Obesity and SARS-CoV-2 Infection a Multifaceted Interplay - Adipose Tissue Inflammation, Adipokine Disbalance and Immunity

Review Article

Austin Public Health. 2021; 5(1): 1013.

Obesity and SARS-CoV-2 Infection a Multifaceted Interplay - Adipose Tissue Inflammation, Adipokine Disbalance and Immunity

Cherneva RV¹*, Valev D² and Cherneva ZV³

1University Hospital for Respiratory Diseases “St. Sophia’’, Sofia, Bulgaria

2University First Multiple Clinic for Active Treatment, Sofia, Bulgaria

3The Ministry of Internal Affairs, Clinic of Cardiology, Sofia, Bulgaria

*Corresponding author: Radostina Vlaeva Cherneva, Medical University Sofia, University Hospital for Respiratory Diseases “St. Sophia”, Sofia, str. “Han Presian 19”, Bulgaria

Received: April 16, 2021; Accepted: May 04, 2021; Published: May 11, 2021


Overweight and obesity are the most common comorbidities in SARSCoV- 2 patients, requiring hospitalization in intensive care units. The multifaceted nature of obesity including its effects on respiratory mechanics and immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Most coronaviruses overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. Hyperleptinemia, insulin resistance and adipose tissue inflammation are hallmarks of obesity, which is associated with a leptin and insulin resistant state. Leptin regulates appetite and metabolism and through the Jak/STAT and Akt pathways modulates T cell number and function; insulin receptor signaling is closely engaged in T cell proliferation, whereas low garde adipose tissue inflammation provokes aberrant inflammasome activation. The review discusses these phenomena. It presents the reasons for susceptibility to respiratory viral infections in obese patients, as well as, the immunomodulatory effects of obesity to the outcome.

Keywords: Obesity; Adipose tissue inflammation; Adipokine disbalance; SARS-CoV-2; Immunity


In the last fifty years, obesity has tripled. In 2016, more than 1.9 billion adults were with abnormal body mass index [1]. More than 300,000 deaths annually in USA are due to obesity, it reduces the average lifespan with 9-13 years [2,3]. SARS-CoV-2 is a novel Coronavirus (CoV) that has spread through Europe and USA causing pressure to the healthcare system. Advanced age and comorbidities are risk factors for severe forms of the disease [4]. Obesity predisposes patients with SARS-CoV2 infection to higher risk of complications and mortality [5]. In France, 47.6% of patients admitted to the Intensive Care Unit (ICU) had a Body Mass Index (BMI) >30kg/m² and 28.2% had a BMI >35kg/m² [6]. In Spain 48% of the admissions due to SARS-CoV-2 in ICUs were with obese patients [7]. In the ICU in USA there was a significant inverse relationship between BMI and age - advanced age increases the risk of severity of the diseases, but in younger patients, those with severe forms of the infection were more likely to have obesity [8].

Coronavirus Infection

In humans, the viral Spike protein (S) of SARS-CoV-2 binds to the receptor prior to activation and initial entry into the primary target cells. Angiotensin-Converting Enzyme 2 (ACE2) is the receptor for SARS-CoV-2. After viral entry, Pathogen-Associated Molecular Patterns (PAMP) are secreted. These are biomolecules derived from the surface of the viruses or generated during their life cycle [9]. They are recognized by the Toll like receptors. Upon PAMP recognition inflammatory cytokines and antiviral Interferons (IFNs) are secreted - type I IFNs (IFN-α and IFN-β), type II IFNs (IFN-γ), and type III IFNs (IFN-λ) [10]. Type 1 interferon is a key component of the host antiviral defense against SARS-CoV-2 [11]. Gene analyses of cell culture studies of SARS-CoV-2 infection in human airway epithelial cells illustrate a diminished IFN-I and IFN-III expression. This was validated in post mortem lung samples, as well as, serum from SARSCoV- 2 positive patients. SARS-CoV-2 provokes gene signature and transcriptional response characterized by cell death and leukocyte activation. Thus, despite the reduced IFN-1 and IFN-III response to SARS-CoV-2 there is a robust chemotactic and inflammatory response [12].

