Pneumococcal interactions with the host : threats and therapeutic approaches

Abstract

Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium responsible for substantial morbidity and mortality worldwide. Apart from causing severe pneumonia, septicemia or meningitis, pneumococci are also major contributors to less severe diseases like otitis media and sinusitis. Pneumococcal autolysis was thought to be the main route that S. pneumoniae utilizes in order to deliver its virulence factors. Recently a new mechanism has been proposed, the release of extracellular vesicles (EVs).

Presence of adhesins and other virulence factors on EVs leads to cell responses after contact with vesicles. We observed that pneumococcal EVs are indeed a mechanism for the delivery of virulence factors to host cells, and that interactions of vesicles with dendritic cells lead to activation of cells and release of pro-inflammatory cytokines. Since EVs mimic the outside of a bacterium, they can play a role as decoys for the immune system. Tightly linked to this decoy function is the ability of EVs to promote immune evasion through binding of serum components. Indeed, we discovered that pneumococcal EVs are able to bind several components of the human complement system, leading to formation of the membrane attack complex on vesicles.

Outer membrane vesicles (OMVs) released from Gram-negative bacteria have been directly used as vaccines in numerous preclinical mouse models. We isolated pneumococcal vesicles and found that they are able to confer serotype-independent protection in mice. Moreover, these vesicles stimulate the production of antibodies directed against pneumococcal antigens. These antibodies are able to increase opsonophagocytosis of pneumococci by mouse macrophages, and are required for protection, as demonstrated by the absence of protection in mice that are not able to produce B lymphocytes. Moreover, in our model the vesicles are able to protect mice against an infection with a pneumococcal strain of serotype 3, to a higher degree than what we observed for the currently available pneumococcal vaccine PCV13. The protective effect in humans of PCV13 against IPD caused by serotype 3 is debated.

The structure of the pneumococcal capsule differs vastly between serotypes. We found that these differences have profound consequences in determining the disease progression in terms of pneumonia or septicemia, in mice. In particular, we observed that serotype 2 was quickly cleared from the lungs but migrated efficiently to the blood, while serotype 3 remained in the lungs, since the thick capsule made bacteria able to adhere less to cells and better avoid opsonization by the complement system. Fate of pneumococcal disease is tightly linked to the immune response against pneumococci. We found that a compound used in traditional Chinese medicine is able to potentiate the response of dendritic cells against pathogens, as well as increase the antimicrobial activities of host cells.

Overall, the work in this thesis provides information on pneumococcal interactions with the host immune system and highlights the potential use of vesicles in future vaccination strategies.