The Role of Obesity in Severe COVID-19 Pathophysiology

Официальное название

SARS-CoV-2 Antibody-mediated Inflammatory Responses by Macrophages in Individuals With and Without Obesity

Обзор

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide. As of 2024, the SARS-CoV-2 Omicron variant is the predominant strain circulating within the population, generally causing mild upper respiratory tract infections. However, hospitalizations and case fatalities due to COVID-19 continue, and there is a high probability that a new human coronavirus will emerge in the future. Understanding the pathophysiology of severe COVID-19 remains highly relevant, as its mechanisms may be comparable to those of other respiratory viral infections. SARS-CoV-2 infects human cells primarily by binding to angiotensin-converting enzyme 2 (ACE2) and type 2 transmembrane serine protease (TMPRSS2) receptors, which are both expressed in alveolar epithelial type II cells, through the virus' spike protein. In a later stage, the replication of SARS-CoV-2 and activation of resident immune cells lead to the infiltration and activation of large numbers of innate immune cells. Consequently, this results in an excessive pro-inflammatory immune response, including increased production of IL-6, a hallmark cytokine of severe COVID-19. Eventually, the excessive inflammation results in microthrombus formation and pulmonary edema. Further studies have indicated that SARS-CoV-2 spike-specific antibodies, along with alveolar macrophages, play a pivotal role in the pathophysiology of severe COVID-19. Alveolar macrophages, which reside in the lung alveoli, are typically the first immune cells to sense pulmonary pathogens. However, these cells can also bind IgG antibodies through their Fc-receptor, leading to cellular activation. When stimulated with both a viral stimulus and anti-SARS-CoV-2 IgG antibodies from severe COVID-19 patients (a situation similar to that in the lungs of these patients) alveolar macrophages elicit a significant proinflammatory response. This response aligns with the observed post-seral conversion deterioration in COVID-19 patients. Obesity is a significant risk factor for developing severe COVID-19, but the underlying mechanism is not well understood. Previous studies report that macrophages in obese patients are skewed towards a pro-inflammatory phenotype due to altered fatty acid contents, particularly increased saturated fatty acids. Using our in vitro obesity model, which incorporates higher saturated fatty acid contents, the investigators already demonstrated that SARS-CoV-2 antibody-mediated inflammation of alveolar macrophages is increased (unpublished data). Thus, this may explain why obese patients are more likely to develop severe COVID-19. To validate these in vitro findings, the investigators aim to confirm these results in monocyte-derived macrophages isolated from individuals with and without obesity. Additionally, the investigators will investigate the underlying mechanisms involved in detail. This study will provide valuable insights into the role of obesity in severe COVID-19 and potentially inform therapeutic strategies for at-risk populations.

Подробное описание

This is a mono-center, prospective cohort study involving both a test group and a control group. The test group comprises patients with obesity eligible for bariatric surgery at Franciscus Hospital, while the control group consists of age- (maximum 5-year difference) and sex-matched non-obese healthcare workers at Franciscus Hospital. Blood samples will be collected from all participants at a single time point.

Obese patients will be approached for informed consent during their intake appointments, typically weeks to months before their bariatric surgery. Blood samples will be collected before surgery or during surgery to minimize any potential adverse effects. Collaborating researchers from the surgery department will manage the inclusion of obese patients and coordinate their blood collection.

For the non-obese control group, investigators from MMI will manage participant inclusion and blood sample collection.

Participants from Franciscus Hospital with obesity (Cohort 1) and healthcare workers without obesity (Cohort 2) will undergo a single venipuncture after an 8-hour fasting period. A total of 40 mL of blood will be collected in four 10 mL EDTA tubes.

