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Recruitment and Maintenance of CX3CR1+CD4+ T Cells during Helminth Infection

Loredan, Denis G; Devlin, Joseph C; Khanna, Kamal M; Loke, P'ng
Distinct subsets of T lymphocytes express CX3CR1 under inflammatory conditions, but little is known about CX3CR1+CD4+ T cells during type 2 inflammation in helminth infections. In this study, we used a fate-mapping mouse model to characterize CX3CR1+CD4+ T cells during both acute Nippostrongylus brasiliensis and chronic Schistosoma mansoni murine models of helminth infections, revealing CX3CR1+CD4+ T cells to be an activated tissue-homing subset with varying capacity for cytokine production. Tracking these cells over time revealed that maintenance of CX3CR1 itself along with a TH2 phenotype conferred a survival advantage in the inflamed tissue. Single-cell RNA sequencing analysis of fate-mapped CX3CR1+CD4+ T cells from both the peripheral tissue and the spleen revealed a considerable level of diversity and identified a distinct population of BCL6+TCF-1+PD1+CD4+ T cells in the spleen during helminth infections. Conditional deletion of BCL6 in CX3CR1+ cells resulted in fewer CX3CR1+CD4+ T cells during infection, indicating a role in sustaining CD4+ T cell responses to helminth infections. Overall, our studies revealed the behavior and heterogeneity of CX3CR1+CD4+ T cells during type 2 inflammation in helminth infections and identified BCL6 to be important in their maintenance.
PMID: 38180236
ISSN: 1550-6606
CID: 5633132

Spatiotemporal-social association predicts immunological similarity in rewilded mice

Downie, Alexander E; Oyesola, Oyebola; Barre, Ramya S; Caudron, Quentin; Chen, Ying-Han; Dennis, Emily J; Garnier, Romain; Kiwanuka, Kasalina; Menezes, Arthur; Navarrete, Daniel J; Mondragón-Palomino, Octavio; Saunders, Jesse B; Tokita, Christopher K; Zaldana, Kimberly; Cadwell, Ken; Loke, P'ng; Graham, Andrea L
Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.
PMCID:10745690
PMID: 38134275
ISSN: 2375-2548
CID: 5611862

Single-Cell Analysis of CX3CR1+ Cells Reveals a Pathogenic Role for BIRC5+ Myeloid Proliferating Cells Driven by Staphylococcus aureus Leukotoxins

Loredan, Denis G; Devlin, Joseph C; Lacey, Keenan A; Howard, Nina; Chen, Ze; Zwack, Erin E; Lin, Jian-Da; Ruggles, Kelly V; Khanna, Kamal M; Torres, Victor J; Loke, P'ng
Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage-tracing cells derived from CX3CR1+ precursors in mice during infection and profiling by single-cell RNA sequencing, in this study, we identify a cluster of BIRC5+ myeloid cells that expanded in the liver during chronic infection with either the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue-damaging toxins, S. aureus infection does not elicit these BIRC5+ cells. Moreover, deletion of BIRC5 from CX3CR1-expressing cells results in improved survival during S. aureus infection. Hence the combination of single-cell RNA sequencing and genetic fate-mapping CX3CR1+ cells revealed a toxin-dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection.
PMID: 37466391
ISSN: 1550-6606
CID: 5535762

Rewilding of laboratory mice enhances granulopoiesis and immunity through intestinal fungal colonization

Chen, Ying-Han; Yeung, Frank; Lacey, Keenan A; Zaldana, Kimberly; Lin, Jian-Da; Bee, Gavyn Chern Wei; McCauley, Caroline; Barre, Ramya S; Liang, Shen-Huan; Hansen, Christina B; Downie, Alexander E; Tio, Kyle; Weiser, Jeffrey N; Torres, Victor J; Bennett, Richard J; Loke, P'ng; Graham, Andrea L; Cadwell, Ken
The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component β-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.
PMCID:10350741
PMID: 37352372
ISSN: 2470-9468
CID: 5537252

