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Identifier 000431693
Title The role of LC3-associated phagocytosis pathway in Group B Streptococcus (GBS) elimination in adult and neonatal macrophages
Alternative Title Ο ρόλος του μονοπατιού της LC3-associated phagocytosis στην καταπολέμηση του Στρεπτοκόκκου Ομάδας Β σε ενήλικα και νεογνικά μακροφάγα
Author Λάπι, Ιωάννα
Thesis advisor Τσατσάνης, Χρήστος
Reviewer Χαμηλός, Γεώργιος
Καρδάσης, Δημήτριος
Abstract Group B Streptococcus (GBS) or Streptococcus agalactiae is a Gram-positive commensal bacterium that colonizes the gastrointestinal and genitourinary tract. This unharmful microorganism is able to transit from being part of the normal flora to becoming a highly invasive pathogen, afflicting immunocompromised, elderly and pregnant adults as well as infants and neonates. Since 1970, GBS remains a leading cause of neonatal sepsis, pneumonia and meningitis, accompanied by high morbidity and mortality rates. Although the widespread screening of pregnant women for this pathogen and the subsequent antibiotic prophylaxis has reduced the risk of transmission to the baby, yet no vaccine has been developed to protect from all strains of GBS. Neonates possess a naive immune system that is constantly developing. In particular, the adaptive immune responses are inadequate due to limited exposures to antigens in utero in combination with the short-lived protection transplacentally transferred maternal antibodies provide. Therefore, the innate immunity plays a crucial role during the neonatal period. Macrophages, key components of the innate immune system, are required for controlling bacterial infections, including GBS. Canonical autophagy is a vital mechanism that engulfs and degrades a variety of intracellular cargos to maintain cellular homeostasis. However, this highly conserved mechanism has been also implicated in pathogen elimination. Over the past decade, another molecular pathway involved in microbial clearance has emerged, LC3-associated phagocytosis. Upon receptor engagement, LAP utilizes members of the canonical autophagy machinery to sequester cargos, such as intracellular bacterial pathogens, in single-membrane vesicles, delivering them to lysosomes for degradation. Since newborns are considered more vulnerable to GBS infection, we sought to identify potential differences between adult and neonatal macrophages that account for the increased neonatal susceptibility to the disease. Hence, we investigated the molecular mechanisms utilized by neonatal and adult cells in response to GBS infection. First, we verified that neonatal macrophages have reduced bactericidal capacity compared to adult ones. Apart from eliminating GBS more efficiently, adult macrophages also presented enhanced LC3-II co-localization with GBS in contrast to the corresponding neonatal cells. The involvement of LC3-II led us to explore distinct components of canonical and non-canonical autophagy using bacterial survival assays and confocal microscopy. Our findings demonstrated that LC3-associated phagocytosis pathway is activated in adult macrophages to facilitate GBS clearance, but in neonatal cells is dysfunctional. We further explored factors, such as cytokines, that may have an impact on the antimicrobial activity of neonates. Interestingly, neonates were capable of producing pro-inflammatory cytokines, IL-6 and TNFα, as well as the anti-inflammatory cytokine IL-10, at higher levels compared to adults upon infection. In conclusion, we identified a molecular pathway, LC3-associated phagocytosis (LAP), which is involved in GBS clearance in adult macrophages, but seems to be dysfunctional in neonatal ones. Neonatal macrophages were not deficient in their cytokine responses, but simply distinct from adult like immune responses. We observed that neonates produced higher levels of IL-6 and IL-10 compared to adults, which may contribute to their deficit in the LAP pathway and the subsequent reduced bactericidal capacity. Understanding the molecular mechanisms and the factors implicated in GBS elimination would assist in developing new therapeutics for this highly versatile and invasive pathogen.
Language English
Subject Νεογνά
Στρεπτόκοκκος ομάδας Β
Issue date 2020-08-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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