An immune system fighting against pneumococcus

Abstract

Pneumococcus is a common coloniser of the human nasopharynx. However, it can also cause human diseases such as otitis or pneumonia, which may progress into invasive forms such as bacteremic pneumonia, meningitis, or sepsis. This bacterium reaches and establishes itself in the nasopharynx through different mechanisms, which include evasion of the host immune system. Moreover, certain factors such as the coinfection with viruses favour colonisation, as well as the ability of pneumococcus to cause diseases. Our immune system responds to pneumococcal colonisation and infection through the innate and adaptive responses, which can be stimulated by pneumococcal vaccines. In the following article, we will briefly review the mechanisms of pneumococcal infection and how our immune system responds to it; as well as the immune response generated after vaccination and its impact on the prevention of pneumococcal disease.

Resumen

El neumococo es un común colonizador de la nasofaringe humana. Sin embargo, en ocasiones puede causar enfermedades no invasivas como otitis o neumonías, que pueden progresar a formas invasivas de la enfermedad como neumonías bacteriémicas, meningitis o sepsis. Esta bacteria es capaz de establecerse en la nasofaringe mediante diversos mecanismos, que incluyen la evasión del sistema inmune del huésped. Además, ciertos factores como la coinfección con virus favorecen la colonización, así como la capacidad del neumococo para causar enfermedades. Por otro lado, nuestro sistema inmune responde a la colonización y a la infección por neumococo por medio de las respuestas innata y adaptativa, las cuales pueden ser estimuladas mediante vacunas antineumocócicas. En este artículo se revisan brevemente los mecanismos de infección del neumococo y la manera en la que nuestro sistema inmune se defiende de éste, así como la respuesta que se produce tras la vacunación y su impacto en la prevención de la enfermedad neumocócica.

Introduction

Respiratory infections are a major public health challenge and, despite most being immune-preventable, they are among the most frequent causes of death in Spain. Pneumonia in particular is the most notable respiratory disease in terms of number of deaths in Spain (with the exception of deaths due to COVID-19), having increased by 28.6% in the last year.¹

The main pathogen causing community-acquired pneumonia is Streptococcus pneumoniae (S. pneumoniae), also called pneumococcus.^2,3 This bacterium is naturally present, without causing disease, in the nasopharynx of children and adults.⁴ However, to understand the mechanisms that trigger non-invasive clinical forms such as pneumonia or otitis, or invasive forms of pneumococcal disease (bacteraemic pneumonia, meningitis, sepsis, etc.), it is important to understand the pathogenesis of the bacterium and the immune response generated after infection naturally or after vaccination.

Development of the topic

Pneumococcus as a coloniser

Nasopharyngeal colonisation is the main means of pneumococcal transmission, and its gateway to invasive infection. During the colonisation process, pneumococcus must contend with the host's defences (physical and immunological) and compete with other colonising organisms.⁵ As part of the physical barriers, the first line of defence encountered by pneumococcus is the interaction with mucus, which contains antimicrobial peptides and immunoglobulins. Pneumococcus manages to overcome this barrier, thanks to its capsular polysaccharide which, being negatively charged, repels the mucopolysaccharides present in the mucus. In addition, using a combination of virulence factors such as metalloproteinase enzymes, it is able to eliminate the IgA immunoglobulins present in the mucus and prevent activation of the complement system.⁵

Thus, S. pneumoniae can gain access to the second physical barrier; the epithelial cells of the mucosa where it establishes itself as a coloniser. Pneumococcus binds to mucosal cells with various mucosal surface components, the expression of which increases in response to proinflammatory stimuli from the host.⁶ This bacterium can also alter its phenotype through a process called phase shift, in which it changes from an ‘opaque’ phenotype with high expression of capsular polysaccharide to a ‘transparent’ phenotype, with reduced expression of the capsule, which facilitates colonisation of the nasopharynx.^6–8 However, the presence of previous viral infections favours a proinflammatory environment in the nasopharynx and thus facilitates colonisation by pneumococcus. In this regard, several studies have shown that the interaction of pneumococcus in the nasopharynx with different viruses favours both viral infection and pneumococcal colonisation and invasive infection.^9–14 Dagan et al. recently observed a relationship between respiratory syncytial virus infection and subsequent pneumococcal disease,⁹ a relationship also observed previously in the case of influenza.^12,13 Conversely, pneumococcal infection has also been associated with a decreased immune response to different viruses, such as SARS-CoV-2¹⁰ or the influenza virus.¹¹ Thus, virus-bacteria co-infection could explain the spike in cases of invasive pneumococcal disease observed in Spain after the COVID-19 pandemic, coinciding with the increased circulation of respiratory viruses.^15–17

The host immune system is activated to prevent colonisation by recruiting numerous components of the innate and adaptive immune system. In particular, Th17 lymphocytes appear to be particularly involved in the control of S. pneumoniae colonisation, as they mediate the recruitment of neutrophils, an important defence mechanism against extracellular bacteria, stimulating the phagocytic capacity of macrophages and the production of antimicrobial substances.^18–20

