The influence of bitter-taste receptor (TAS2R) expression in pharmacological response to Chloroquine in obese patients with COVID-19

Lígia Moriguchi Watanabe Izabella Ferreira Pires Natália Yumi Noronha Marcela Augusta de Souza Pinhel Carla Barbosa Nonino About the authors

The coronavirus disease 2019, referred to as COVID-19 by the World Health Organization (WHO), is an ongoing viral pandemic caused by the influenza-like virus strain SARS-CoV-2 (11. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9(1):221-36. https://doi.org/10.1080/22221751.2020.1719902
https://doi.org/10.1080/22221751.2020.17...
). According to WHO (2020), SARS-CoV-2 infection has been responsible for approximately 10,185,374 confirmed cases of COVID-19 and more than 500,000 deaths worldwide (22. World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. Available from: https://covid19.who.int/ [Accessed in June, 2020]
https://covid19.who.int/...
). In Brazil, 1,368,195 cases have been confirmed, and 58,314 deaths have occurred as of June 30, 2020 (33. Ministério da Saúde Brazil. Painel Coronavírus. Painel Coronavírus 2020. Available from: https://covid.saude.gov.br/
https://covid.saude.gov.br/...
).

The coronaviruses are one of the primary pathogens that target the human respiratory system. These viruses often cause pneumonia-like symptoms that can develop into Severe Acute Respiratory Syndrome (SARS), causing higher leukocyte production, abnormal respiratory findings, and increased levels of plasma pro-inflammatory cytokines (44. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433. https://doi.org/10.1016/j.jaut.2020.102433
https://doi.org/10.1016/j.jaut.2020.1024...
). COVID-19 may manifest either as an asymptomatic infection or as a mild to severe pneumonia (55. Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. COVID-19 (Novel Coronavirus 2019) - recent trends. Eur Rev Med Pharmacol Sci. 2020;24(4):2006-11.). The most common initial symptoms at the onset of COVID-19 are fever, cough, and fatigue, while sputum production, headache, hemoptysis, diarrhea, dyspnea, and lymphopenia are less frequent (66. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
https://doi.org/10.1016/S0140-6736(20)30...
).

The severity of the COVID-19 infection varies among individuals and may relate to several reported risk factors, such as aging, diabetes mellitus, cardiovascular risk (including hypertension), and respiratory or kidney disease. Moreover, an increasing number of studies have linked obesity to more severe COVID-19 symptoms and, ultimately, increased mortality (77. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell L, Chernyak Y, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966. https://doi.org/10.1016/10.1136/bmj.m1966
https://doi.org/10.1016/10.1136/bmj.m196...

8. Abu-Raya B. Predictors of Refractory Coronavirus Disease (COVID-19) Pneumonia. Clin Infect Dis. 2020;71(15):895-6. https://doi.org/10.1093/cid/ciaa409
https://doi.org/10.1093/cid/ciaa409...
-99. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. 2020. https://doi.org/10.1001/jama.2020.4683
https://doi.org/10.1001/jama.2020.4683...
).

Recently, a retrospective analysis of 3,615 patients with COVID-19 at the New York academic hospital system reported that approximately 38% of these patients were obese (Body Mass Index, BMI >30 kg/m2). Moreover, obese patients under 60 years of age had twofold susceptibility to being admitted in critical care compared to non-obese individuals (88. Abu-Raya B. Predictors of Refractory Coronavirus Disease (COVID-19) Pneumonia. Clin Infect Dis. 2020;71(15):895-6. https://doi.org/10.1093/cid/ciaa409
https://doi.org/10.1093/cid/ciaa409...
).

Obesity-related conditions worsen the impact of COVID-19 symptoms due to complications associated with excessive body weight, metabolic dysfunction, cardiovascular risk, sleep apnea, vitamin D deficiency, dysregulation of the renin-angiotensin-aldosterone system, and sarcopenia (1010. Zores F, Rebeaud ME. COVID and the Renin-Angiotensin System: Are Hypertension or Its Treatments Deleterious? Front Cardiovasc Med. 2020;7:71. https://doi.org/10.3389/fcvm.2020.00071
https://doi.org/10.3389/fcvm.2020.00071...
). Furthermore, obese patients have altered levels of circulating cytokines. Notably, these individuals exhibit higher concentrations of TNF-alpha, MCP-1, and IL-6, which are generated by visceral and subcutaneous adipose tissue (1111. Lorenzo A De, Tarsitano M, Falcone C, Renzo L, Romano L, Macheda S, et al. Fat mass prevalence and influence on nutritional status in ICU COVID-19 patients. 2020. Preprint. https://doi.org/10.21203/rs.3.rs-33974/v1
https://doi.org/10.21203/rs.3.rs-33974/v...
). This alteration in inflammatory profile appears to predict the severity and prognosis of obese patients and COVID-19 (1111. Lorenzo A De, Tarsitano M, Falcone C, Renzo L, Romano L, Macheda S, et al. Fat mass prevalence and influence on nutritional status in ICU COVID-19 patients. 2020. Preprint. https://doi.org/10.21203/rs.3.rs-33974/v1
https://doi.org/10.21203/rs.3.rs-33974/v...
,1212. Li X, Zhang C, Liu L, Gu M. Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases. FASEB J. 2020;34(5):6008-16. https://doi.org/10.1096/fj.202000502
https://doi.org/10.1096/fj.202000502...
). Thus, special attention should be considered for this population.

