key: cord-0813509-d8broqz0
authors: Tan, J.; Anderson, D.; Rathore, A. P. S.; O'Neill, A.; Mantri, C. K.; Saron, W. A. A.; Lee, C.; Chu, W. C.; Kang, A.; Foo, R.; Kalimuddin, S.; Low, J.; Ho, L.; Tambyah, P.; Burke, T. W.; Woods, C. W.; Chan, K. R.; Karhausen, J.; St John, A. L.
title: Signatures of mast cell activation are associated with severe COVID-19
date: 2021-06-01
journal: medRxiv : the preprint server for health sciences
DOI: 10.1101/2021.05.31.21255594
sha: 3e84c3888915d99cc489ed82c46a42ed34eb43b0
doc_id: 813509
cord_uid: d8broqz0

Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in severely ill patients and the pathophysiology of disease is thought to be immune-mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens, often promoting inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and non-human primates. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype. MC activation in humans was confirmed, through detection of the MC-specific protease, chymase, levels of which were significantly correlated with disease severity. These results support the association of MC activation with severe COVID-19, suggesting potential strategies for intervention.

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 14

(SARS-CoV-2), a recently emerged coronavirus that has resulted in an ongoing global pandemic. Clinical 15 disease ranges from asymptomatic to mild to severe, and manifestations include upper respiratory tract 16 symptoms, pneumonia and, in some cases, acute respiratory distress syndrome (ARDS) (1) . Fever, cough 17 and anosmia are most commonly experienced at disease presentation and complications involving the 18 vascular system can occur during severe disease (1) . The lung is a major target organ of SARS-CoV- 2 19 infection due to abundant expression of the angiotensin converting enzyme 2 (ACE2) receptor, a cellular 20 entry receptor for SARS-CoV-2 (2) . The virus is typically shed from the nasopharyngeal tract and 21 disseminated by coughing, but it can also be detected in fecal excretions (3) . Various mouse and non-22 human primate (NHP) models have been utilized to study COVID-19 (4) . Non-human primates (NHPs) 23 and human ACE2 (hACE2) knock-in mice both have been shown to experience infection and recapitulate 24 human signs of disease in the lung, including lung pathology (4) . In human autopsy studies of severe 25 disease, infiltration of mononuclear cells in the lung tissue concurrent with edema and hemorrhage are 26 frequently described (5) . It is believed that lung pathology during COVID-19 is immune-mediated and 27 compounded by the infiltration of monocytes, neutrophils and subsets of T cells (6) . Interestingly, 28

perturbations in the numbers of granulocytes in the blood, such as neutrophils and eosinophils have also 29 been shown to be associated with severe disease (1, 7, 8) . 30 31 Another granulocyte that responds to viral infections and is found in the lung tissue is the mast cell (MC). 32

MCs are long-lived granulated immune cells that are present in both connective and mucosal tissues (9) . 33

In adults, MCs are thought to be derived from precursor cells circulating in the blood, known as MC 34 progenitors, but they are only found in mature form in tissues (10) , making them difficult to study in 35 humans. Tissue resident MCs have a mature phenotype and express a variety of pathogen recognition 36 molecules on their surface and inside cytosolic compartments (11, 12) . Their granules are loaded with pre-37 formed mediators such as histamine, serotonin and unique MC-specific proteases, chymase and tryptase, 38 among others. Some of their mediators, including soluble cytokines and lipid mediators, may be also 39 produced by other granulocytes and immune cells (13) . MC-derived products not only promote tissue 40 inflammation through the recruitment of cells such as monocytes, neutrophils and T cells, they also have 41 significant effects on vascular permeability and vasomotor control (9, 12, 14) . The influence of MCs on 42 vasomotor control, including vasoconstriction and vasodilation, may also contribute to hypoxia that occurs 43 through shunting, which can influence vascular and tissue integrity (15) . The tissue-specific 44 microenvironment where a MC resides influences its phenotype. For example, MCs in the atopic lung 45 express higher levels of IgE receptor, FcεR1 than in the skin (16, 17) and lung MCs are well characterized 46 to contribute to pathological lung inflammation during conditions such as asthma (18) . MCs are known to 47 coordinate effective immune responses against invading pathogens, including viruses(12) but their 48 activation has also been linked to severe tissue damage, such as during dengue virus (DENV) 49

infection (19) . In the lung, MC hyperplasia has also been reported during respiratory syncytial virus or 50 parainfluenza virus infections (20, 21) and therapeutic stabilization of MCs was shown to reduce lung 51 lesions in a model of highly pathogenic H5N1 influenza infection (22) . However, sustained and systemic 52 activation of MCs could also result in severe pathologies such as coagulation disorders and vascular leak. 53