Suppression of Host Antiviral Response

Viruses encode products that mimic cellular components of the IFN signal transduction pathway. They suppress host interferon production and impair the development of an antiviral state [13]. In addition, Corona Viruses (CoV) can synthesize molecules that either suppress, or induce cell death. The molecules that suppress apoptosis extend the production of new virions in the infected cells. Those that function as inducers of apoptosis facilitate the release and dissemination of progeny virions [13]. Pyroptosis is cell death that results from an exuberant proinflammatory cytokine release [14]. The severe forms of SARS-CoV infection are associated with high levels of proinflammatory cytokines [11]. PAMPS generated during viral replication stimulate the NLRP3 antiviral immune response. NLRP3 inflammasome (NACHT, LRR, and PYD domains-containing protein 3) is an oligomeric complex that is critical in host antiviral response. Viruses either evade NLRP3 activation and facilitate viral replication, or trigger NLRP3 activation for pathological inflammatory response. Aberrant NLRP3 activation or chronic systemic inflammation lead to severe pathological injury. The pathogenicity of the virus is related to its capacity to suppress host immunity [14]. CoVs have evolved features that suppress the human IFN pathway [15-18]. Sets of tissues that harbor SARS-CoV-2 show that in human airway epithelial cells, IFN-I, and IFN II, upregulate ACE2 expression [19]. Angiotensin- Converting Enzyme (ACE) cleaves angiotensin I to angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. Angiotensin II drives acute lung injury through various mechanisms - plasma leakage, increased vascular permeability [20]. ACE2 is critical for early tissue tolerance to respiratory infection [19]. In influenza angiotensin, II levels rise and ACE2 provides protection to tissues reducing it [21]. SARS-CoV-S binds to ACE2 and reduces ACE2 expression causing acid-aspiration - induced lung failure [22]. Low levels of IFN-I are produced in response to SARS-CoV-2 infection, which blunts the protective effect of ACE2.

Adipose Tissue Inflammation

Adipose tissue inflammation is a hallmark of obesity [23]. Macrophages and dendritic cells, infiltrating adipose tissue provoke the production of the proinflammatory cytokines closely related to the metabolic consequences of obesity [24]. CD8+ T-cell infiltration precedes macrophage accumulation and is essential for their differentiation, activation, and migration. Adipose tissue itself activates the CD8+ T-cells without the need for a systemic increase in T-cells. The activated CD8+ T-cells create a local proinflammatory milleu. In obesity, CD4+ T-cells and Treg also contribute to adipose tissue inflammation. CD4+ T-cells, balance the immune response, but are reduced in obesity. Treg cells mitigate the effects on the adaptive immune responses, [25]. In humans with obesity, adipose tissue depots contain ~40% macrophages [24]. They are primary mediators of the innate immune response and have an important role in the adaptive immune response. What is reasonably expected is that individuals with obesity would have increased mortality when afflicted with ARDS. In contrast, inflammatory cytokine milieu in obesity is not associated with mortality in mechanically ventilated patients with acute lung injury - obesity paradox in ARDS [26,27].

Obesity and Mortality in SARS-CoV-2

The high mortality rate among SARS-CoV-2 patients with obesity has however prompted against obesity paradox in ARDS [28]. During an infection, T-cell activation is accompanied by high-energy requirements to support biosynthesis of intracellular components. From an evolutionary perspective, downregulation of non-essential, energy-consuming pathways such as immune cell activation is pragmatic [29]. As leptin is the link between metabolism and the immune response, it seems reasonable that its dysregulation would have serious consequences during an infection. In SARS-CoV-2 infections, Lymphopenia occurs in almost 80% of patients. Patients with infection demonstrate low levels of circulating CD4+ and CD8+ T lymphocytes. In contrast, in lungs there is accumulation of mononuclear cells and macrophages [30,31]. Peripheral Lymphopenia and macrophage predominance in SARSCoV infection reflect the suppression of host antiviral response [32]. Immune evasion may increase viral replication and hinder its clearance. This causes tissue damage and further stimulation of macrophages. The enhanced secretion of cytokines results in cytokine-storm syndrome and precipitates multi-organ failure [33]. It is assumed that hyperleptinemia and insulin resistance in obesity disrupts additionally disrupts T-cell function and suppresses T-cell response to infection [34,35].

Leptin and Immune Cell Function

In a mouse model of diet-induced obesity, Hyperleptinemia was associated with increased mortality, viral spread, and lung levels of proinflammatory cytokines including Interleukin 6 (IL-6) and IL- 1β, following infection with influenza (H1N1) in a mouse model of diet-induced obesity. Administration of anti-leptin antibody led to a decrease in the proinflammatory response and improved lung pathology and survival rate [36]. In patients with diabetes and ARDS, elevated leptin levels in bronchoalveolar fluid are associated with increased mortality [37]. Obesity is marked by persistent hyperleptinemia and is a state of leptin resistance. Excess leptin secretion from adipocytes may have paracrine effects on T-cells and promote the development of systemic inflammation [38]. Leptin is a mediator of pulmonary immunity and its chronically elevated levels impair host defenses [39,40]. Leptin is produced by adipocytes, bronchial epithelial cells, type II pneumocytes, and lung macrophages [41]. In addition to satiety, leptin regulates immune cell number and function [42-45]. It is secreted by adipocytes in proportion to fat mass and is essential to upregulate glucose metabolism in activated T-cells [46]. Leptin deficiency reduces T-cell numbers, decreases CD4+ helper T-cells, increases proliferation of regulatory T-cells (Treg, suppressor of effector T-cells activation and excessive inflammatory responses) and provokes aberrant cytokine production [42-45]. Leptin induces Th cells toward the Th1 subset, which has a more proinflammatory response than the Th2 subset that has predominantly regulatory functions [47]. The metabolic derangements that occur when the immune system is activated is regulated by leptin. It inhibits the apoptosis of immune cells and its deficits contribute to the defective immune response. Leptin administration inhibits baseline thymic apoptosis in young rats by 15-30%. [48]. Leptin has an important role in the metabolic regulation of Treg cells. These cells expressed high amounts of both Leptin and its Receptor (LepR). High leptin levels can promote hyporesponsiveness of Treg cells, whereas leptin neutralization rescued Treg cells from their hyporesponsiveness [49]. High circulating leptin have a detrimental effect on intracellular signaling and the response to an infection.

