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Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens
Lacey, Keenan A; Pickrum, Adam M; Gonzalez, Sandra; Bartnicki, Eric; Castellaw, Ashley H; Rodrick, Tori C; Jones, Drew R; Khanna, Kamal M; Torres, Victor J
Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown. We report that DWR markedly increased susceptibility to systemic infection by ESKAPE pathogens. Using a murine bloodstream model of methicillin-resistant Staphylococcus aureus infection, we show that DWR leads to significantly increased mortality and morbidity. DWR causes increased bacterial burden, severe pathology, and increased numbers of phagocytes in the kidney. DWR appears to alter the functionality of these phagocytes and is therefore unable to control infection. Mechanistically, we show that DWR impairs the ability of macrophages to phagocytose multiple bacterial pathogens and efferocytose apoptotic neutrophils. Together, this work highlights the crucial impact that diet and hydration play in protecting against infection.
PMCID:11268424
PMID: 39047095
ISSN: 2375-2548
CID: 5696022
Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients
Barnett, Clea R; Krolikowski, Kelsey; Postelnicu, Radu; Mukherjee, Vikramjit; Sulaiman, Imran; Chung, Matthew; Angel, Luis; Tsay, Jun-Chieh J; Wu, Benjamin G; Yeung, Stephen T; Duerr, Ralf; Desvignes, Ludovic; Khanna, Kamal; Li, Yonghua; Schluger, Rosemary; Rafeq, Samaan; Collazo, Destiny; Kyeremateng, Yaa; Amoroso, Nancy; Pradhan, Deepak; Das, Sanchita; Evans, Laura; Uyeki, Timothy M; Ghedin, Elodie; Silverman, Gregg J; Segal, Leopoldo N; Brosnahan, Shari B
INTRODUCTION/UNASSIGNED:Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. MATERIAL AND METHODS/UNASSIGNED:We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. RESULTS/UNASSIGNED:While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. DISCUSSION/UNASSIGNED:Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.
PMCID:11228597
PMID: 38978558
ISSN: 2312-0541
CID: 5732242
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer
Pillai, Ray; LeBoeuf, Sarah E; Hao, Yuan; New, Connie; Blum, Jenna L E; Rashidfarrokhi, Ali; Huang, Shih Ming; Bahamon, Christian; Wu, Warren L; Karadal-Ferrena, Burcu; Herrera, Alberto; Ivanova, Ellie; Cross, Michael; Bossowski, Jozef P; Ding, Hongyu; Hayashi, Makiko; Rajalingam, Sahith; Karakousi, Triantafyllia; Sayin, Volkan I; Khanna, Kamal M; Wong, Kwok-Kin; Wild, Robert; Tsirigos, Aristotelis; Poirier, John T; Rudin, Charles M; Davidson, Shawn M; Koralov, Sergei B; Papagiannakopoulos, Thales
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
PMID: 38536921
ISSN: 2375-2548
CID: 5644942
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
KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
Zavitsanou, Anastasia-Maria; Pillai, Ray; Hao, Yuan; Wu, Warren L; Bartnicki, Eric; Karakousi, Triantafyllia; Rajalingam, Sahith; Herrera, Alberto; Karatza, Angeliki; Rashidfarrokhi, Ali; Solis, Sabrina; Ciampricotti, Metamia; Yeaton, Anna H; Ivanova, Ellie; Wohlhieter, Corrin A; Buus, Terkild B; Hayashi, Makiko; Karadal-Ferrena, Burcu; Pass, Harvey I; Poirier, John T; Rudin, Charles M; Wong, Kwok-Kin; Moreira, Andre L; Khanna, Kamal M; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Koralov, Sergei B
Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
PMID: 37889752
ISSN: 2211-1247
CID: 5590262
Mouse genome rewriting and tailoring of three important disease loci
Zhang, Weimin; Golynker, Ilona; Brosh, Ran; Fajardo, Alvaro; Zhu, Yinan; Wudzinska, Aleksandra M; Ordoñez, Raquel; Ribeiro-Dos-Santos, André M; Carrau, Lucia; Damani-Yokota, Payal; Yeung, Stephen T; Khairallah, Camille; Vela Gartner, Antonio; Chalhoub, Noor; Huang, Emily; Ashe, Hannah J; Khanna, Kamal M; Maurano, Matthew T; Kim, Sang Yong; tenOever, Benjamin R; Boeke, Jef D
Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases1,2. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling. Existing methods set limits on the size and efficiency of DNA delivery, hampering the routine creation of highly informative models that we call genomically rewritten and tailored GEMMs (GREAT-GEMMs). Here we describe 'mammalian switching antibiotic resistance markers progressively for integration' (mSwAP-In), a method for efficient genome rewriting in mouse embryonic stem cells. We demonstrate the use of mSwAP-In for iterative genome rewriting of up to 115 kb of a tailored Trp53 locus, as well as for humanization of mice using 116 kb and 180 kb human ACE2 loci. The ACE2 model recapitulated human ACE2 expression patterns and splicing, and notably, presented milder symptoms when challenged with SARS-CoV-2 compared with the existing K18-hACE2 model, thus representing a more human-like model of infection. Finally, we demonstrated serial genome writing by humanizing mouse Tmprss2 biallelically in the ACE2 GREAT-GEMM, highlighting the versatility of mSwAP-In in genome writing.