For example, MC-specific products such as chymase have been shown to be predictive of dengue 54 hemorrhagic fever and the severity of vascular leakage and coagulopathy that characterize severe 55 disease (19, 23, 24) . MCs are present both in the nasal mucosae as well as in the deeper lung tissue 56

where SARS-CoV-2 infection occurs; however, it is unknown whether MCs respond to highly pathogenic 57 coronaviruses or if they could be involved in exacerbating the severe inflammation seen in SARS-CoV-2 58 infection. 59

In this study we aimed to assess MC activation in response to SARS-CoV-2 infection. Using mouse and 61 NHP models of COVID-19 we identified wide-spread MC degranulation in both acute and convalescent 62 lung tissues. In a human cohort, prospective analysis of the transcriptional signatures of MC-precursors 63 were highly enriched in the blood of patients who presented with severe COVID-19 disease, suggesting 64 modulation of this cell type during disease, as were several host response pathways for prominent MC-65 derived products. Furthermore, the MC-specific product, chymase was significantly elevated in the sera of 66 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Given the association of MCs with chronic airway inflammation, their immune sentinel role for certain viral 74 pathogens, and knowing that severe lung inflammation also characterizes COVID-19, we first questioned 75 whether MCs are activated in animal models of SARS-CoV-2 infection. We used an established mouse 76 model where the receptor for SARS-CoV-2, hACE2, is delivered to the lungs using an adenovirus 77 vector (25) . After hACE2-AAV inoculation, mice were infected with SARS-CoV-2 (Fig. 1A) . Blood was 78 collected at multiple time points to assess MC-associated inflammatory products and tissues were 79 collected on days 5 and 7 post-infection for virus quantification by PCR. Mice showed the highest 80 infection burden in the lungs, but for at least some of the animals, SARS-CoV-2 could also be detected in 81 the spleen, liver, kidney, brain, and bone marrow (Fig. 1B) , while the brachial lymph nodes were PCR-82 negative at both time points (Fig. S1) . Tissue histology revealed degranulation of MCs in the airways, as 83

shown in a representative image of the trachea at day 5 post-infection (Fig. 1C) , where toluidine blue 84 staining of MC granules indicated extensive degranulation that coincided with edema in the tissue. In 85 contrast, granulated resting MCs can be observed in control trachea tissue (Fig. 1C) . The trachea tissue 86 from control uninfected animals also appears healthy and compact, while the thickness of the trachea 87 tissue in SARS-CoV-2 infected animals appears increased as a result of inflammation and swelling (Fig.  88   1C ). To provide a quantitation of MC activation, we also measured serum levels of the mouse chymase 89 MCPT1, which is a MC-specific protease that can be used as a biomarker of MC activation (19) . MCPT1 90 levels were significantly elevated days 1, 3 and 5 post-SARS-CoV-2 infection and remained high, but 91 trending lower on day 7 (Fig. 1D) , which we noted also coincided with reductions in viral burden in the 92 tissues (Fig. 1B) . The evidence of MC degranulation in the airways combined with systemically elevated 93 MC products indicates that SARS-CoV-2 induces substantial activation of MCs during infection in vivo. 94

