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Inhibiting influenza virus transmission using a broadly acting neuraminidase that targets host sialic acids in the upper respiratory tract

Ortigoza, Mila B; Mobini, Catherina L; Rocha, Hedy L; Bartlett, Stacey; Loomis, Cynthia A; Weiser, Jeffrey N
The ongoing transmission of influenza A viruses (IAV) for the past century continues to be a burden to humans. IAV binds terminal sialic acids (SA) of sugar molecules present within the upper respiratory tract (URT) in order to successfully infect hosts. The two most common SA structures that are important for IAV infection are those with α2,3- and α2,6-linkages. While mice were once considered to be an unsuitable system for studying IAV transmission due to their lack of α2,6-SA in the trachea, we have successfully demonstrated that IAV transmission in infant mice is remarkably efficient. This finding led us to re-evaluate the SA composition of the URT of mice using in situ immunofluorescence and examine its in vivo contribution to transmission for the first time. We demonstrate that mice express both α2,3- and α2,6-SA in the URT and that the difference in expression between infants and adults contributes to the variable transmission efficiencies observed. Furthermore, selectively blocking α2,3-SA or α2,6-SA within the URT of infant mice using lectins was necessary but insufficient at inhibiting transmission, and simultaneous blockade of both receptors was crucial in achieving the desired inhibitory effect. By employing a broadly acting neuraminidase to indiscriminately remove both SA moieties in vivo, we effectively suppressed viral shedding and halted the transmission of different strains of influenza viruses. These results emphasize the utility of the infant mouse model for studying IAV transmission and strongly indicate that broadly targeting host SA is an effective approach that inhibits IAV contagion.IMPORTANCEInfluenza virus transmission studies have historically focused on viral mutations that alter hemagglutinin binding to sialic acid (SA) receptors in vitro. However, SA binding preference does not fully account for the complexities of influenza A virus transmission in humans. Our previous findings reveal that viruses that are known to bind α2,6-SA in vitro have different transmission kinetics in vivo, suggesting that diverse SA interactions may occur during their life cycle. In this study, we examine the role of host SA on viral replication, shedding, and transmission in vivo. We highlight the critical role of SA presence during virus shedding, such that attachment to SA during virion egress is equally important as detachment from SA during virion release. These insights support the potential of broadly acting neuraminidases as therapeutic agents capable of restraining viral transmission in vivo. Our study unveils intricate virus-host interactions during shedding, highlighting the necessity to develop innovative strategies to effectively target transmission.
PMID: 38206008
ISSN: 2150-7511
CID: 5635222

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

Wise, David R; Pachynski, Russell K; Denmeade, Samuel R; Aggarwal, Rahul R; Deng, Jiehui; Febles, Victor Adorno; Balar, Arjun V; Economides, Minas P; Loomis, Cynthia; Selvaraj, Shanmugapriya; Haas, Michael; Kagey, Michael H; Newman, Walter; Baum, Jason; Troxel, Andrea B; Griglun, Sarah; Leis, Dayna; Yang, Nina; Aranchiy, Viktoriya; Machado, Sabrina; Waalkes, Erika; Gargano, Gabrielle; Soamchand, Nadia; Puranik, Amrutesh; Chattopadhyay, Pratip; Fedal, Ezeddin; Deng, Fang-Ming; Ren, Qinghu; Chiriboga, Luis; Melamed, Jonathan; Sirard, Cynthia A; Wong, Kwok-Kin
BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
PMID: 38341461
ISSN: 1476-5608
CID: 5635542

Digital spatial profiling to predict recurrence in grade 3 stage I lung adenocarcinoma

Chang, Stephanie H; Mezzano-Robinson, Valeria; Zhou, Hua; Moreira, Andre; Pillai, Raymond; Ramaswami, Sitharam; Loomis, Cynthia; Heguy, Adriana; Tsirigos, Aristotelis; Pass, Harvey I
OBJECTIVE:Early-stage lung adenocarcinoma is treated with local therapy alone, although patients with grade 3 stage I lung adenocarcinoma have a 50% 5-year recurrence rate. Our objective is to determine if analysis of the tumor microenvironment can create a predictive model for recurrence. METHODS:Thirty-four patients with grade 3 stage I lung adenocarcinoma underwent surgical resection. Digital spatial profiling was used to perform genomic (n = 31) and proteomic (n = 34) analyses of pancytokeratin positive and negative tumor cells. K-means clustering was performed on the top 50 differential genes and top 20 differential proteins, with Kaplan-Meier recurrence curves based on patient clustering. External validation of high-expression genes was performed with Kaplan-Meier plotter. RESULTS:There were no significant clinicopathologic differences between patients who did (n = 14) and did not (n = 20) have recurrence. Median time to recurrence was 806 days; median follow-up with no recurrence was 2897 days. K-means clustering of pancytokeratin positive genes resulted in a model with a Kaplan-Meier curve with concordance index of 0.75. K-means clustering for pancytokeratin negative genes was less successful at differentiating recurrence (concordance index 0.6). Genes upregulated or downregulated for recurrence were externally validated using available public databases. Proteomic data did not reach statistical significance but did internally validate the genomic data described. CONCLUSIONS:Genomic difference in lung adenocarcinoma may be able to predict risk of recurrence. After further validation, stratifying patients by this risk may help guide who will benefit from adjuvant therapy.
PMID: 37890657
ISSN: 1097-685x
CID: 5620342

A comparative study of in vitro air-liquid interface culture models of the human airway epithelium evaluating cellular heterogeneity and gene expression at single cell resolution