Insulin Resistance, Obesity and Immune Activation

After activation, T-cells use glycolysis to produce the biosynthetic precursors required for rapid cell growth and proliferation. If glucose metabolism is insufficient, T-cells become hyporesponsive or nonresponsive [38]. The activation of the PI3K/Akt/mTOR pathway in T-cells facilitates their differentiation and primarily occurs through triggering of the T-cell receptor and CD28 co-receptor. The insulin receptor has also been shown to have a role in PI3K/Akt/mTOR pathway. Signaling downstream of the insulin receptor is reduced in CD4+ T-cells from insulin receptor knock-down transgenic rats [50,51]. Insulin resistance commonly co-exists with obesity. In these subjects, impaired insulin receptor signaling may contribute to insufficient energy supply for effector T-cells to mount an effective response to infection.

Obesity, Pulmonary Mechanics and ARDS

Another feature of ARDS associated with SARS-CoV-2 is that it presents in an atypical form of preserved lung mechanics and severe hypoxemia. The accumulation of fat in the mediastinum and in the abdominal and thoracic cavities decreases functional residual capacity in patients with obesity. This alters the mechanical properties of the chest wall. The diaphragm is elevated and its downward pressure is limited, which elevates pleural pressure. In supine patients with abdominal obesity, diaphragmatic excursion is perturbed, making ventilation difficult. That is why prone positioning is recommended to improve oxygenation in patients with refractory hypoxemia due to SARS-CoV-2 ARDS [26-28].


Obesity predispose patients to morbidity and mortality from the SARS-CoV-2 infection through a compromised immune response. The diminished immune response fails to limit the viral replication and provokes a series of events culminating in heightened cytokine release that can cause ARDS and multiorgan failure. The high mortality rates from SARS-CoV-2 infection in individuals with obesity suggests that the metabolic consequences of obesity compromise host antiviral defenses. Hyperleptinemia is a common feature of obesity and links the regulation of metabolism and immunity. Leptin and insulin resistance (commonly encountered in obesity) are closely associated with T cell activation. His high pathogenicity of the virus in obesity is the result of: 1) Suppressed host interferon production; 2) Proinflammatory state of adipose tissue that contributes to low grade protracted activation of T-cells and their premature senescence; 3) Monocyte-macrophage overstimulation and cytokine oversecretion. Finally yet importantly, obesity hinders respiratory mechanics proturbating respiratory systems.


