Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection

Kenney, Devin; O'Connell, Aoife K; Turcinovic, Jacquelyn; Montanaro, Paige; Hekman, Ryan; Tamura, Tomokazu; Berneshawi, Andrew R; Cafiero, Thomas R.; Abdullatif, Salam Al; Blum, Benjamin; Goldstein, Stanley L.; Heller, Brigitte; Gertje, Hans; Bullitt, Esther; Trachtenberg, Alexander J.; Chavez, Elizabeth; Nono, Evans Tuekam; Morrison, Catherine J.; Tseng, Anna; Sheikh, Amira; Kurnick, Susanna; Grosz, Kyle; Bosmann, Markus; Ericsson, Maria; Huber, Bertrand R.; Saeed, Mohsan; Balazs, Alejandro B.; Francis, Kevin P.; Klose, Alexander D.; Paragas, Neal; Campbell, Joshua D.; Connor, John H.; Emili, Andrew; Crossland, Nicholas A.; Ploß, Alexander; Douam, Florian

doi:10.1016/j.celrep.2022.110714

Cited by 25 publications

(34 citation statements)

References 56 publications

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“…In our model, pathology appeared dependent on the infecting viral variant with B.1.1.7 producing significantly fewer lesions in animals solely implanted with human lung and not a human immune system, whereas VIDO-01 pathology was similar in both situations. Overall and similar to our findings, most models showed generation of pathogenic lesions and induction of cytokines responses that are associated with SARS-CoV-2 infection in humans and a role for the implanted human immune system in clearing the infection [ 37 , 44 , 68 , 74 ]. However, it appears imperative to carefully design studies of SARS-CoV-2 and interpret data with the limitations of each specific type of humanized lung mouse model and the specific viral variant being used in mind.…”

Section: Discussionsupporting

confidence: 88%

“…Other humanized lung mice have been generated on immunocompromised mouse backgrounds for the study of SARS-CoV-2 [ 37 , 44 , 68 , 74 ]. To our knowledge, ours is the first bone marrow, liver, thymus (BLT) model to be implanted with lung and used to assess SARS-CoV-2 infection whereas previous SARS-CoV-2 investigations were performed either in models solely implanted with human lung [ 37 , 44 ] and/or were additionally injected with fetal liver CD34 + cells to generate human immune system (HIS) mice [ 68 , 74 ]. Direct comparisons between the lung lesions and immune responses are difficult between the models as each type of humanization results in different levels of human immune reconstitution and immune functionality.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, different viral variants and doses were used and different time points often assessed in the limited studies currently available. There is some disparity between the models regarding the contribution of the implanted human immune system to virus-related lesions in the human organoid [ 44 , 68 , 74 ]. In our model, pathology appeared dependent on the infecting viral variant with B.1.1.7 producing significantly fewer lesions in animals solely implanted with human lung and not a human immune system, whereas VIDO-01 pathology was similar in both situations.…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model

Lew

Goncin

et al. 2022

Viruses

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Small animal models that accurately model pathogenesis of SARS-CoV-2 variants are required for ongoing research efforts. We modified our human immune system mouse model to support replication of SARS-CoV-2 by implantation of human lung tissue into the mice to create TKO-BLT-Lung (L) mice and compared infection with two different variants in a humanized lung model. Infection of TKO-BLT-L mice with SARS-CoV-2 recapitulated the higher infectivity of the B.1.1.7 variant with more animals becoming infected and higher sustained viral loads compared to mice challenged with an early B lineage (614D) virus. Viral lesions were observed in lung organoids but no differences were detected between the viral variants as expected. Partially overlapping but distinct immune profiles were also observed between the variants with a greater Th1 profile in VIDO-01 and greater Th2 profile in B.1.1.7 infection. Overall, the TKO-BLT-L mouse supported SARS-CoV-2 infection, recapitulated key known similarities and differences in infectivity and pathogenesis as well as revealing previously unreported differences in immune responses between the two viral variants. Thus, the TKO-BLT-L model may serve as a useful animal model to study the immunopathobiology of newly emerging variants in the context of genuine human lung tissue and immune cells.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model

