Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue

Abstract

Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans.

IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia

“…Therefore, each cytokine, upregulated in response to the IL-37-induced modulation of the immune response, might be specifically involved in exacerbating disease pathology. The downregulation of IL-1β, which has been shown to be required for protective immunity against respiratory infections with S. pneumoniae , may aggravate the pathogen ability to invade sterile compartments where it can continue multiplication without being eliminated [45,46] . Moreover, the elevated levels of IL-1β, which we observed later in infected IL-37tg mice, have the potential to aggravate tissue damage [13] .…”

Understanding the Intersection of Environmental Pollution, Pneumonia, and Inflammation: Does Gender Play a Role?

“…The earlier presence of surfactant in female neonatal lungs helps open the small airways and may contribute to their higher airflow rate observed [50]. Evidence from human studies suggests that male infants are more susceptible to lung infection, with greater associated morbidity and mortality than female infants, but the reverse is applied in children and adolescents [47,51,52]. Regarding respiratory tract infections (RTIs), women are more 3.…”

“…Studies using depletion of alveolar macrophages have demonstrated that these contribute largely to the stimulation of pro-inflammatory cytokines, such as IL-6 and TNFα [48]. Moreover, interleukin-1β (IL-1β) is induced only by strains containing the cholesterol-dependent cytolysin, pneumolysin (PLY), a major virulence factor of pneumococci infection [51]. In addition, the levels of tolllike receptor 2 (TLR2) and toll-like receptor 4 (TLR4) increase after S. pneumoniae infection in the Crl:CD1 mouse strain [96].…”

Human lung ex vivo infection models

“…The ex vivo infection of human lungs with pneumococci induces the expression of immunomodulatory molecules such as tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), granulocyte-macrophage colony-stimulating factor, plateletderived growth factor (PDGF), IL-6, IL-8, IL-10, IL-15, IL-17, or prostaglandin-E 2 (PGE 2 ; Fatykhova et al 2015;Szymanski et al 2012;Xu et al 2008). Experiments performed with the clodronate-induced depletion of alveolar lung macrophages (AM) indicated that these cells might, in particular, contribute to the induction of IL-6 and TNFα (Xu et al 2008).…”

“…Experiments performed with the clodronate-induced depletion of alveolar lung macrophages (AM) indicated that these cells might, in particular, contribute to the induction of IL-6 and TNFα (Xu et al 2008). Fatykhova et al (2015) involved the use of various clinical isolates to investigate their capacity to induce the potent pro-inflammatory cytokine IL-1β. These clinical strains differed in the expression of the cholesterol-dependent cytolysin pneumolysin (PLY), a major virulence factor of pneumococci (Kadioglu et al 2008): Whereas serotypes 2, 3, 6B and 9N pneumococci express fully hemolytic PLY, serotype 1 and 8 strains express non-hemolytic PLY (Fatykhova et al 2015).…”