In the absence of efficient pharmacotherapy, and due to the public health emergency, a significant number of potential drugs was proposed, such as antiviral agents, chloroquine and hydroxychloroquine, and corticosteroids (1313. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938. https://doi.org/10.1016/j.ijantimicag.2020.105938
https://doi.org/10.1016/j.ijantimicag.20...
,1414. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. https://doi.org/10.1038/s41422-020-0282-0
https://doi.org/10.1038/s41422-020-0282-...
).

Chloroquine (CQ) is an amine acidotropic form of quinine. In the past, this compound was the drug of choice against malaria and has been reported to be a potential broad-spectrum antiviral drug (1313. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938. https://doi.org/10.1016/j.ijantimicag.2020.105938
https://doi.org/10.1016/j.ijantimicag.20...
). The mechanism of action of CQ and its analog hydroxychloroquine (HCQ) consists in blocking viral entry into cells by interacting with viral particles that bind to human cell surface receptors (1515. Zhai P, Ding Y, Wu X, Long J, Zhong Y, Li Y. The epidemiology, diagnosis and treatment of COVID-19. Int J Antimicrob Agents. 2020;55(5):105955. https://doi.org/10.1016/j.ijantimicag.2020.105955
https://doi.org/10.1016/j.ijantimicag.20...
). Both CQ and HCQ can have immunomodulatory effects through the modulation of pro-inflammatory cytokines (1313. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938. https://doi.org/10.1016/j.ijantimicag.2020.105938
https://doi.org/10.1016/j.ijantimicag.20...
).

CQ is also an active agonist of bitter-taste receptors (TAS2Rs), first identified in the bud cells of the tongue. These receptors signal information to the brain about the nutritive value or toxicity of ingested foods and beverages (1616. Lu P, Zhang CH, Lifshitz LM, ZhuGe R. Extraoral bitter taste receptors in health and disease. J Gen Physiol. 2017;149(2):181-97. https://doi.org/10.1085/jgp.201611637
https://doi.org/10.1085/jgp.201611637...
,1717. Lee RJ, Cohen NA. Taste receptors in innate immunity. Cell Mol Life Sci. 2015;72(2):217-36. https://doi.org/10.1007/s00018-014-1736-7
https://doi.org/10.1007/s00018-014-1736-...
). Aside from their role in chemosensory cells, these receptors are expressed in an extensive range of tissues and perform varied functions (1818. Wang Q, Liszt KI, Depoortere I. Extra-oral bitter taste receptors: New targets against obesity? Peptides. 2020;127:170284. https://doi.org/10.1016/j.peptides.2020.170284
https://doi.org/10.1016/j.peptides.2020....
). A recent study conducted by Grassin-Delyle et al. (1919. Grassin-Delyle S, Salvator H, Mantov N, Abrial C, Brollo M, Faisy C, et al. Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists. Front Physiol. 2019;10:1267. https://doi.org/10.3389/fphys.2019.01267
https://doi.org/10.3389/fphys.2019.01267...
) suggested that TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39, and 40 were involved in the inhibition of cytokine production. Moreover, Li et al. (1212. Li X, Zhang C, Liu L, Gu M. Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases. FASEB J. 2020;34(5):6008-16. https://doi.org/10.1096/fj.202000502
https://doi.org/10.1096/fj.202000502...
) hypothesized that TAS2R10 might help to prevent the cytokine storm - a key event for patients with more aggressive COVID-19 symptoms - because its receptor regulates natural killer cell-mediated cytotoxicity, and chemokine, T-cell receptor, and TNF signaling pathways (1212. Li X, Zhang C, Liu L, Gu M. Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases. FASEB J. 2020;34(5):6008-16. https://doi.org/10.1096/fj.202000502
https://doi.org/10.1096/fj.202000502...
). CQ binding to TAS2Rs may also result in functional changes in respiratory tract cells, such as smooth muscle, ciliated cells, and blood cell markers. This suggests that the extra-oral effects of CQ could be beneficial against pulmonary diseases (2020. Nayak AP, Shah SD, Michael JV, Deshpande DA. Bitter Taste Receptors for Asthma Therapeutics. Front Physiol. 2019;10:884. https://doi.org/10.3389/fphys.2019.00884
https://doi.org/10.3389/fphys.2019.00884...
).