We next aimed to validate the MC activation phenotype in the non-human primate (NHP) model, which is 96 thought to more closely replicate the signs and symptoms of human SARS-CoV-2 infection (4) . For this, 97 cynomolgus macaques were infected with 3x10 6 TCID-50 of SARS-CoV-2 virus intra-tracheally and they 98 were monitored with minimal interventions for 21 days prior to necropsy ( Fig. 2A) . Throughout the study 99 the animals were generally active, alert, and responsive. There were no significant changes in body 100 weight or temperature during the study (Fig. S2) . Two NHPs (#6699 and 6727) displayed appetite loss, 101 and one was given subcutaneous fluids. SARS-CoV-2 could be detected in the nasal rinse or swab of all 102 NHPs at multiple time points during acute infection, as well as in the throat swab and lung lavage at least 103 one time point post-infection (Fig. 2B) . Additionally, 3 of 4 NHPs were positive by rectal swab and 1 also 104 had detectable SARS-CoV-2 by eye swab (Fig. 2B) . In support of active infection, all NHPs 105 seroconverted by day 14 (Table S1 ). At the time of necropsy on day 21, evidence of severe lung disease 106 was apparent, with all displaying damage to the lung tissue including areas of hemorrhaging visible on the 107 lungs and fluid accumulation in the lungs (Fig. 2C-D) . Additionally, one NHP had blood clots inside the 108 lungs and 50% of NHPs had areas of black necrotic patches on the lungs (Fig. 2C-D) , indicating severe 109 virus-induced pathology. RNA was extracted from lung tissue from each NHP and all samples were PCR-110 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 1, 2021. the alveoli, which were occasionally abnormally thickened ( Fig. 2E-F, S3) , as well as near blood vessels 118 ( Fig. 2G, S3 ). Proximal to blood vessels there was also evidence of infiltration of immune cells into the 119 tissue ( Fig. 2G ) and fibrin deposition (Fig. S3) . In multiple locations within the lung, including in the 120 trachea and the lower lung lobes, as well as near bronchi and near alveolar spaces, hypodense MCs 121 could be observed after staining of tissue sections with toluidine blue, suggesting their recent 122 degranulation (Fig. 2H) . Free granules could be observed extracellularly near MCs (Fig. 2H) , also 123 indicating degranulation. This widespread activation of MCs was confirmed by fluorescence staining to 124 detect heparin-containing granules in the lung tissue ( Fig. 2I-K) . We noted that activated MCs were 125 especially densely located and degranulating within the hemorrhagic regions of the infected lung tissue 126 In healthy humans, MC precursors make up a minor component of the blood, ~0.005% of cells (26) . MCs 134 are known to have a unique transcriptional profile that clusters separately from other immune cells and 135 gene expression patterns have been identified that are either MC-specific or that typify both MCs and 136 basophils (27) . Although MCs are not present in mature form in the blood, we considered that their 137 activation in peripheral tissues could influence the MC precursors or lead to transcriptional activation 138 profiles in immune cells that are consistent with responses to systemically elevated MC-associated 139 products. To investigate this, we examined whole blood transcriptomics data from a cohort of 4 mild and 6 140 severe COVID-19 patients, where clusters of genes that were temporally modulated during severe 141 disease progression and resolution were identified (28) . Consenting patients were prospectively recruited 142 and were defined as severe on the basis of requiring supplemental oxygen during hospitalization. In the 143 patients with severe disease, the gene expression levels were monitored from -4 days to 13 days, 144 relative to the day when their condition peaked in severity of respiratory distress, which was defined as 145 time=0 (28) . Interestingly, many genes associated with the MC lineage ( Fig. 3A-B) or MC and also 146 basophil lineages (Fig. 3C-D) were differentially modulated in the blood of human COVID-19 patients with 147 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 1, 2021. ; https://doi.org/10.1101/2021.05.31.21255594 doi: medRxiv preprint severe disease (p-value < 0.05; q-value < 0.05; likelihood ratio test). Upregulation of several genes 148 associated with the MC-or MC/basophil transcriptional signature (27) occurred during the acute phase of 149 severe disease (Fig. 3A,C) , while others were differentially regulated at the time of disease resolution 150 (Fig. 3B,D) . The increased MC gene expression changes that were observed during the acute phase of 151 disease tracked tightly with respiratory function and resolved commensurate with respiratory improvement 152 (Fig. 3E) . In contrast, these MC-associated transcripts were not collectively changed temporally 153 throughout the period of monitoring in mild COVID-19 presentation (Fig S4A-E) , although some genes 154 that were associated with these signatures were still modulated, but to a lesser extent than in severe 155 patients ( Fig. S4A-D) . Pathway analysis of the temporally modulated genes over the disease course of 156 severely ill patients revealed significant perturbation of pathways downstream of key MC-associated 157 immune receptors (Fig. 3F ) such as KIT (Fig. 3G) , the receptor for stem cell factor, which is an important 158 stem cell-associated gene that is retained on MC precursors and mature MCs and regulates MC survival 159 and proliferation (29) , and FcεRI (Fig. 3H) , which is upregulated with MC maturation, although also 160 expressed by other cell types such as basophils (26, 27) . These data show an enrichment of MC-161 associated transcripts in patients with severe COVID-19 and support a potential role of MCs in shaping 162 disease severity. 163 164