At the Medical Microbiology and Infection Control (MMI) laboratory of Franciscus, blood samples will be collected after which these are sent to the Center for Infection and Molecular Medicine (CIMM) laboratory in Amsterdam UMC. Here, blood will be processed (i.e., isolation of plasma, monocytes, and remaining peripheral blood mononuclear cells (PBMCs)), where after monocytes will be put into culture to become monocyte-derived macrophages. Macrophage stimulations and additional macrophage analyses will be performed at Amsterdam UMC. Data obtained from analyses in Amsterdam UMC will be further analyzed in Amsterdam UMC by coordinating investigator Ashwin Mak (who is also affiliated at CIMM in Amsterdam UMC) and co-investigator Dr. Jeroen den Dunnen. Monocytes and plasma will be stored in Amsterdam UMC until the end of this study, where after the remaining materials will be transported to Franciscus.

Isolated PBMCs and plasma will be transported in the following days after isolation to Franciscus MMI for T cell stimulations and antibody analyses. In the analyses overview below, the location where each analysis will be performed is noted (i.e., MMI and CIMM). Coded samples and data will be stored at Amsterdam UMC until the end of this study, where after these samples are destroyed and data are deleted. MTA and DTA documents will be prepared for the transfer of blood and data to Amsterdam UMC.

Вмешательства

• Процедура Venipuncture
  Simple blood collection

Первичные конечные точки

• The concentration of pro-inflammatory cytokines (IL-6, IL-1β, and TNF) produced by macrophages upon both SARS-CoV-2 viral and antibody costimulation. [Срок оценки: Baseline]

Вторичные конечные точки (10)

• The concentration of pro-inflammatory cytokines (IL-6, IL-1β, and TNF) produced by macrophages upon separate viral stimulation or SARS-CoV-2 antibody stimulation [Срок оценки: Baseline]
• The plasma concentration of pro-inflammatory cytokines [Срок оценки: Baseline]
• Measurement of other cytokines that are produced by macrophages upon viral stimulation, antibody stimulation, or both [Срок оценки: Baseline]
• Expression levels of Fc receptors on the surface of macrophages [Срок оценки: Baseline]
• The level of intracellular lipids in monocytes [Срок оценки: Baseline]
• Gene expression levels of proteins related to immune signalling or metabolic pathways [Срок оценки: Baseline]
• Chromatin accessibility, measured as the number of 'reads per genomic region' of genes related to Fc-receptor activation in macrophages [Срок оценки: Baseline]
• The level of lactate production by macrophages upon stimulation with anti-SARS-CoV-2 IgG. [Срок оценки: Baseline]
• The concentration of proteins in plasma [Срок оценки: Baseline]
• The level of SARS-CoV-2 specific T cell responses and plasma antibodies [Срок оценки: Baseline]

Критерии участия

Критерии включения

Cohort 1 (obesity cohort)

• ≥18 and ≤65 years of age
• BMI ≥30 kg/m²
• Patient of Franciscus Hospital

Cohort 2 (control cohort)

• ≥18 and ≤65 years of age
• BMI <25 kg/m²
• Healthcare workers of Franciscus Hospital

Exclusion Criteria (for both cohorts):

• Acute infection or current systemic immunological disorders
• Use of immune-modulatory medication (i.e., corticosteroids and biologicals)
• Hormonal therapy

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Нидерланды · 1 центр

• Franciscus — Rotterdam

Публикации

• Hoepel W, Chen HJ, Geyer CE, Allahverdiyeva S, Manz XD, de Taeye SW, Aman J, Mes L, Steenhuis M, Griffith GR, Bonta PI, Brouwer PJM, Caniels TG, van der Straten K, Golebski K, Jonkers RE, Larsen MD, Linty F, Nouta J, van Roomen CPAA, van Baarle FEHP, van Drunen CM, Wolbink G, Vlaar APJ, de Bree GJ, Sanders RW, Willemsen L, Neele AE, van de Beek D, Rispens T, Wuhrer M, Bogaard HJ, van Gils MJ, Vida PMID 33979301

Идентификаторы

NCT: NCT06968442 · NL88800.100.25

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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