Interestingly, extra-oral TAS2R expression could be reduced in obese subjects compared to non-obese individuals (1818. Wang Q, Liszt KI, Depoortere I. Extra-oral bitter taste receptors: New targets against obesity? Peptides. 2020;127:170284. https://doi.org/10.1016/j.peptides.2020.170284
https://doi.org/10.1016/j.peptides.2020....
). This may result in a decreased sensitivity to bitter taste, which is often observed in obese individuals, and may affect food choices (1818. Wang Q, Liszt KI, Depoortere I. Extra-oral bitter taste receptors: New targets against obesity? Peptides. 2020;127:170284. https://doi.org/10.1016/j.peptides.2020.170284
https://doi.org/10.1016/j.peptides.2020....
). Considering the role of TAS2R and its agonists on immune responses, and the fact that CQ is a TAS2R agonist, we hypothesized that COVID-19-infected obese patients could respond differently to pharmacological treatment with CQ and side effects could occur more frequently due to overdosage in this population. This hypothesis is supported by a recent study that evaluated the risk of retinopathy - one of the most important long-term side effects of HCQ treatment - related to clinical characteristics and HCQ blood levels of 537 patients (2121. Petri M, Elkhalifa M, Li J, Magder LS, Goldman DW. Hydroxychloroquine Blood Levels Predict Hydroxychloroquine Retinopathy. Arthritis Rheumatol. 2020;72(3):448-53. https://doi.org/10.1002/art.41121
https://doi.org/10.1002/art.41121...
). The authors found a significant association between higher BMI and a higher risk of HCQ toxicity, suggesting a limited HCQ dosage at 400 mg daily, irrespective of how high is the patient’s BMI (2121. Petri M, Elkhalifa M, Li J, Magder LS, Goldman DW. Hydroxychloroquine Blood Levels Predict Hydroxychloroquine Retinopathy. Arthritis Rheumatol. 2020;72(3):448-53. https://doi.org/10.1002/art.41121
https://doi.org/10.1002/art.41121...
).

Moreover, according to Karalis et al. (2222. Karalis V, Ismailos G, Karatza E. Chloroquine dosage regimens in patients with COVID-19: Safety risks and optimization using simulations. Saf Sci. 2020;129:104842. https://doi.org/10.1016/j.ssci.2020.104842
https://doi.org/10.1016/j.ssci.2020.1048...
), dosage regimens of CQ/HCQ used for treating COVID-19 symtoms could be linked to high toxicity risk. Thus, to avoid adverse effects due to CQ/HCQ overdosage, the authors proposed dosage regimens tailored to the patient’s characteristics, such as body weight, age, and severity of COVID-19 symptoms (2222. Karalis V, Ismailos G, Karatza E. Chloroquine dosage regimens in patients with COVID-19: Safety risks and optimization using simulations. Saf Sci. 2020;129:104842. https://doi.org/10.1016/j.ssci.2020.104842
https://doi.org/10.1016/j.ssci.2020.1048...
). However, more studies are required to further address the influence of individual factors in the CQ/HCQ pharmacodynamics and the optimal dosage of CQ/HCQ for treating COVID-19 symptoms (1515. Zhai P, Ding Y, Wu X, Long J, Zhong Y, Li Y. The epidemiology, diagnosis and treatment of COVID-19. Int J Antimicrob Agents. 2020;55(5):105955. https://doi.org/10.1016/j.ijantimicag.2020.105955
https://doi.org/10.1016/j.ijantimicag.20...
,2323. Smit C, Peeters MYM, van den Anker JN, Knibbe CAJ. Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties. Clin Pharmacokinet. 2020;59(6):659-69. https://doi.org/10.1007/s40262-020-00891-1
https://doi.org/10.1007/s40262-020-00891...
). Figure 1 summarizes the association of TAS2R expression and the response to CQ and HCQ of obese patients in the context of COVID-19 infection.

Figure 1
TAS2R molecular mechanisms in response to CQ and HCQ in obese patients on COVID-19 infection context.

CONCLUSION

The COVID-19 pandemic is a significant global public health challenge, especially concerning the pursuit of effective drugs for its prevention and treatment. Considering the prevalence of obesity worldwide and the complications associated with excessive body mass ratio, special attention should be given to patients with obesity. In a condition of obesity, reduced TAS2R expression could affect the response to medications such as CQ. Altogether, we highlighted the importance of obese patient care, particularly during the current COVID-19 pandemic.

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Publication Dates

  • Publication in this collection
    26 Aug 2020
  • Date of issue
    2020

History

  • Received
    1 July 2020
  • Accepted
    22 July 2020
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