Prescott, Rachel A; Pankow, Alec P; de Vries, Maren; Crosse, Keaton M; Patel, Roosheel S; Alu, Mark; Loomis, Cynthia; Torres, Victor; Koralov, Sergei; Ivanova, Ellie; Dittmann, Meike; Rosenberg, Brad R
BACKGROUND:The airway epithelium is composed of diverse cell types with specialized functions that mediate homeostasis and protect against respiratory pathogens. Human airway epithelial (HAE) cultures at air-liquid interface are a physiologically relevant in vitro model of this heterogeneous tissue and have enabled numerous studies of airway disease. HAE cultures are classically derived from primary epithelial cells, the relatively limited passage capacity of which can limit experimental methods and study designs. BCi-NS1.1, a previously described and widely used basal cell line engineered to express hTERT, exhibits extended passage lifespan while retaining the capacity for differentiation to HAE. However, gene expression and innate immune function in BCi-NS1.1-derived versus primary-derived HAE cultures have not been fully characterized. METHODS:BCi-NS1.1-derived HAE cultures (n = 3 independent differentiations) and primary-derived HAE cultures (n = 3 distinct donors) were characterized by immunofluorescence and single cell RNA-Seq (scRNA-Seq). Innate immune functions were evaluated in response to interferon stimulation and to infection with viral and bacterial respiratory pathogens. RESULTS:We confirm at high resolution that BCi-NS1.1- and primary-derived HAE cultures are largely similar in morphology, cell type composition, and overall gene expression patterns. While we observed cell-type specific expression differences of several interferon stimulated genes in BCi-NS1.1-derived HAE cultures, we did not observe significant differences in susceptibility to infection with influenza A virus and Staphylococcus aureus. CONCLUSIONS:Taken together, our results further support BCi-NS1.1-derived HAE cultures as a valuable tool for the study of airway infectious disease.
PMID: 37635251
ISSN: 1465-993x
CID: 5606922

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

Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
PMID: 37400453
ISSN: 2041-1723
CID: 5539082

Calcitonin Related Polypeptide Alpha Mediates Oral Cancer Pain

Tu, Nguyen Huu; Inoue, Kenji; Lewis, Parker K; Khan, Ammar; Hwang, Jun Hyeong; Chokshi, Varun; Dabovic, Branka Brukner; Selvaraj, Shanmugapriya; Bhattacharya, Aditi; Dubeykovskaya, Zinaida; Pinkerton, Nathalie M; Bunnett, Nigel W; Loomis, Cynthia A; Albertson, Donna G; Schmidt, Brian L
Oral cancer patients suffer pain at the site of the cancer. Calcitonin gene related polypeptide (CGRP), a neuropeptide expressed by a subset of primary afferent neurons, promotes oral cancer growth. CGRP also mediates trigeminal pain (migraine) and neurogenic inflammation. The contribution of CGRP to oral cancer pain is investigated in the present study. The findings demonstrate that CGRP-immunoreactive (-ir) neurons and neurites innervate orthotopic oral cancer xenograft tumors in mice. Cancer increases anterograde transport of CGRP in axons innervating the tumor, supporting neurogenic secretion as the source of CGRP in the oral cancer microenvironment. CGRP antagonism reverses oral cancer nociception in preclinical oral cancer pain models. Single-cell RNA-sequencing is used to identify cell types in the cancer microenvironment expressing the CGRP receptor components, receptor activity modifying protein 1 Ramp1 and calcitonin receptor like receptor (CLR, encoded by Calcrl). Ramp1 and Calcrl transcripts are detected in cells expressing marker genes for Schwann cells, endothelial cells, fibroblasts and immune cells. Ramp1 and Calcrl transcripts are more frequently detected in cells expressing fibroblast and immune cell markers. This work identifies CGRP as mediator of oral cancer pain and suggests the antagonism of CGRP to alleviate oral cancer pain.
PMCID:10341289
PMID: 37443709
ISSN: 2073-4409
CID: 5535282

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

Castillo, Rochelle L; Sidhu, Ikjot; Dolgalev, Igor; Chu, Tinyi; Prystupa, Aleksandr; Subudhi, Ipsita; Yan, Di; Konieczny, Piotr; Hsieh, Brandon; Haberman, Rebecca H; Selvaraj, Shanmugapriya; Shiomi, Tomoe; Medina, Rhina; Girija, Parvathy Vasudevanpillai; Heguy, Adriana; Loomis, Cynthia A; Chiriboga, Luis; Ritchlin, Christopher; Garcia-Hernandez, Maria De La Luz; Carucci, John; Meehan, Shane A; Neimann, Andrea L; Gudjonsson, Johann E; Scher, Jose U; Naik, Shruti
Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.
PMID: 37267384
ISSN: 2470-9468
CID: 5536642

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

Hedgehog and PDGF Signaling Intersect During Postnatal Lung Development

Yie, Ting-An; Loomis, Cynthia A; Nowatzky, Johannes; Khodadadi-Jamayran, Alireza; Lin, Ziyan; Cammer, Michael; Barnett, Clea; Mezzano, Valeria; Alu, Mark; Novick, Jackson A; Munger, John S; Kugler, Matthias C
Normal lung development critically depends on Hedgehog (HH) and Platelet-derived growth factor (PDGF) signaling, which coordinate mesenchymal differentiation and proliferation. PDGF signaling is required for postnatal alveolar septum formation by myofibroblasts. Recently, we demonstrated a requirement for HH in postnatal lung development involving alveolar myofibroblast differentiation. Given shared features of HH and PDGF signaling and their impact/convergence on this key cell type, we sought to clarify their relationship during murine postnatal lung development. Timed experiments revealed that HH inhibition phenocopies the key lung myofibroblast phenotypes of Pdgfa and Pdgfra knockouts during secondary alveolar septation. Utilizing a dual signaling reporter, Gli1IZ;PdgfraEGFP
PMID: 36693140
ISSN: 1535-4989
CID: 5419542