LAPped in Proof: LC3‐Associated Phagocytosis and the Arms Race Against Bacterial Pathogens

Grijmans, Bart J. M.; Kooij, Sander B. van der; Varela, Mónica; Meijer, Annemarie H.

doi:10.3389/fcimb.2021.809121

Cited by 18 publications

(21 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antibody staining against the Outer Surface Protein A (OspA) of B. burgdorferi showed coiled, DAPI positive spirochetes in the macrophage cytoplasm, as well as a punctate, DAPI negative OspA staining indicative of bacterial destruction. B. burgdorferi OspA also colocalized with the autophagy marker p62/Sequestosome-1 (SQSTM1), suggesting spirochete degradation via macrophage autophagy and/or LC3-associated phagocytosis pathways (74–76). Collectively, these data indicate that B. burgdorferi are taken up by murine macrophages and sensed by the cGAS-STING pathway for engagement of IFN-I responses.…”

Section: Resultsmentioning

confidence: 99%

Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

Farris

Torres-Odio

Adams

et al. 2022

Preprint

View full text Add to dashboard Cite

Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multi-system inflammatory disease in humans. B. burgdorferi infection can lead to Lyme carditis, neurologic complications, and arthritis, dependent upon the ability of specific borrelial strains to disseminate, invade, and drive inflammation. B. burgdorferi elicits type I interferon (IFN-I) responses in mammalian cells and tissues that are associated with the development of severe arthritis or other Lyme-related complications. However, the innate immune sensors and signaling pathways controlling IFN-I induction remain unclear. In this study, we examined whether intracellular nucleic acid sensing is required for the induction of IFN-I to B. burgdorferi. Using confocal microscopy, we show that B. burgdorferi is taken up by mouse and human cells in culture, indicating a route for intracellular detection. In addition, we report that IFN-I responses in primary mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) or its adaptor Stimulator of Interferon Genes (STING), which function together to sense and respond to intracellular DNA. In vivo tracking of bioluminescent B. burgdorferi during infection of C57BL/6 wild-type, cGAS knockout, or STING deficient mice revealed similar dissemination kinetics and borrelial load. However, tibiotarsal joint pathology and inflammation were reduced in cGAS knockout compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is an innate immune sentinel of B. burgdorferi that plays a key role in the induction of mammalian IFN-I responses.

show abstract

Section: Resultsmentioning

confidence: 99%

Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

Farris

Torres-Odio

Adams

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…LC3 associated phagocytosis (LAP) is a receptor-mediated phagocytosis that utilizes some components of the autophagy machinery to process extracellular cargo (Grijmans et al, 2022; Heckmann and Green, 2019; Sanjuan et al, 2007). Dectin-1 mediated LAP has been demonstrated in phagocytosis of fungi by professional phagocytes such as macrophages and dendritic cells (Ma et al, 2012; Tam et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis

Cohen-Kedar

Barda

Rabinowitz

et al. 2022

Preprint

View full text Add to dashboard Cite

Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3 associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles via LAP. Zymosan (β-glucan particle) and Heat-killed and UV inactivated C. albicans were phagocytosed by monolayers of human colonic (n=18) and ileal (n=4) organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases. Our results show that human IECs sense luminal fungal particles and internalize them via LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi.

show abstract

“…Due to distinct virulence factors, some bacterial pathogens can evade the destruction in the phagosome, either by re-modulation of the phagosomal milieu or via escape into the cytosol. Activation of LAP, a highly microbicidal non-canonical autophagy pathway ( Herb et al., 2020 ; Grijmans et al., 2022 ), enhances the degradative capacity of macrophages. We recently described another non-canonical autophagy pathway termed PINCA ( Gluschko et al., 2021 ), which is triggered by perforation of bacteria-containing phagosomes, independent of the ULK complex components ULK1/2 and FIP200 and also independent of Nox2-derived ROS, therefore representing a non-canonical autophagy pathway distinct from LAP.…”

Section: Discussionmentioning

confidence: 99%

“…Several factors, like vacuolar-type H + -ATPase (V-ATPase)-mediated acidification ( Sun-Wada et al., 2009 ; Dragotakes et al., 2020 ; Westman and Grinstein, 2021 ), production of reactive oxygen species (ROS) ( Craig and Slauch, 2009 ; Slauch, 2011 ; Wink et al., 2011 ; Herb and Schramm, 2021 ) and exposure to hydrolases after fusion with lysosomes ( del Cerro-Vadillo et al., 2006 ; Schramm et al., 2014 ; Weiss and Schaible, 2015 ) lead to the formation of a highly antimicrobial environment for engulfed pathogens and, in most cases, result in their degradation ( Haas, 2007 ). However, several bacterial pathogens have established strategies to evade this degradative fate in the phagosome ( Mitchell et al., 2016 ; Grijmans et al., 2022 ), e.g. Staphylococcus aureus ( S. aureus ) ( Fraunholz and Sinha, 2012 ; Moldovan and Fraunholz, 2019 ; Rao et al., 2020 ), Salmonella typhimurium ( S. typhimurium ) ( Eriksson et al., 2003 ; Fenlon and Slauch, 2014 ; Burton et al., 2014 ; Rhen, 2019 ; Rao et al., 2020 ) or Mycobacterium tuberculosis ( Queval et al., 2017 ; Koster et al., 2017 ), which can alter the phagosomal composition and structure for their benefit and do not only remain unharmed, but also replicate inside the phagosome.…”

Section: Phagocytosis: Main Weapon Of Macrophagesmentioning

confidence: 99%

When the Phagosome Gets Leaky: Pore-Forming Toxin-Induced Non-Canonical Autophagy (PINCA)

Herb

Gluschko

Farid

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Macrophages remove bacteria from the extracellular milieu via phagocytosis. While most of the engulfed bacteria are degraded in the antimicrobial environment of the phagolysosome, several bacterial pathogens have evolved virulence factors, which evade degradation or allow escape into the cytosol. To counter this situation, macrophages activate LC3-associated phagocytosis (LAP), a highly bactericidal non-canonical autophagy pathway, which destroys the bacterial pathogens in so called LAPosomes. Moreover, macrophages can also target intracellular bacteria by pore-forming toxin-induced non-canonical autophagy (PINCA), a recently described non-canonical autophagy pathway, which is activated by phagosomal damage induced by bacteria-derived pore-forming toxins. Similar to LAP, PINCA involves LC3 recruitment to the bacteria-containing phagosome independently of the ULK complex, but in contrast to LAP, this process does not require ROS production by Nox2. As last resort of autophagic targeting, macrophages activate xenophagy, a selective form of macroautophagy, to recapture bacteria, which evaded successful targeting by LAP or PINCA through rupture of the phagosome. However, xenophagy can also be hijacked by bacterial pathogens for their benefit or can be completely inhibited resulting in intracellular growth of the bacterial pathogen. In this perspective, we discuss the molecular differences and similarities between LAP, PINCA and xenophagy in macrophages during bacterial infections.

show abstract

LAPped in Proof: LC3‐Associated Phagocytosis and the Arms Race Against Bacterial Pathogens

Cited by 18 publications

References 118 publications

Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis

When the Phagosome Gets Leaky: Pore-Forming Toxin-Induced Non-Canonical Autophagy (PINCA)

Contact Info

Product

Resources

About