We next examined mild and severe COVID-19 patient blood for evidence that could indicate responses to 167 MC products and for biomarkers of MC activation. We noted that in addition to the significant modulation 168 of pathways associated with MC identity and maturation ( Fig. 3F-H) , pathway analysis of the whole blood 169 transcriptomics from severe patients also revealed significant modulation of pathways associated with 170 responses to well-established MC products (Fig. 4A) . For example, Gap and adherens junction signaling, 171 which are influenced by MC proteases to promote vascular permeability (14) , were activated, as was 172 signaling downstream of important, albeit not cell-specific, MC products, such as VEGF, TNF, Endothelin 173 1, and Eicosanoids (Fig. 4A) . We also noted a significant influence on the renin-angiotensin pathway, 174 which is intriguing since chymase mediates angiotensin-converting enzyme (ACE)-independent 175 angiotensin II production (Fig. 4A) . 176

To confirm the activation of MCs in humans, we also measured plasma chymase levels in two other 178 separate cohorts of COVID-19 patients. In the first cohort, the levels of plasma chymase were measured 179 in 13 patients that presented with mild disease and were treated as outpatients, ("community"), and 180 compared to the plasma chymase levels of 24 patients, in whom severe disease necessitated 181 hospitalization ("inpatients"), or to non-COVID-19 controls (Fig. 4B) . The WHO 10-point median clinical 182 disease severity (30) in inpatients was 6 (25 th and 75 th interquartile, 5 and 7.25), including 7 intubated 183 patients and 3 patients with lethal outcomes. As non-COVID-19 controls we obtained baseline plasma 184 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 1, 2021. ; https://doi.org/10.1101/2021.05.31.21255594 doi: medRxiv preprint samples (after the induction of anesthesia, before incision) from patients who underwent coronary bypass 185 surgery. This cohort was chosen since they have many of the risk factors of COVID-19 patients and are of 186 a similar age. In both mild and severe COVID-19 cases, the plasma sample was collected at the time of 187 diagnosis for the majority of patients. These results indicated that hospitalized COVID-19 inpatients have 188 significantly higher levels of plasma chymase compared to community cases (Fig. 4B) . This difference 189 was emphasized when the chymase levels in community cases were compared to hospitalized patients 190 that required intubation (Fig. 4B) . Published reports highlight the importance of microvascular 191 abnormalities in defining COVID-19 severity (31) and are supported by the demonstration of alveolar 192 edema and hemorrhagic lesions in our murine and NHP models. MC activation has direct impact on 193 vascular function and integrity and, therefore, we tested if MC activation was linked to vascular barrier 194 dysfunction. For this, we measured Angiopoietin (Ang)-1 and -2 levels as markers of endothelial 195 activation, which are strongly linked with disease severity in ARDS(32) and COVID-19 (32) and found no 196 change in Ang1 levels (Fig. 4C ), yet higher Ang2 levels (Fig. 4D) , resulting in higher Ang2/Ang1 ratios 197 (Fig 4E) in hospitalized and intubated vs. community COVID-19 cases. We also recruited a smaller 198 number of COVID-19 patients in Singapore. Indeed, this second cohort of COVID-19 patients also had 199 elevated chymase that was much higher than healthy controls and also averaged higher than the 200 concentrations detected in acute dengue patients (Fig. S5) . These data were not stratified by severity due The activation response involves a degranulation and release of MC-associated pre-formed mediators, 208 which was confirmed visually by imaging of tissue sections as well as quantitatively by detection of MC-209 specific chymase in the serum. MCs are present in the lung tissue, even prior to birth, and they are 210 important for regulating lung tissue inflammation during homeostasis and disease (33) . The heightened 211 levels of persistent activation of MCs that we detected through the acute phase of natural and 212 experimental SARS-CoV-2 infections are likely to be important for amplifying inflammation, which could 213 be detrimental to recovery from infection and return to tissue homeostasis following infection clearance. In 214 mouse and NHP lung tissue, MCs were observed to be strongly degranulating, and their increased 215 density and morphological appearance of activation was associated with areas of tissue damage 216 characterized by edema, hemorrhaging and necrosis. This is consistent with the role for MCs in mediating 217 inflammation and pathology in the lung that was suggested by mouse models of highly pathogenic 218 influenza (22, 34) . The persistent activated state observed in the lungs of NHPs, with sustained evidence 219 of MC activation at the relatively late time point post-infection when samples were no longer PCR-positive 220 for virus detection, suggests that ongoing inflammation in the tissue may occur even after infection has 221 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 1, 2021. IgE levels have been detected in severe COVID-19 patients (35) (36) (37) (38) . MCs respond to antibodies in unique 227 ways when triggered by antigen/antibody immune complexes. Classically, known for its activation by 228 crosslinking of IgE-FcεRI in the presence of an antigen, MCs can also be activated by IgG immune 229 complexes owing to their surface expression of activating FcγRs (39) (40) (41) . In addition to genes that are 230 consistent with a MC-specific transcriptional profile, we also found significant upregulation of pathways 231 typifying both MCs and basophils (27) in severe compared to mild COVID-19 patients, such as multiple Fc also suggestive of MC precursor migration into lung, as was seen in the context of other diseases (42) . 253

