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S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes

Dixit, Dhaval; Hallisey, Victoria M; Zhu, Ethan Ys; Okuniewska, Martyna; Cadwell, Ken; Chipuk, Jerry E; Axelrad, Jordan E; Schwab, Susan R
Effective immunity requires a large, diverse naive T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization were required to prevent this proapoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naive T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.
PMID: 38194271
ISSN: 1558-8238
CID: 5635202

Cytokine signature in convalescent SARS-CoV-2 patients with inflammatory bowel disease receiving vedolizumab

Dallari, Simone; Martinez Pazos, Vicky; Munoz Eusse, Juan; Wellens, Judith; Thompson, Craig; Colombel, Jean-Frederic; Satsangi, Jack; Cadwell, Ken; Wong, Serre-Yu; ,
While differential antibody responses SARS-CoV-2 in patients with inflammatory bowel disease (IBD) receiving infliximab and vedolizumab are well-characterized, the immune pathways underlying these differences remain unknown. Prior to COVID-19 vaccine development, we screened 235 patients with IBD receiving biological therapy for antibodies to SARS-CoV-2 and measured serum cytokines. In seropositive patients, we prospectively collected clinical data. We found a cytokine signature in patients receiving vedolizumab who are seropositive compared with seronegative for SARS-CoV-2 antibodies that may be linked to repeated SARS-CoV-2 infections. However, there were no differences between seropositive and seronegative patients receiving infliximab. In this single-center cohort of patients with IBD with anti-SARS-CoV-2 antibodies at the onset of the COVID-19 pandemic, and therefore without influence of vaccination, there is a cytokine signature in patients receiving vedolizumab but not infliximab. These findings lay the groundwork for further studies on immune consequences of viral infection in patients with IBD, which is postulated to evolve from aberrant host-microbe responses.
PMID: 38168138
ISSN: 2045-2322
CID: 5626042

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.
PMID: 38134275
ISSN: 2375-2548
CID: 5611862

Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis

Muharram, Ghaffar; Thépaut, Marion; Lobert, Pierre-Emmanuel; Grandjean, Teddy; Boulard, Olivier; Delacre, Myriam; Wakeford, Emmrich; Wheeler, Richard; Poulin, Lionel Franz; Boneca, Ivo Gomperts; Lafont, Frank; Michallet, Marie-Cécile; Hober, Didier; Cadwell, Ken; Chamaillard, Mathias
Over 90% of epidemic non-bacterial gastroenteritis are caused by human noroviruses (NoVs), which persist in a substantial subset of people allowing their spread worldwide. This has led to a significant number of endemic cases and up to 70,000 children deaths in developing countries. NoVs are primarily transmitted through the fecal-oral route. To date, studies have focused on the influence of the gut microbiota on enteric viral clearance by mucosal immunity. In this study, the use of mouse norovirus S99 (MNoV_S99) and CR6 (MNoV_CR6), two persistent strains, allowed us to provide evidence that the norovirus-induced exacerbation of colitis severity relied on bacterial sensing by nucleotide-binding oligomerization domain 2 (Nod2). Consequently, Nod2-deficient mice showed reduced levels of gravity of Dextran sodium sulfate (DSS)-induced colitis with both viral strains. And MNoV_CR6 viremia was heightened in Nod2
PMID: 37655966
ISSN: 1949-0984
CID: 5618092


Yang, Katharine Lu; Mullins, Briana J; Lejeune, Alannah; Ivanova, Ellie; Shin, Jong; Bajwa, Sofia; Possemato, Richard; Cadwell, Ken; Scher, Jose U; Koralov, Sergei B
OBJECTIVE:To study the effects of Short Chain Fatty Acids (SCFAs) on arthritic bone remodeling. METHODS:CD4Cre mice, with SCFA supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum-level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by transcriptional analysis. RESULTS:CD4Cre mice. Further interrogation revealed that bone marrow derived OCPs from diseased mice expressed a higher level of SCFA receptors than that of control mice and that the progenitor cells in the bone marrow of SCFA-treated mice presented a modified transcriptomic landscape, suggesting a direct impact of SCFAs on bone marrow progenitors in the context of osteoporosis. CONCLUSION/CONCLUSIONS:We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology, i.e., osteoporosis, and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut-bone axis in these disorders.
PMID: 37994265
ISSN: 2326-5205
CID: 5608662

Immunomodulation by Enteric Viruses

Bernard-Raichon, Lucie; Cadwell, Ken
Enteric viruses display intricate adaptations to the host mucosal immune system to successfully reproduce in the gastrointestinal tract and cause maladies ranging from gastroenteritis to life-threatening disease upon extraintestinal dissemination. However, many viral infections are asymptomatic, and their presence in the gut is associated with an altered immune landscape that can be beneficial or adverse in certain contexts. Genetic variation in the host and environmental factors including the bacterial microbiota influence how the immune system responds to infections in a remarkably viral strain-specific manner. This immune response, in turn, determines whether a given virus establishes acute versus chronic infection, which may have long-lasting consequences such as susceptibility to inflammatory disease. In this review, we summarize our current understanding of the mechanisms involved in the interaction between enteric viruses and the immune system that underlie the impact of these ubiquitous infectious agents on our health. Expected final online publication date for the Annual Review of Virology, Volume 10 is September 2023. Please see for revised estimates.
PMID: 37380186
ISSN: 2327-0578
CID: 5540362

Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Jang, Kyung Ku; Heaney, Thomas; London, Mariya; Ding, Yi; Putzel, Gregory; Yeung, Frank; Ercelen, Defne; Chen, Ying-Han; Axelrad, Jordan; Gurunathan, Sakteesh; Zhou, Chaoting; Podkowik, Magdalena; Arguelles, Natalia; Srivastava, Anusha; Shopsin, Bo; Torres, Victor J; Keestra-Gounder, A Marijke; Pironti, Alejandro; Griffin, Matthew E; Hang, Howard C; Cadwell, Ken
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
PMID: 37652008
ISSN: 1934-6069
CID: 5618182

Bacterial contact induces polar plug disintegration to mediate whipworm egg hatching

Robertson, Amicha; Sall, Joseph; Venzon, Mericien; Olivas, Janet J; Zheng, Xuhui; Cammer, Michael; Antao, Noelle; Zhou, Chunyi; Devlin, Joseph C; Saes Thur, Rafaela; Bethony, Jeffrey; Nejsum, Peter; Shopsin, Bo; Torres, Victor J; Liang, Feng-Xia; Cadwell, Ken
The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs. Egg hatching was most efficient when high densities of bacteria were bound to the poles. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.
PMID: 37738244
ISSN: 1553-7374
CID: 5627842

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.
PMID: 37352372
ISSN: 2470-9468
CID: 5537252

A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8

Rodriguez-Rodriguez, Bruno A; Ciabattoni, Grace O; Duerr, Ralf; Valero-Jimenez, Ana M; Yeung, Stephen T; Crosse, Keaton M; Schinlever, Austin R; Bernard-Raichon, Lucie; Rodriguez Galvan, Joaquin; McGrath, Marisa E; Vashee, Sanjay; Xue, Yong; Loomis, Cynthia A; Khanna, Kamal M; Cadwell, Ken; Desvignes, Ludovic; Frieman, Matthew B; Ortigoza, Mila B; Dittmann, Meike
Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context.
PMID: 37230979
ISSN: 2041-1723
CID: 5508612