A human apolipoprotein L with detergent-like activity kills intracellular pathogens

Gaudet, Ryan G.; Zhu, S. J.; Halder, Anushka; Kim, Bae-Hoon; Bradfield, Clinton; Huang, Shuai; Xu, Duanyi; Mamińska, Agnieszka; Nguyen, Thanh Ngoc; Lazarou, Michael; Karatekin, Erdem; Gupta, K. P.; MacMicking, John D.

doi:10.1126/science.abf8113

Cited by 63 publications

(68 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the most highly induced ISGs were those encoding cell-autonomous immunity proteins of the guanylate-binding family ( GBP1-6 ), proteins involved in antigen presentation ( HLA-DOA, HLA-DRA, HLA-DRB1, 5 ), sensors of exogenous-RNA from the oligoadenylate synthase family ( OAS1-3, OASL ), chemokines ( CXCL9-11, CX3CL1 ), and other genes with known immune functions ( e.g. , IDO1, IRF8, APOL1-4, 6 ) (Gaudet et al, 2021; MacMicking, 2012; Tretina et al, 2019). Based on Gene Ontology (GO) classification, we identified a subset of 50 (∼5.1%) fibroblast DEGs associated with actin-related functions ( Figure 1a ).…”

Section: Resultsmentioning

confidence: 99%

“…Although we focused on macrophage podosomes, we also observed XIRP1 at focal adhesions ( Figure supplement 2 ) and other actin-rich structures in fibroblasts. These stromal cells have underappreciated roles in host-microbe interactions, yet they are known to regulate immune processes and even restrict microbial pathogens (Davidson et al, 2021; Gaudet et al, 2016; Gaudet et al, 2021; McCormack et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human XIRP1 is a macrophage podosome protein utilized by Listeria for actin-based motility

Urbano

Park

Tretina

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Actin is integral to eukaryotic physiology as a biomechanical polymer and as a structural barrier for cell-autonomous defense against infection. Some microbial pathogens exploit the actin cytoskeleton, however, to evade cell-autonomous immunity. Subversion of actin to enter host cells and for actin-based motility are often employed by intracellular pathogens to spread from cell-to-cell. Using RNA-sequencing and computational data mining, we identify the host actin-binding protein XIRP1 as commonly induced during infection. XIRP1 is expressed by fibroblasts and macrophages in response to immune cytokines such as interferon-gamma (IFN-γ) and infection with bacteria such as Listeria, Shigella, and Salmonella. Confocal and super-resolution structured illumination microscopy (SIM) found XIRP1 localizes to fibroblast focal adhesions and macrophages podosomes. Within human macrophages, XIRP1 is recruited to cytosolic Listeria monocytogenes in an ActA-dependent manner as it replicates and uses actin-based motility for host cell escape. Chromosomal removal of XIRP1 in mice impaired this dissemination and rendered them more resistant to Listeria infection than C57BL/6NJ wildtype controls in vivo. We propose that professional cytosolic pathogens like Listeria can co-opt XIRP1 to escape the hostile intracellular environment of IFN-γ-activated macrophages as part of the host-pathogen arms race during cell-autonomous immunity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human XIRP1 is a macrophage podosome protein utilized by Listeria for actin-based motility

Urbano

Park

Tretina

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The principal mechanistic differences in hematopoietic immunity to staphylococcal infections between humans and mice have been characterized (77,78). By contrast, the mechanisms of cellintrinsic immunity in nonhematopoietic cells have been minimally studied in humans or mice (80,(88)(89)(90). Staphylococcal virulence factors, such as a-toxin, are considered potential targets for strategies aiming to treat and prevent infection (77,78).…”

Section: Discussionmentioning

confidence: 99%

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Spaan

Neehus

Laplantine

et al. 2022

Science

View full text Add to dashboard Cite

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients present episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but TNF-receptor NF-κB-signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts—but not leukocytes—facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in non-leukocytic cells.

show abstract

“…Our data also suggest that cell-intrinsic immune responses in hepatocytes may be instrumental in routinely eliminating the majority of Plasmodium in infected hepatocytes. Although type I IFNs are considered key drivers of immune responses induced by or in immune cells, the roles of IFN-induced pathways in controlling infections in ‘non-immune’ cell-types are increasingly being appreciated (Gaudet et al, 2021; MacMicking, 2012). Given that type I IFNs are the only known drivers of innate immune control of Plasmodium in the liver, our work offers important insights into how malaria infection is naturally limited in the liver.…”

Section: Discussionmentioning

confidence: 99%

Direct type I Interferon signaling in hepatocytes control malaria

Marques-da-Silva

Peissig

Walker

et al. 2022

Preprint

View full text Add to dashboard Cite

Malaria is a devastating disease impacting over half of the world's population. Plasmodium parasites that cause malaria undergo obligatory development and replication in hepatocytes before infecting red blood cells and initiating clinical disease. While type I interferons (IFNs) are known to facilitate innate immune control to Plasmodium in the liver, how they do so has remained unresolved, preventing the manipulation of such responses to combat malaria. Utilizing transcriptomics, infection studies, and a novel transgenic Plasmodium strain that exports and traffics Cre recombinase, we show that direct type I IFN signaling in Plasmodium-infected hepatocytes is necessary and sufficient to control malaria. We also show that the majority of infected hepatocytes naturally eliminate Plasmodium infection, revealing the potential existence of anti-malarial cell-autonomous immune responses in such hepatocytes. These discoveries challenge the existing paradigms in Plasmodium immunobiology and are expected to inspire new anti-malarial drugs and vaccine strategies.

show abstract

A human apolipoprotein L with detergent-like activity kills intracellular pathogens

Cited by 63 publications

References 63 publications

Human XIRP1 is a macrophage podosome protein utilized by Listeria for actin-based motility

Human XIRP1 is a macrophage podosome protein utilized by Listeria for actin-based motility

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Direct type I Interferon signaling in hepatocytes control malaria

Contact Info

Product

Resources

About