  1. WHO. Obesity and Overweight. 2018.
  2. Prospective Studies. Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009; 373: 1083-1096.
  3. Masters RK, Powers DA, Link BG. Obesity and US mortality risk over the adult life course. Am J Epidemiol. 2013; 177: 431-442.
  4. CDC. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions among Patients with Coronavirus Disease 2019. United States, February 12-March 28, 2020. 2020.
  5. Sattar N, McInnes IB, McMurray JJV. Obesity a risk factor for severe COVID-19 infection: multiple potential mechanisms. Circulation. 2020; 142: 4-6.
  6. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity. 2020; 28: 1195-1199.
  7. Barrasa H, Rello J, Tejada S, Martín A, Balziskueta G, Vinuesa C, et al. SARS-Cov-2 in Spanish intensive care: early experience with 15-day survival in Vitoria. Anaesth Crit Care Pain Med. 2020.
  8. Kass DA, Duggal P, Cingolani O. Obesity could shift severe COVID-19 disease to younger ages. Lancet. 2020; 395: 1544-1545.
  9. Wong LY, Lui PY, Jin DY. A molecular arms race between host innate antiviral response and emerging human coronaviruses. Virol Sin. 2016; 31: 12-23.
  10. Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type I and type III interferons. Immunity. 2019; 50: 907-923.
  11. He L, Ding Y, Zhang Q, Che X, He Y, Shen H, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoVinfected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. 2006; 210: 288-297.
  12. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced Host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020; 181: 1036-1045.e9.
  13. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001; 14: 778- 809.
  14. Jewell NA, Cline T, Mertz SE, Smirnov SV, Flaño E, Schindler Ch, et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol. 2010; 84: 11515-11522.
  15. Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol. 2019; 73: 529-557.
  16. Mar KB, Rinkenberger NR, Boys IN, Eitson JL, McDougal MB, Richardson RB, et al. LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step. Nat Commun. 2018; 9: 3603.
  17. Zhao X, Guo F, Liu F, Cuconati A, Chang J, Block T, et al. Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. Proc Natl Acad Sci USA. 2014; 111: 6756-6761.
  18. Broggi A, Granucci F, Zanoni I. Type III interferons: balancing tissue tolerance and resistance to pathogen invasion. J Exp Med. 2020; 217: e20190295.
  19. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020; 181: 1016-1035.e19.
  20. Imai Y, Kuba K, Rao S, Guo F, Guan B, Yang P, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436: 112- 116.
  21. Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X, et al. Angiotensin converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014; 5: 3594.
  22. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11: 875-879.
  23. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444: 860-867.
  24. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel R, Ferrante A, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112: 1796-1808.
  25. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009; 15: 914-920.
  26. O’Brien JM Jr., Welsh CH, Fish RH, Ancukiewicz M, Kramer AM, National Heart, Lung, et al. Excess body weight is not independently associated with outcome in mechanically ventilated patients with acute lung injury. Ann Intern Med. 2004; 140: 338-345.
  27. Anzueto A, Frutos-Vivar F, Esteban A, Bensalami N, Marks D, Raymondos K, et al. Influence of body mass index on outcome of the mechanically ventilated patients. Thorax. 2011; 66: 66-73.
  28. Jose RJ, Manuel A. Does COVID-19 disprove the obesity paradox in ARDS? Obesity. 2020; 6: 1007.
  29. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013; 31: 259-283.
  30. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130: 2620-2629.
  31. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis. 2020; 221: 1762-1769.
  32. Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol. 2010; 84: 1289-1301.
  33. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID19: implications for the cardiovascular system. Circulation. 2020.
  34. Ubags ND, Stapleton RD, Vernooy JH, Burg E, Bement J, Hayes C, et al. Hyperleptinemia is associated with impaired pulmonary host defense. JCI Insight. 2016; 1: e82101.
  35. Green WD, Beck MA. Obesity impairs the adaptive immune response to influenza virus. Ann Am Thorac Soc. 2017; 14: S406-S409.
  36. Zhang AJ, To KK, Li C, Lau C, Poon V, Chan Ch, et al. Leptin mediates the pathogenesis of severe 2009 pandemic influenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity. J Infect Dis. 2013; 207: 1270-1280.
  37. Jain M, Budinger GR, Lo A, Urich D, Rivera S, Ghosh A, et al. Leptin promotes fibroproliferativ acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-gamma. Am J Respir Crit Care Med. 2011; 183: 1490-1498.
  38. Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol. 2001; 212: 83-91.
  39. Mancuso P. Obesity and lung inflammation. J Appl Physiol. 2010; 108: 722- 728.
  40. Kordonowy LL, Burg E, Lenox CC, Gauthier LM, Petty JM, Antkowiak M, et al. Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. Am J Respir Cell Mol Biol. 2012; 47: 120-127.
  41. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11: 875-879.
  42. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017; 39: 529-539.
  43. Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol. 2001; 212: 83-91.
  44. Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell Immunol. 2001; 211: 30-36.
  45. Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol. 2005; 174: 3137-3142.
  46. Saucillo DC, Gerriets VA, Sheng J, Rathmell J, Maciver N. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol. 2014; 192: 136-144.
  47. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998; 394: 897-901.
  48. Mansour E, Pereira FG, Araujo EP, Amaral M, Morari J, Ferraroni N, et al. Leptin inhibits apoptosis in thymus through a janus kinase-2-independent, insulin receptor substrate-1/phosphatidylinositol-3 kinase-dependent pathway. Endocrinology. 2006; 147: 5470-5479.
  49. De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007; 26: 241-255.
  50. Frauwirth KA, Thompson CB. Regulation of T lymphocyte metabolism. J Immunol. 2004; 172: 4661-4665.
  51. Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, et al. The insulin receptor plays a critical role in T cell function and adaptive immunity. J Immunol. 2017; 198: 1910-1920.

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Citation: Cherneva RV, Valev D and Cherneva ZV. Obesity and SARS-CoV-2 Infection a Multifaceted Interplay - Adipose Tissue Inflammation, Adipokine Disbalance and Immunity. Austin Public Health. 2021; 5(1): 1013.

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