T-cell infiltration correlates with CXCL10 expression in ganglia of cynomolgus macaques with reactivated simian varicella virus.

Journal of virology, 87(5), 2979–2982.

Ouwendijk WJ, Abendroth A, Traina-Dorge V, Getu S, Steain M, Wellish M, Andeweg AC, Osterhaus AD, Gilden D, Verjans GM, Mahalingam R (2013).
PMID: 23269790 | DOI: 10.1128/JVI.03181-12.

Ganglia of monkeys with reactivated simian varicella virus (SVV) contained more CD8 than CD4 T cells around neurons. The abundance of CD8 T cells was greater less than 2 months after reactivation than that at later times and correlated with that of CXCL10 RNA but not with those of SVV protein or open reading frame 61 (ORF61) antisense RNA. CXCL10 RNA colocalized with T-cell clusters. After SVV reactivation, transient T-cell infiltration, possibly mediated by CXCL10, parallels varicella zoster virus (VZV) reactivation in humans.

Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update

Virology journal

2022 Jun 25

Yang, Y;Wei, Z;Xiong, C;Qian, H;
PMID: 35752810 | DOI: 10.1186/s12985-022-01833-y

Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin-angiotensin-aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).

Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma

Cancer cell

2023 Apr 08

Gaglia, G;Burger, ML;Ritch, CC;Rammos, D;Dai, Y;Crossland, GE;Tavana, SZ;Warchol, S;Jaeger, AM;Naranjo, S;Coy, S;Nirmal, AJ;Krueger, R;Lin, JR;Pfister, H;Sorger, PK;Jacks, T;Santagata, S;
PMID: 37059105 | DOI: 10.1016/j.ccell.2023.03.015

Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T cell anti-tumor responses.

SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

Cell

2022 Dec 02

Wu, CT;Lidsky, PV;Xiao, Y;Cheng, R;Lee, IT;Nakayama, T;Jiang, S;He, W;Demeter, J;Knight, MG;Turn, RE;Rojas-Hernandez, LS;Ye, C;Chiem, K;Shon, J;Martinez-Sobrido, L;Bertozzi, CR;Nolan, GP;Nayak, JV;Milla, C;Andino, R;Jackson, PK;
PMID: 36580912 | DOI: 10.1016/j.cell.2022.11.030

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.

Exposure Route Influences Disease Severity in the COVID-19 Cynomolgus Macaque Model

Viruses

2022 May 10

Bixler, SL;Stefan, CP;Jay, AN;Rossi, FD;Ricks, KM;Shoemaker, CJ;Moreau, AM;Zeng, X;Hooper, JW;Dyer, DN;Frick, OM;Koehler, JW;Kearney, BJ;DiPinto, N;Liu, J;Tostenson, SD;Clements, TL;Smith, JM;Johnson, JA;Berrier, KL;Esham, HL;Delp, KL;Coyne, SR;Bloomfield, HA;Kuehnert, PA;Akers, K;Gibson, KM;Minogue, TD;Nalca, A;Pitt, MLM;
PMID: 35632755 | DOI: 10.3390/v14051013

The emergence of SARS-CoV-2 and the subsequent pandemic has highlighted the need for animal models that faithfully replicate the salient features of COVID-19 disease in humans. These models are necessary for the rapid selection, testing, and evaluation of potential medical countermeasures. Here, we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure-combined intratracheal/intranasal and small particle aerosol-in two nonhuman primate species, rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models produced suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.

Positional influence on cellular transcriptional identity revealed through spatially segmented single-cell transcriptomics

Cell systems

2023 Jun 21

Morse, DB;Michalowski, AM;Ceribelli, M;De Jonghe, J;Vias, M;Riley, D;Davies-Hill, T;Voss, T;Pittaluga, S;Muus, C;Liu, J;Boyle, S;Weitz, DA;Brenton, JD;Buenrostro, JD;Knowles, TPJ;Thomas, CJ;
PMID: 37348462 | DOI: 10.1016/j.cels.2023.05.003

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for describing cell states. Identifying the spatial arrangement of these states in tissues remains challenging, with the existing methods requiring niche methodologies and expertise. Here, we describe segmentation by exogenous perfusion (SEEP), a rapid and integrated method to link surface proximity and environment accessibility to transcriptional identity within three-dimensional (3D) disease models. The method utilizes the steady-state diffusion kinetics of a fluorescent dye to establish a gradient along the radial axis of disease models. Classification of sample layers based on dye accessibility enables dissociated and sorted cells to be characterized by transcriptomic and regional identities. Using SEEP, we analyze spheroid, organoid, and in vivo tumor models of high-grade serous ovarian cancer (HGSOC). The results validate long-standing beliefs about the relationship between cell state and position while revealing new concepts regarding how spatially unique microenvironments influence the identity of individual cells within tumors.