Gut microbiome of helminth-infected indigenous Malaysians is context dependent

Tee, Mian Zi; Er, Yi Xian; Easton, Alice V; Yap, Nan Jiun; Lee, Ii Li; Devlin, Joseph; Chen, Ze; Ng, Kee Seong; Subramanian, Poorani; Angelova, Angelina; Oyesola, Oyebola; Sargsian, Shushan; Ngui, Romano; Beiting, Daniel P; Boey, Christopher Chiong Meng; Chua, Kek Heng; Cadwell, Ken; Lim, Yvonne Ai Lian; Loke, P'ng; Lee, Soo Ching
BACKGROUND:While microbiomes in industrialized societies are well characterized, indigenous populations with traditional lifestyles have microbiomes that are more akin to those of ancient humans. However, metagenomic data in these populations remains scarce, and the association with soil-transmitted helminth infection status is unclear. Here, we sequenced 650 metagenomes of indigenous Malaysians from five villages with different prevalence of helminth infections. RESULTS:Individuals from villages with higher prevalences of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition were most strongly associated with different villages and the effects of helminth infection status on the microbiome varies by village. Longitudinal changes in the microbiome in response to albendazole anthelmintic treatment were observed in both helminth infected and uninfected individuals. Inference of bacterial population replication rates from origin of replication analysis identified specific replicating taxa associated with helminth infection. CONCLUSIONS:Our results indicate that helminth effects on the microbiota were highly dependent on context, and effects of albendazole on the microbiota can be confounding for the interpretation of deworming studies. Furthermore, a substantial quantity of the microbiome remains unannotated, and this large dataset from an indigenous population associated with helminth infections is a valuable resource for future studies. Video Abstract.
PMCID:9727879
PMID: 36476263
ISSN: 2049-2618
CID: 5378722

Clostridia isolated from helminth-colonized humans promote the life cycle of Trichuris species

Sargsian, Shushan; Chen, Ze; Lee, Soo Ching; Robertson, Amicha; Thur, Rafaela Saes; Sproch, Julia; Devlin, Joseph C; Tee, Mian Zi; Er, Yi Xian; Copin, Richard; Heguy, Adriana; Pironti, Alejandro; Torres, Victor J; Ruggles, Kelly V; Lim, Yvonne A L; Bethony, Jeffrey; Loke, P'ng; Cadwell, Ken
Soil-transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolate and sequence the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with a high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians confirm the prevalence of species corresponding to these isolates and reveal a specific association between Peptostreptococcaceae family members and helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli display superior capacity to promote the life cycle of whipworm species, including hatching of eggs from Trichuris muris and Trichuris trichiura. These findings support a model in which helminths select for gut colonization of microbes that support their life cycle.
PMID: 36450245
ISSN: 2211-1247
CID: 5374022

Plasmodium falciparum and TNF-α Differentially Regulate Inflammatory and Barrier Integrity Pathways in Human Brain Endothelial Cells

Zuniga, Marisol; Gomes, Claudia; Chen, Ze; Martinez, Criseyda; Devlin, Joseph Cooper; Loke, P'ng; Rodriguez, Ana
Cerebral malaria is a severe complication of Plasmodium falciparum infection characterized by the loss of blood-brain barrier (BBB) integrity, which is associated with brain swelling and mortality in patients. P. falciparum-infected red blood cells and inflammatory cytokines, like tumor necrosis factor alpha (TNF-α), have been implicated in the development of cerebral malaria, but it is still unclear how they contribute to the loss of BBB integrity. Here, a combination of transcriptomic analysis and cellular assays detecting changes in barrier integrity and endothelial activation were used to distinguish between the effects of P. falciparum and TNF-α on a human brain microvascular endothelial cell (HBMEC) line and in primary human brain microvascular endothelial cells. We observed that while TNF-α induced high levels of endothelial activation, it only caused a small increase in HBMEC permeability. Conversely, P. falciparum-infected red blood cells (iRBCs) led to a strong increase in HBMEC permeability that was not mediated by cell death. Distinct transcriptomic profiles of TNF-α and P. falciparum in HBMECs confirm the differential effects of these stimuli, with the parasite preferentially inducing an endoplasmic reticulum stress response. Our results establish that there are fundamental differences in the responses induced by TNF-α and P. falciparum on brain endothelial cells and suggest that parasite-induced signaling is a major component driving the disruption of the BBB during cerebral malaria, proposing a potential target for much needed therapeutics. IMPORTANCE Cerebral malaria is a severe complication of Plasmodium falciparum infection that causes the loss of blood-brain barrier integrity and frequently results in death. Here, we compared the effect of P. falciparum-infected red blood cells and inflammatory cytokines, like TNF-α, in the loss of BBB integrity. We observed that while TNF-α induced a small increase in barrier permeability, P. falciparum-infected red blood cells led to a severe loss of barrier integrity. Our results establish that there are fundamental differences in the responses induced by TNF-α and P. falciparum on brain endothelial cells and suggest that parasite-induced signaling is a major component driving the disruption of the BBB during cerebral malaria, proposing a potential target for much needed therapeutics.
PMCID:9601155
PMID: 36036514
ISSN: 2150-7511
CID: 5371222

