicins, cytolysins, hemolysins, diphtheria toxin, anthrax toxin protective antigen, and/or pore inducing toxins of the Repeats in ToXins (RTX) family work [28]. The formation of the pore itself is a very dynamic process and therefore difficult to observe. This is a challenge for researchers.

Lipids and proteins, what a pair!

Pore-forming toxins, for successful incorporation into the cell membrane, are often accompanied by membrane lipids. Lipids can precisely adjust the process both directly and indirectly. On the one hand, they can interact specifically with proteins [26, 36, 4o]; on the other hand, the biophysical characteristics of the membrane (fluidity, phase separation, thickness, tension, etc.) they can be modulated [10, 21, 39]. Thus, they may alter the structure and function of the protein.

Membrane cholesterol, for example, controls the activity of a wide variety of membrane receptors through specific interactions. Also, some proteins may contain regions that specifically recognize cholesterol: receptors for neurotransmitters and ABC transporters, for example. These regions are referred to as CRAC (Cholesterol Recognition Amino acid Consensus) or reverse CARC motifs, and although they have a variety of structures, they use similar mechanisms for binding to cholesterol. As can be read from the literature, certain amino acids often appear in these segments following a pattern already known and described [14, 13].

Many researchers have focused precisely on the interaction between membrane lipids and proteins. It is currently a subject of great interest that combines different scientific disciplines such as biochemistry, biophysics, cell biology and bioinformatics. Our group has studied the interaction of adenylate cyclase with the membrane in recent years, mainly combining biophysics and biochemistry. We have recently shown that the toxic activity of the protein depends on membrane cholesterol [18], and that the interaction between the protein and cholesterol is specific [1].

Why Basic Research?

Man has learned to coexist with whooping cough, and the situation has improved significantly since vaccines are available to everyone. This is undoubtedly due to basic and applied research. The identification, description and understanding of the tools used by the bacteria to harm humans has been essential to explain the molecular mechanisms of the disease and to be able to fight whooping cough.

With respect to the porous toxin agents, they have a variable nature depending on the environment. They change their appearance very quickly, making it very difficult to observe such dynamic processes. However, these are not isolated mechanisms, but occur in nature in other proteins, such as certain proteins of the vertebrate immune system and/or amyloid proteins [27, 37]. Therefore, the effort made to understand these proteins can help other areas as well.

We have already mentioned that pore-forming toxins can actually be harmful to human health. On the contrary, they have long been investigated and are now known to be useful for a number of promising biotechnological and technological applications: to attack cancer cells [31], to kill pathogenic bacteria [5], to make biosensors for detection [2]... They have also already shown that the Adenylate Cyclase toxin can be used as a carrier vaccine [6]. For the development of all these applications, it has first been necessary to understand the physico-chemical rules behind these processes, which requires basic research. In addition, collaboration and communication between researchers from many disciplines will undoubtedly pave the way and accelerate.

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