Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1

McElroy, Anita K.; Shrivastava-Ranjan, Punya; Harmon, Jessica R.; Martines, Roosecelis B; Silva‐Flannery, Luciana; Flietstra, Timothy D.; Kraft, Colleen S.; Mehta, Aneesh K.; Lyon, G. Marshall; Varkey, Jay B.; Ribner, Bruce S.; Nichol, Stuart T.; Zaki, Sherif R.; Spiropoulou, Christina F.

doi:10.3201/eid2502.181326

Cited by 37 publications

(36 citation statements)

References 47 publications

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“…Indeed, by 6 DPI, viral titers in the blood were 2 log 10 higher than in liver, adrenal gland, and lymphoid tissues (20). Similar to what we reported recently in the blood (8), the source of inflammation is likely myeloid cells, notably monocytes/ macrophages, as recently shown in human cases (50). Macrophages may amplify the pathogenic cascade by secreting proinflammatory cytokines (IL-1, IL-6, tumor necrosis facto [TNF]), chemokines, growth factors, and reactive oxygen species, thereby increasing vascular permeability and contributing to endothelial dysfunction.…”

Section: Discussionsupporting

confidence: 88%

Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

Jankeel

Menicucci

Woolsey

et al. 2020

J Virol

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Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013–2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease. IMPORTANCE Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.

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Section: Discussionsupporting

confidence: 88%

Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

Jankeel

Menicucci

Woolsey

et al. 2020

J Virol

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“…Another remarkable finding in the case presented here was the extremely high level of ferritin (> 100,000 ng/mL [normal range 30-400 ng/mL]) at ICU admission. Although hyperferritinemia has been reported in other viral hemorrhagic fevers, such as dengue and Ebola, 9,10 this is, to our knowledge, the first time it has been reported in yellow fever. The pathogenesis of the hyperferritinemia in our patient was probably multifactorial.…”

Section: Discussionmentioning

confidence: 55%

Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange

Sztajnbok

Málaque

Nihei

et al. 2019

The American Journal of Tropical Medicine and Hygiene

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A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels.

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“…Our data showing a great accumulation of CD163 positive myeloid cells in the lung consolidations and hilar lymph nodes in parallel with CD8 T, NK and B cell depletions in these tissues are in line with previous suggestions of M2 polarized macrophage induced effector T cell depletion (Liu et al, 2020)(Schulte-Schrepping et al, 2020). The elevated level of CD163 with the subsequent shedding is an emerging marker of virus infection associated macrophage activation syndrome with dismal outcome (McElroy et al, 2019) (Loomba et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death

Szekeres

Bozóky

Béndek

et al. 2020

Preprint

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SummaryMost Covid-19 victims are old and die from unrelated causes. Here we present twelve complete autopsies, including two rapid autopsies of young patients where the cause of death was Covid-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163+ macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothel, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced Covid-19 ARDS.

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Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1

Cited by 37 publications

References 47 publications

Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange

Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death

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