Staphylococcus aureus induces a muted host response in human blood that blunts the recruitment of neutrophils

Zwack, Erin E; Chen, Ze; Devlin, Joseph C; Li, Zhi; Zheng, Xuhui; Weinstock, Ada; Lacey, Keenan A; Fisher, Edward A; Fenyö, David; Ruggles, Kelly V; Loke, P'ng; Torres, Victor J
PMID: 35881802
ISSN: 1091-6490
CID: 5276372

Efficacy of triple dose albendazole treatment for soil-transmitted helminth infections

Tee, Mian Zi; Lee, Soo Ching; Er, Yi Xian; Yap, Nan Jiun; Ngui, Romano; Easton, Alice V; Siow, Vinnie Wei Yin; Ng, Kee Seong; Boey, Christopher Chiong Meng; Chua, Kek Heng; Cadwell, Ken; Loke, P'ng; Lim, Yvonne Ai Lian
In Malaysia, soil-transmitted helminth (STH) infections still persist among indigenous communities. In the past, local studies have focused mostly on epidemiologic aspects of STH infections with a scarcity of information on the efficacy of deworming treatment. The present study consisted of 2 phases: a cross-sectional phase on current epidemiological status and risk factors of STH infections and a longitudinal study over 6 weeks on triple dose albendazole efficacy against STH infections. A total of 253 participants were recruited at baseline and a pre-tested questionnaire was administered to obtain information on socio-demographics, environmental and behavioural risk factors. Stool samples were evaluated using a modified Kato-Katz technique. Cure rate (CR) and egg reduction rate (ERR) were assessed at 3 weeks following a 3-day course of 400mg albendazole treatment and infection status were observed again at 6 weeks. Baseline positivity of trichuriasis, ascariasis and hookworm infections were 56.1%, 11.9% and 20.2%, respectively. Multivariate analysis showed age below 18 years old (P = 0.004), without latrine in house (P = 0.042) and indiscriminate defecation (P = 0.032) were associated with STH infections. In the longitudinal study (N = 89), CR for trichuriasis was 64.6%, while CR of 100% was observed for both ascariasis and hookworm. ERR was above 90% for all three STH species. A rapid increased of Trichuris trichiura egg output was observed at 6 weeks. In conclusion, STH infections are highly prevalent among indigenous communities. Children and teenagers, poor sanitation and hygiene behaviour were determinants for STH infections. Triple dose albendazole is found to be efficacious against Ascaris lumbricoides and hookworm infections but has moderate curative effect with high ERR against T. trichiura. Although triple dose albendazole regimen has logistic challenges and may not be a routine option, consideration of this treatment regime may still be necessary in selective communities to reduce high intensity of T. trichiura infection.
PMID: 35960935
ISSN: 1932-6203
CID: 5287372

TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity

Fu, Wenyu; Hu, Wenhuo; Yi, Young-Su; Hettinghouse, Aubryanna; Sun, Guodong; Bi, Yufei; He, Wenjun; Zhang, Lei; Gao, Guanmin; Liu, Jody; Toyo-Oka, Kazuhito; Xiao, Guozhi; Solit, David B; Loke, Png; Liu, Chuan-Ju
TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical co-purification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously-unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε anti-inflammatory pathway.
PMID: 34185706
ISSN: 1558-8238
CID: 4937152