Similarly, other studies have identified transcriptional signatures of granulocyte activation as well as 254 increases in cells such as neutrophils, eosinophils and basophils and T cells in the blood or lung tissue 255 itself in severe COVID-19 (1, (6) (7) (8) . As tissue-resident cells, MCs are considered sentinels and they can 256 promote the trafficking of many of these cell types into tissues during both allergic and infection-induced 257 inflammation (9, 12, 43) . 258 All rights reserved. No reuse allowed without permission.

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Aside from the lung-associated pathologies of COVID-19, some individuals also experience other 260 hematological changes and cardiovascular events, including intra-vascular coagulation, endothelial 261 damage with ischemic complications, the development of rashes that could be accentuated by damaged 262 microvasculature, and increased incidence of myocardial infarction (1, 44) . These effects on the 263 vasculature and cardiovascular system are also consistent with the effects of MCs in other sterile 264 inflammatory conditions. MCs line the blood vessels within tissues (14) , which not only places them in a 265 location where they can directly exert their effects on the vasculature, but also where their mediators can 266 gain access to the blood. We observe that lung SARS-CoV-2 inoculation in mice and humans both results 267 in increased levels of MC-specific chymase, on a systemic level. In the renin-angiotensin system, MC-268 chymase is a potent converter of angiotensin I to angiotensin II, which regulates microvascular blood flow 269

and systemic blood pressure (45) (46) (47) . However, production of chymase by MCs is also associated with 270 vascular diseases. For example, in atherosclerotic aorta, angiotensin II activity was largely ACE-271 independent and dependent on chymase (48) and increased expression of chymase in the lung was 272 associated with early pulmonary vascular disease (49) . Notably, higher levels of angiotensin II in the 273 plasma of COVID-19 patients are correlated with lung injury suggesting its involvement in the tissue 274 damage (50) . Moreover, angiotensin II could increase the expression of endothelial-specific receptor 275 tyrosine kinase (TIE2) ligand, Ang2 (51) . An imbalance of Ang2/1 is known to be associated with vascular 276 leakage and coagulation in other diseases (52) . We observed increased plasma levels of Ang2 and 277 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. intranasally with hACE2-AAV to induce hACE2 expression in the airways. SARS-CoV-2 (2x10 7 TCID 50 ) TCID-50) was inoculated intranasally into hACE2-AAV C57BL/6 mice. Blood was taken on days 1, 3, 5, and 7, and organs were harvested after 5 or 7 days for histology and virus quantification. (B) Virus quantification from the organs harvested shows detection in the lung, spleen, liver, kidney, brain, and bone marrow both Days 5 and 7. (C) Histology images of toluidine blue-stained trachea sections from uninfected and SARS-CoV-2 infected mice. Degranulating MCs (red arrow) could be observed in SARS-CoV-2 infected mice as well as tissue edema and airway narrowing. (D) Western blot images after chymase detection in serum Days 3, 5 and 7 post-infection shows systemic elevation of chymase, which was quantitated by densitometry from 3 individual mouse samples and presented as fold-increase over uninfected controls. Error bars represent the SEM. Chymase was significantly elevated in serum of infected mice compared to uninfected controls, determined by 1-way ANOVA with Dunnett's post-test; *p<0.05, **p<0.01. Nonsignificant p-values below p=0.01 are shown on the graph. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 1, 2021. ; https://doi.org/10.1101/2021.05.31.21255594 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 1, 2021. ; https://doi.org/10.1101/2021.05.31.21255594 doi: medRxiv preprint Figure 4 : MC products and activation pathways associated with severe COVID-19. (A) Pathway analysis indicates a significant perturbation of pathways associated with host-responses to characteristic MC products. (B) Plasma chymase levels are increased in hospitalized patients "inpatient" compared to mild "community" patients and in intubated patients compared to mild patients. (C) No significant changes in ANG1 levels in inpatient and intubated patients compared to community cases and non-COVID-19 controls. (D) Significantly increased plasma ANG2 levels and (E) ANG2/ANG1 ratios in inpatients compared to community patients. One-way ANOVA was performed and considered significant for post-test p-values <0.05. For panels, B-E, non-COVID-19 patients n=12-15; For community, n=13; for inpatients n=24; n=7. All rights reserved. No reuse allowed without permission.

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