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Nature cell biology

2023 Mar 09

Gioia, U;Tavella, S;Martínez-Orellana, P;Cicio, G;Colliva, A;Ceccon, M;Cabrini, M;Henriques, AC;Fumagalli, V;Paldino, A;Presot, E;Rajasekharan, S;Iacomino, N;Pisati, F;Matti, V;Sepe, S;Conte, MI;Barozzi, S;Lavagnino, Z;Carletti, T;Volpe, MC;Cavalcante, P;Iannacone, M;Rampazzo, C;Bussani, R;Tripodo, C;Zacchigna, S;Marcello, A;d'Adda di Fagagna, F;
PMID: 36894671 | DOI: 10.1038/s41556-023-01096-x

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs' biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.

An Engineered IgG-VHH Bispecific Antibody against SARS-CoV-2 and Its Variants

Small methods

2022 Oct 27

Chi, H;Wang, L;Liu, C;Cheng, X;Zheng, H;Lv, L;Tan, Y;Zhang, N;Zhao, S;Wu, M;Luo, D;Qiu, H;Feng, R;Fu, W;Zhang, J;Xiong, X;Zhang, Y;Zu, S;Chen, Q;Ye, Q;Yan, X;Hu, Y;Zhang, Z;Yan, R;Yin, J;Lei, P;Wang, W;Lang, G;Shao, J;Deng, Y;Wang, X;Qin, C;
PMID: 36300882 | DOI: 10.1002/smtd.202200932

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID-19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G-variable domains of heavy-chain-only antibody (IgG-VHH) format bsAb derived from a potent human antibody R15-F7 and a humanized nanobody P14-F8-35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild-type SARS-CoV-2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo-electron microscopy structural analysis reveals that R15-F7 and P14-F8-35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS-CoV-2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy.

Rational development of a combined mRNA vaccine against COVID-19 and influenza

NPJ vaccines

2022 Jul 26

Ye, Q;Wu, M;Zhou, C;Lu, X;Huang, B;Zhang, N;Zhao, H;Chi, H;Zhang, X;Ling, D;Zhang, RR;Li, Z;Luo, D;Huang, YJ;Qiu, HY;Song, H;Tan, W;Xu, K;Ying, B;Qin, CF;
PMID: 35882870 | DOI: 10.1038/s41541-022-00478-w

As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor-binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

Spatially organized multicellular immune hubs in human colorectal cancer

Cell

2021 Aug 24

Pelka, K;Hofree, M;Chen, JH;Sarkizova, S;Pirl, JD;Jorgji, V;Bejnood, A;Dionne, D;Ge, WH;Xu, KH;Chao, SX;Zollinger, DR;Lieb, DJ;Reeves, JW;Fuhrman, CA;Hoang, ML;Delorey, T;Nguyen, LT;Waldman, J;Klapholz, M;Wakiro, I;Cohen, O;Albers, J;Smillie, CS;Cuoco, MS;Wu, J;Su, MJ;Yeung, J;Vijaykumar, B;Magnuson, AM;Asinovski, N;Moll, T;Goder-Reiser, MN;Applebaum, AS;Brais, LK;DelloStritto, LK;Denning, SL;Phillips, ST;Hill, EK;Meehan, JK;Frederick, DT;Sharova, T;Kanodia, A;Todres, EZ;Jané-Valbuena, J;Biton, M;Izar, B;Lambden, CD;Clancy, TE;Bleday, R;Melnitchouk, N;Irani, J;Kunitake, H;Berger, DL;Srivastava, A;Hornick, JL;Ogino, S;Rotem, A;Vigneau, S;Johnson, BE;Corcoran, RB;Sharpe, AH;Kuchroo, VK;Ng, K;Giannakis, M;Nieman, LT;Boland, GM;Aguirre, AJ;Anderson, AC;Rozenblatt-Rosen, O;Regev, A;Hacohen, N;
PMID: 34450029 | DOI: 10.1016/j.cell.2021.08.003

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

In situ detection of vaccine mRNA in the cytoplasm of hepatocytes during COVID19 vaccine-related hepatitis

Journal of hepatology

2022 Sep 15

Martin-Navarro, L;de Andrea, C;Sangro, B;Argemi, J;
PMID: 36116717 | DOI: 10.1016/j.jhep.2022.08.039

Spike Protein-independent Attenuation of SARS-CoV-2 Omicron Variant in Laboratory Mice

Cell Reports

2022 Aug 01

Liu, S;Selvaraj, P;Sangare, K;Luan, B;Wang, T;
| DOI: 10.1016/j.celrep.2022.111359

Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration; Silver Spring, Maryland, USA, 20993

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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