TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

AbstractThe COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant®), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

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Fucoxanthin Ameliorates Oxidative Stress and Airway Inflammation in Tracheal Epithelial Cells and Asthmatic Mice

Cells ◽

10.3390/cells10061311 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1311

Author(s):

Shu-Ju Wu ◽

Chian-Jiun Liou ◽

Ya-Ling Chen ◽

Shu-Chen Cheng ◽

Wen-Chung Huang

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Airway Inflammation ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Eosinophil Infiltration ◽

Tracheal Epithelial Cells ◽

Tracheal Epithelial ◽

And Oxidative Stress

Fucoxanthin is isolated from brown algae and was previously reported to have multiple pharmacological effects, including anti-tumor and anti-obesity effects in mice. Fucoxanthin also decreases the levels of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. The purpose of the present study was to investigate the effects of fucoxanthin on the oxidative and inflammatory responses in inflammatory human tracheal epithelial BEAS-2B cells and attenuated airway hyperresponsiveness (AHR), airway inflammation, and oxidative stress in asthmatic mice. Fucoxanthin significantly decreased monocyte cell adherence to BEAS-2B cells. In addition, fucoxanthin inhibited the production of pro-inflammatory cytokines, eotaxin, and reactive oxygen species in BEAS-2B cells. Ovalbumin (OVA)-sensitized mice were treated by intraperitoneal injections of fucoxanthin (10 mg/kg or 30 mg/kg), which significantly alleviated AHR, goblet cell hyperplasia and eosinophil infiltration in the lungs, and decreased Th2 cytokine production in the BALF. Furthermore, fucoxanthin significantly increased glutathione and superoxide dismutase levels and reduced malondialdehyde (MDA) levels in the lungs of asthmatic mice. These data demonstrate that fucoxanthin attenuates inflammation and oxidative stress in inflammatory tracheal epithelial cells and improves the pathological changes related to asthma in mice. Thus, fucoxanthin has therapeutic potential for improving asthma.

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The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽

10.3390/pathogens10070866 ◽

2021 ◽

Vol 10 (7) ◽

pp. 866

Author(s):

Baca Chan ◽

Maja Arapović ◽

Laura Masters ◽

Francois Rwandamuiye ◽

Stipan Jonjić ◽

...

Keyword(s):

Nk Cells ◽

Salivary Glands ◽

Natural Killer ◽

Nk Cell ◽

Acute Infection ◽

Killer Cell ◽

Viral Escape ◽

Murine Cytomegalovirus ◽

Viral Shedding ◽

Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

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Changes in Upper and Lower Airway Inflammation Following Administration of Mometasone Furoate in Allergen-Challenged Brown Norway Rats

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2007.12.764 ◽

2008 ◽

Vol 121 (2) ◽

pp. S205-S205

Author(s):

J ANTHES ◽

R MCLEOD ◽

R CHAPMAN ◽

Y JIA ◽

J PHILLIPS

Keyword(s):

Airway Inflammation ◽

Mometasone Furoate ◽

Brown Norway ◽

Lower Airway ◽

Norway Rats

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Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates

Journal of Experimental Medicine ◽

10.1084/jem.20071641 ◽

2008 ◽

Vol 205 (3) ◽

pp. 625-640 ◽

Cited By ~ 396

Author(s):

Surojit Sarkar ◽

Vandana Kalia ◽

W. Nicholas Haining ◽

Bogumila T. Konieczny ◽

Shruti Subramaniam ◽

...

Keyword(s):

T Cells ◽

Expression Profiles ◽

Acute Infection ◽

Killer Cell ◽

Gene Expression Profiles ◽

Antigenic Stimulation ◽

T Cell Subsets ◽

Genomic Profiling ◽

Memory Cells ◽

Effector Cells

An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.

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Exhaled breath condensate hydrogen peroxide and pH for the assessment of lower airway inflammation in the horse

Research in Veterinary Science ◽

10.1016/j.rvsc.2009.03.014 ◽

2009 ◽

Vol 87 (2) ◽

pp. 307-312 ◽

Cited By ~ 12

Author(s):

M. Duz ◽

A.G. Whittaker ◽

S. Love ◽

T.D.H. Parkin ◽

K.J. Hughes

Keyword(s):

Hydrogen Peroxide ◽

Airway Inflammation ◽

Exhaled Breath Condensate ◽

Lower Airway ◽

Exhaled Breath ◽

Breath Condensate

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Elevated expression of inducible nitric oxide synthase and inflammatory cytokines in the alveolar macrophages after esophagectomy

Critical Care Medicine ◽

10.1097/00003246-200201000-00011 ◽

2002 ◽

Vol 30 (1) ◽

pp. 71-76 ◽

Cited By ~ 33

Author(s):

Kunihiko Kooguchi ◽

Atsuko Kobayashi ◽

Yoshihiro Kitamura ◽

Hiroshi Ueno ◽

Yoji Urata ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inflammatory Cytokines ◽

Inducible Nitric Oxide Synthase ◽

Alveolar Macrophages ◽

Elevated Expression ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00528.2020 ◽

2021 ◽

Author(s):

Joseph J. Mackel ◽

Jaleesa M. Garth ◽

MaryJane Jones ◽

Diandra A. Ellis ◽

Jonathan P. Blackburn ◽

...

Keyword(s):

Airway Inflammation ◽

Periodic Acid ◽

Acute Infection ◽

Allergic Bronchopulmonary Aspergillosis ◽

Allergic Airway Inflammation ◽

Lung Edema ◽

Periodic Acid Schiff ◽

Wide Range ◽

Type 2 Inflammation

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

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