The introduction of pneumococcal conjugate vaccines (PCVs) in the childhood immunisation schedule has been associated with a significant decrease in pneumococcal disease in all age groups in the Spanish population, showing herd protection.^21,22 This protection is largely due to the effect of PCV on nasopharyngeal colonisation, which decreases transmission of the bacteria. These vaccines stimulate the production of memory B cells, which after differentiation into plasma cells produce IgG immunoglobulins in the mucosa that favour opsonophagocytosis of the bacteria; both elements are related to protection against colonisation.^23,24 IgA levels after PCV vaccination have not shown a clear correlation with the decrease in nasopharyngeal colonisation, probably due to the enzymatic degradation of this immunoglobulin by pneumococcus, as mentioned above.^6,24

Pneumococcus as a pathogen

Streptococcus pneumoniae is a natural coloniser of the human nasopharynx. However, different factors may favour its localised penetration into different host organs to cause non-invasive disease such as otitis or pneumonia, as well as progression to invasive disease such as bacteraemic pneumonia, meningitis, or sepsis. The proinflammatory environment and damage to the respiratory epithelium caused by previous viral infections that increase colonisation density are some of the factors favouring pneumococcal invasiveness.^5,6,14 In addition, the capsular polysaccharide surrounding the bacterium plays a key role in its ability to cause disease. It has been shown that pneumococcus is able to increase the expression levels of its polysaccharide capsule to generate a more virulent phenotype (‘opaque’ phenotype), in which it hides the bacterial surface from immune system components such as antibodies or the complement system, making opsonophagocytosis by phagocytes more difficult.^5,6,25

The defence mechanisms of the immune system vary according to the site of disease caused by pneumococcus, and involve numerous components of the innate and adaptive immune system.⁵ In the case of invasive disease, immunoglobulins or antibodies to bacterial membrane proteins and to capsular polysaccharide are particularly important due to the rapid progression of these forms of disease following infection.²⁶ The mechanisms involved in bacterial clearance are numerous and include bacterial neutralisation, stimulation of opsonophagocytosis of the pneumococcus by phagocytes, as well as bacterial clearance by natural killer cells and activation of the complement system.²⁰ In the case of non-invasive diseases, such as otitis or pneumonia, which occur in mixed areas with a mucosal and systemic component, both antibodies and Th17 lymphocytes have been shown to play an important role in their prevention, similar to their role in the nasopharynx in preventing colonisation.^18,19

The implementation of childhood pneumococcal conjugate vaccination programmes has had a major impact on both invasive and non-invasive forms of the disease.²⁷ This is due to the immune response that PCVs trigger in vaccinated individuals; these vaccines stimulate both humoral and cellular immune responses.²⁸ In terms of the humoral response, conjugate vaccines generate IgG antibodies to a greater extent, which are particularly relevant for the prevention of pneumococcal disease.¹⁸ However, when assessing the immunogenicity of PCVs, the quantitative measurement of IgG production by ELISA (enzyme-linked immunosorbent assay) is not the only parameter to be taken into account, but also the capacity of the antibodies produced to neutralise pneumococcus, activate the complement system, and stimulate opsonophagocytosis by phagocytes.^26,29 In this regard, several studies indicate that there is no direct correlation between IgG titres and prevention of pneumococcal disease.^29–31 However, prevention does seem to be related to the production of opsonophagocytic antibodies. These are measured by the opsonophagocytic assay technique, which assesses antibody functionality in vitro by mimicking the mechanism of complement activation and opsonophagocytosis by phagocytes that occurs in vivo.²⁹ An example of this correlation was seen during the approval of PCV13; this vaccine had a lower IgG antibody response measured by ELISA than PCV7 for serotypes 6B and 9V, but had a similar opsonophagocytic antibody response. Despite having a lower IgG response, PCV13 retained effectiveness against 6B and 9V, demonstrating a stronger association with opsonophagocytic antibodies.^29,32–34

Regarding the cellular response, it has been observed that after vaccination with PCV, effector T and B cells are activated, as well as memory cells that will allow protection to be maintained over time.²⁸ Although the quantification and characterisation of memory B and T cells is not an easily standardised technique and therefore not routinely studied at present for the approval of new PCVs, there are indirect measurements of the memory response generated by these vaccines. Some studies, and even the World Health Organisation, suggest that a possible indicator of the presence of a memory immune response is the observation of an increase in IgG and/or opsonophagocytic antibody titres between the primary vaccination and the booster dose (known as the booster effect),^35,36 which indirectly points to more extended protection over time and a decrease in nasopharyngeal colonisation.^23,24

Conclusion

Streptococcus pneumoniae is a bacterium that causes complex disease in humans. In response, our immune system defends itself with a variety of elements, the relevance of which varies depending on the site of bacterial infection in the body. Pneumococcal conjugate vaccines, developed more than 2 decades ago to prevent pneumococcal disease caused by prevalent and epidemiologically relevant serotypes, have had a major impact in reducing the disease due to the complex immune response they trigger. Although various components of the immune system such as IgG production or opsonophagocytic antibody production are evaluated in the approval of new pneumococcal conjugate vaccines, only IgG production is considered in the primary targets of paediatric vaccine approval trials, which simplifies and possibly underestimates the extent of the complex immune response generated by these vaccines. Evaluation of other components such as opsonophagocytic antibodies (used for licencing of adult vaccines), related to the functional antibody response, or the booster effect, an indirect measure of the memory response, could give a more complete picture of the extent of immunity and protection generated by these vaccines.

Funding

The authors declare that they received no funding for this article.