Lew

Goncin

et al. 2022

Viruses

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“…This shows that infection with all SARS-CoV-2 variants in macrophages presents no replication although a discrete increased viral load was observed with α-SARS-CoV-2 (Wuhan), δ-B.1.617 (India) and β-B.1.351 (South Africa) variants. This is reminiscent of previous studies showing that SARS-CoV-2 efficiently infects human macrophages without replication ( 17 , 47 , 48 ), similar to SARS-CoV-1 ( 16 , 49 – 51 ) suggesting a protective role for macrophage during SARS-CoV infection at it was recently reported in humanized mice model ( 52 ). It is likely that variations in macrophage response to SARS-CoV-2 variants may be a consequence of changes in ACE2 expression.…”

Section: Discussionsupporting

confidence: 83%

Macrophages and γδ T cells interplay during SARS-CoV-2 variants infection

et al. 2022

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IntroductionThe emergence of several SARS-CoV-2 variants during the COVID pandemic has revealed the impact of variant diversity on viral infectivity and host immune responses. While antibodies and CD8 T cells are essential to clear viral infection, the protective role of innate immunity including macrophages has been recognized. The aims of our study were to compare the infectivity of different SARS-CoV-2 variants in monocyte-derived macrophages (MDM) and to assess their activation profiles and the role of ACE2 (Angiotensin-converting enzyme 2), the main SARS-CoV-2 receptor. We also studied the ability of macrophages infected to affect other immune cells such as γδ2 T cells, another partner of innate immune response to viral infections.ResultsWe showed that the SARS-CoV-2 variants α-B.1.1.7 (United Kingdom), β-B.1.351 (South Africa), γ-P.1 (Brazil), δ-B.1.617 (India) and B.1.1.529 (Omicron), infected MDM without replication, the γ-Brazil variant exhibiting increased infectivity for MDM. No clear polarization profile of SARS-CoV-2 variants-infected MDM was observed. The β-B.1.351 (South Africa) variant induced macrophage activation while B.1.1.529 (Omicron) was rather inhibitory. We observed that SARS-CoV-2 variants modulated ACE2 expression in MDM. In particular, the β-B.1.351 (South Africa) variant induced a higher expression of ACE2, related to MDM activation. Finally, all variants were able to activate γδ2 cells among which γ-P.1 (Brazil) and β-B.1.351 (South Africa) variants were the most efficient.ConclusionOur data show that SARS-CoV-2 variants can infect MDM and modulate their activation, which was correlated with the ACE2 expression. They also affect γδ2 T cell activation. The macrophage response to SARS-CoV-2 variants was stereotypical.

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“…Conversely, the tenascin-X member of the tenascin family is significantly downregulated in COVID-19 patient sera compared to healthy controls ( 67 ), as well as in lung tissue as a result of remodeling and destruction of ECM components that occur during COVID-19 progression ( 68 ). These findings are recapitulated in a humanized animal model of SARS-CoV-2 infection, where tenascin-X levels are significantly downregulated in the lung 2 days postinfection ( 69 ). As SARS-CoV-2 cannot infect mice, these humanized mouse models represent relevant systems to study lung and immune human responses during infection in vivo ( 70 , 71 ).…”

Section: What Is the Function Of Tenascin-c In Viral Infection?mentioning

confidence: 80%

A virological view of tenascin-C in infection

Zuliani-Alvarez

Piccinini

2023

American Journal of Physiology-Cell Physiology

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Tenascin-C is a large extracellular matrix glycoprotein with complex, not yet fully unveiled roles. Its context- and structure-dependent modus operandi renders tenascin-C a puzzling protein. Since its discovery ~40 years ago, research into tenascin-C biology continues to reveal novel functions, the most recent of all being its immunomodulatory activity, especially its role in infection, which is just now beginning to emerge. Here, we explore the role for tenascin-C in the immune response to viruses, including SARS-CoV-2 and HIV-1. Recently, tenascin-C has emerged as a biomarker of disease severity during COVID-19 and other viral infections and we highlight relevant RNA-Seq and proteomic analyses that suggest a correlation between tenascin-C levels and disease severity. Finally, we ask what the function of this protein during viral replication is and propose tenascin-C as an intercellular signal of inflammation shuttled to distal sites via exosomes, a player in the repair and remodeling of infected and damaged tissues during severe infectious disease as well as a ligand for specific pathogens with distinct implications for the host.

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Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection

Cited by 25 publications

References 56 publications

SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model

SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model

Macrophages and γδ T cells interplay during SARS-CoV-2 variants infection

A virological view of tenascin-C in infection

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