PMCID:10632133
PMID: 37914927
ISSN: 1476-4687
CID: 5606842
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
MAVS signaling is required for preventing persistent chikungunya heart infection and chronic vascular tissue inflammation
Noval, Maria G; Spector, Sophie N; Bartnicki, Eric; Izzo, Franco; Narula, Navneet; Yeung, Stephen T; Damani-Yokota, Payal; Dewan, M Zahidunnabi; Mezzano, Valeria; Rodriguez-Rodriguez, Bruno A; Loomis, Cynthia; Khanna, Kamal M; Stapleford, Kenneth A
Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.
PMCID:10400619
PMID: 37537212
ISSN: 2041-1723
CID: 5594762
Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth
Rashidfarrokhi, Ali; Pillai, Ray; Hao, Yuan; Wu, Warren L; Karadal-Ferrena, Burcu; Dimitriadoy, Sofia G; Cross, Michael; Yeaton, Anna H; Huang, Shih Ming; Bhutkar, Arjun J; Herrera, Alberto; Rajalingam, Sahith; Hayashi, Makiko; Huang, Kuan-Lin; Bartnicki, Eric; Zavitsanou, Anastasia-Maria; Wohlhieter, Corrin A; Leboeuf, Sarah E; Chen, Ting; Loomis, Cynthia; Mezzano, Valeria; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Rudin, Charles M; Moreira, Andre L; Khanna, Kamal M; Pass, Harvey I; Wong, Kwok-Kin; Koide, Shohei; Tsirigos, Aristotelis; Koralov, Sergei B; Papagiannakopoulos, Thales
Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1 -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 + interstitial macrophages and SiglecF Hi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1 -mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1 -mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1 + interstitial macrophages and SiglecF Hi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1 -mutant tumors.
PMCID:10370066
PMID: 37502974
ISSN: 2692-8205
CID: 5743132
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer
Pillai, Ray; LeBoeuf, Sarah E; Hao, Yuan; New, Connie; Blum, Jenna L E; Rashidfarrokhi, Ali; Huang, Shih Ming; Bahamon, Christian; Wu, Warren L; Karadal-Ferrena, Burcu; Herrera, Alberto; Ivanova, Ellie; Cross, Michael; Bossowski, Jozef P; Ding, Hongyu; Hayashi, Makiko; Rajalingam, Sahith; Karakousi, Triantafyllia; Sayin, Volkan I; Khanna, Kamal M; Wong, Kwok-Kin; Wild, Robert; Tsirigos, Aristotelis; Poirier, John T; Rudin, Charles M; Davidson, Shawn M; Koralov, Sergei B; Papagiannakopoulos, Thales
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We have previously shown that KEAP1 mutant tumors have increased glutamine consumption to support the metabolic rewiring associated with NRF2 activation. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we discover that DRP-104 reverses T cell exhaustion and enhances the function of CD4 and CD8 T cells culminating in an improved response to anti-PD1 therapy. Our pre-clinical findings provide compelling evidence that DRP-104, currently in phase 1 clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer. Furthermore, we demonstrate that by combining DRP-104 with checkpoint inhibition, we can achieve suppression of tumor intrinsic metabolism and augmentation of anti-tumor T cell responses.
PMID: 37425844
ISSN: 2692-8205
CID: 5743142