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Helminth infections affect host immune responses to viral infections and vaccines
Diego, Juan García-Bernalt; Desai, Pritesh; Yeung, Stephen T; Damani-Yokota, Payal; Khanna, Kamal M; Diamond, Michael S; Schotsaert, Michael
Helminths are highly prevalent in many regions of the world. Due to the chronic nature of most helminth infections, these parasites are proficient immunomodulators of their hosts. This modulation often leads to skewed or even impaired immune responses against unrelated antigens, such as viruses and vaccines, which can be both beneficial and detrimental for the host. The extent of these effects and the impact on the outcomes of viral infection depends on a variety of factors including timing and tropism of both infections, pathological mechanisms, genetic background, and environmental factors. In this review, we dissect these complex interactions between virus and helminths in the context of co-infection and the impact of helminth infection on antiviral vaccine efficacy. We characterize the key contributing mechanisms that have been defined in pre-clinical models and human trials and describe the immune actors involved in the modulation of the antiviral and vaccine immune response by helminths. Finally, we address the limitations of our current understanding of helminth-virus interactions.
PMID: 40796112
ISSN: 1574-6976
CID: 5907212
Vagal TRPV1+ sensory neurons protect against influenza virus infection by regulating lung myeloid cell dynamics
Almanzar, Nicole; Yang, Daping; Xia, Jingya; Udit, Swalpa; Joshi, Prabhu; Adhikari, Sandeep; Hoagland, Daisy A; Yeung, Stephen T; Khairallah, Camille; Huerta, Tomas; Wallrapp, Antonia; Umans, Benjamin D; Sarden, Nicole; Erdogan, Ozge; Baalbaki, Nadia; Hou, Jiawei; Beekmayer-Dhillon, Anna; Lee, Juhyun; Meerschaert, Kimberly A; Liberles, Stephen D; Franklin, Ruth A; Yipp, Bryan G; Khanna, Kamal M; Baral, Pankaj; Haber, Adam L; Chiu, Isaac M
Influenza viruses are a major global cause of morbidity and mortality. Although vagal TRPV1+ nociceptive sensory neurons are known to mediate defenses against harmful agents, including pathogens, their function in lung antiviral defenses remains unclear. Our study demonstrates that both systemic and vagal-specific ablation of TRPV1+ nociceptors reduce survival in mice infected with influenza A virus (IAV). Despite no difference in viral load, mice lacking TRPV1+ neurons exhibited increased viral spread, exacerbated lung pathology, and elevated levels of proinflammatory cytokines. Loss of TRPV1+ neurons altered the lung immune landscape, including an expansion of neutrophils and monocyte-derived macrophages. Transcriptional analysis revealed impaired interferon signaling in myeloid cells and an imbalance in distinct neutrophil subpopulations in the absence of nociceptors. Furthermore, antibody-mediated depletion of myeloid cells during IAV infection substantially improved survival after nociceptor ablation, underscoring the role of TRPV1+ neurons in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality.
PMID: 40749036
ISSN: 2470-9468
CID: 5903842
Macrophages: sentinels, warriors, and healers
Bernier, Eduardo D; Bartnicki, Eric; Khanna, Kamal M
Macrophages are versatile innate immune cells that act as sentinels, warriors, and healers in virtually every tissue. This review synthesizes current insights into their developmental origins and the organ-specific cues that imprint diverse tissue-resident and monocyte-derived programs. We detail how pattern-recognition pathways, metabolic and epigenetic rewiring, and environmental signals govern macrophage plasticity, steering transitions between pro-inflammatory and reparative phenotypes during homeostasis, infection, and sterile injury. Dysregulated macrophage responses drive chronic inflammatory, autoimmune, metabolic, neurodegenerative, and neoplastic diseases; inter-individual variability rooted in genetic polymorphisms and enhancer landscapes further modulates susceptibility. Advances in single-cell and spatial multi-omics are redefining macrophage subsets and exposing disease-associated states, while approaches such as checkpoint blockade, chimeric antigen receptor macrophages, nanoparticles, metabolic modulators, and pro-resolving mediators showcase the therapeutic promise of re-programming these cells. Remaining challenges include integrating the layered genetic, metabolic, and microenvironmental inputs that dictate macrophage fate. Addressing these gaps will unlock precision strategies that harness macrophage plasticity to combat infection, resolve inflammation, repair tissue, and augment anti-tumor immunity.
PMID: 40479537
ISSN: 1460-2083
CID: 5862842
Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling
Yeung, Stephen T; Damani-Yokota, Payal; Thannickal, Sara A; Bartnicki, Eric; Bernier, Eduardo D; Barnett, Clea R; Khairallah, Camille; Duerr, Ralf; Noval, Maria G; Segal, Leopoldo N; Stapleford, Kenneth A; Khanna, Kamal M
Despite vaccines, rapidly mutating viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to threaten human health due to an impaired immunoregulatory pathway and a hyperactive immune response. Our understanding of the local immune mechanisms used by tissue-resident macrophages to safeguard the host from excessive inflammation during SARS-CoV-2 infection remains limited. Here, we found that nerve- and airway-associated interstitial macrophages (NAMs) are required to control mouse-adapted SARS-CoV-2 (MA-10) infection. Control mice restricted lung viral distribution and survived infection, whereas NAM depletion enhanced viral spread and inflammation and led to 100% mortality. Mechanistically, type I interferon receptor (IFNAR) signaling by NAMs was critical for limiting inflammation and viral spread, and IFNAR deficiency in CD169+ macrophages mirrored NAM-depleted outcomes and abrogated their expansion. These findings highlight the essential protective role of NAMs in regulating viral spread and inflammation, offering insights into SARS-CoV-2 pathogenesis and underscoring the importance of NAMs in mediating host immunity and disease tolerance.
PMID: 40286790
ISSN: 1097-4180
CID: 5830932
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