Review: Pathophysiology of COVID-19 in diabetic patients Aim: investigate the connections between diabetes and covid-19 mortality-morbidity.   Objective: First Section   · What is stru

PATHOPHYSIOLOGY OF COVID-19 IN DIABETIC PATIENTS

Student’s Name

Course Professor’s Name

University

City (State)

Date

Pathophysiology of COVID-19 in Diabetic Patients

During the wake of COVID-19 pandemic, diabetes has been the most frequently reported comorbidities in patients infected with COVID-19. The current data shows that diabetic patients are less likely to contract the SARS-CoV-2 virus compared to the general population. Nonetheless, diabetes is a known risk factor for developing severe and critical forms of COVID-19, which requires admission to an intensive care unit or application of invasive mechanical ventilation that has high mortality rates.1 Due to the high prevalence of diabetes, it is crucial to understand its relationship with COVID-19. Therefore, it is important to understand the structure, pathophysiology, features, and the entry mechanism of COVID-19 to aid in managing diabetic patients infected with the virus.

Structure of COVID-19

            The causal agent of COVID-19 disease is the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Coronaviruses characterized by envelopes enclosing single-stranded positive sense RNA as its genome, are responsible for respiratory diseases in humans. SARS-CoV-2 is a betacoronavirus of zoonotic origin, which are spherical to pleomorphic particles measuring between 80nm and 150nm in diameter. The structure of SARS CoV-2 is made of four main proteins that include Envelope (E), Membrane (M), Spike (S), and Nucleocapsid (N). The S, M, and E proteins constitute the compound that envelope the SARS-CoV-2 virus.4 The most abundant protein is the M, which is responsible for the providing the mechanical support and maintaining the shape of the viral envelope. The S and M transmembrane proteins in the assembly of viral parts during the process of replication. The N proteins, on the other hand, remain connected to the RNA of virus creating a nucleocapsid inside the envelope to protect the genome of the virus. Apart from enclosing and protecting the viral genome, the N protein is also involved in the process of assembly and budding during the CoV replication cycle as well as control aspects of the host’s response to the viral infection. The name coronavirus stems from the crown-like nature of the SARS-CoV-2 virus owing to the polymers of S proteins that remain embedded in the viral envelope (Figure 1).5

Figure 1: The structure of SARS-CoV-2.3

The spike conformation of the SARS-CoV-2 is attributed to the glycoproteins comprised of S1 and S2 subunits. The S1 subunit comprises of a signal protein element, an N-terminal domain, and a receptor-binding protein element. The S2 subunits, on the other hand, are made up of preserved fusion amides, septenary repeat 1 and 2, transmembrane domain, and a cytoplasmic domain. The genomic organization of the SARS-CoV-2 is characterized by single-stranded positive-sense RNA with more than 38% G+C content responsible for 2,891 nucleotides that encode 9,860 amino acids.2 The genome of SARS-CoV-2 lacks the hemagglutinin-esterase gene that is common among lineage A-betacoronaviruses. About two-thirds of the SARS-CoV-2 RNA located in the first open reading frame (ORF) translates two polyproteins, pp1a and pp1ab , which encodes sixteen non-structural proteins while the rest of the ORF encode the structural and accessory proteins. The remaining part of the viral genome codes for the four structural proteins E, M, S, and E along with other accessory proteins that tamper with the host’s immune response.

Pathophysiology of COVID-19

            The cellular entry of SARS-CoV-2 is a complex process that involves the binding of receptors and lysis of proteins resulting in virus-cell fusion. The S protein mediates the binding of receptors to the host’s cell membrane via the receptor-binding domain and fusion of the membrane through the S2 subunit.8 The host receptor protein for SARS-CoV-2 virus is Angiotensin-converting enzyme 2 (ACE2), which uses the dipeptidyl peptidase 4 (DPP4) as its receptor. Upon binding to the ACE2, the proximal serine proteases facilitate the priming of the S protein and cleavage of the spike.7 This is followed by release of the spike fusion proteins by Furin protease, which allows the entry of SARS-CoV-2 virus via the endosomal pathway. The acidic environment and the presence of the cathepsin-L protease facilitates the delivery of SARS-CoV-2 RNA into the cytosol where the further viral replication results in the creation of mature viral particles and subsequent spread to other cells. Infected cells suffer apoptosis and prompt inflammatory responses marked by the triggering pro-inflammatory cytokines and chemokines in the host, resulting in the recruitment of inflammatory cells.6 The SARS-CoV-2 invades circulating immune cells in the body and leads to its apoptosis of CD3, CD4, and CD8 T cells, leading to lymphocytopenia. Circulating levels of cytokines and chemokines are increased in the event of contracting SARS-CoV-2, which drives hyperinflation that results in failure of multiple body organs.

            It is now recognized that patients with old age, hypertension, and diabetes contributes significantly to the high morbidity and mortality rates in patients infected with COVID-19. Some of the factors that increase the susceptibility of diabetic patients to COVID-19 include reduced T cell function, high affinity cellular binding, reduced capacity for viral clearance, and increased susceptibility to hyperinflamation.9 The expression of ACE2 in AT2 cells, kidney, heart, lung, and pancreas increases the chances of cellular binding to SARS-CoV-2. Diabetes is causally associated with the increased lung ACE2 expression.10 The circulating levels of furin protease that is involved in facilitating the entry of SARS-CoV-2 by cleaving  the S1 and S2 domains of the spike proteins has been shown to be relatively high in diabetes patients. In COVID-19 patients, the CD4 and CD8 T cell count is low, but the levels of proinflammatory Th17b CD4 T cells and cytokines are high. Therefore, it is highly likely that diabetic patients may have diminished antiviral IFN responses as well as delayed activation of Th1, which contributes to heightened inflammatory responses.11

Figure 2: Pathophysiology of COVID-19 in patients with Diabetes.6

Features and Entry Mechanisms of COVID-19

            The main features of COVID-19 disease include cough, acute shortness of breath, and fever. These features are used to select people for the testing, but using these clinical features only captures symptomatic presentation of the disease while leaving out unusual manifestation of the virus in patients with mild or no symptoms.12 Some of the common non-respiratory features of COVID-19 include diarrhea, olfactory disorders, headache, and hemorrhagic stroke. Cardiovascular events that have been reported in some COVID-19 patients include myocarditis, cardiac arrhythmias, myopericarditis, and cardiac dysfunction.13 The SARS-CoV-2 virus uses the human ACE2 protein receptor and the human proteases to activate virus cellular entry.14  Understanding the structure, pathophysiology, features, and the cellular entry mechanisms of COVID-19 will enable easy tracing, diagnosis, prevention, and treatment of the COVID-19 disease.

References

1. Singh A, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(4):303-310. doi:10.1016/j.dsx.2020.04.004

2. Chan J, Kok K, Zhu Z 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):221-236. doi:10.1080/22221751.2020.1719902

3. Sapkota A, Aryal S. Structure and Genome of SARS-CoV-2 (COVID-19) with diagram. Online Microbiology Notes. https://microbenotes.com/structure-and-genome-of-sars-cov-2/. Published 2020. Accessed June 10, 2020.

4. Ou X, Liu Y, Lei X et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020;11(1). doi:10.1038/s41467-020-15562-9

5. Schoeman D, Fielding B. Coronavirus envelope protein: current knowledge. Virol J. 2019;16(1). doi:10.1186/s12985-019-1182-0

6. Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. American Journal of Physiology-Endocrinology and Metabolism. 2020;318(5):E736-E741. doi:10.1152/ajpendo.00124.2020

7. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clinical Immunology. 2020;215:108427. doi:10.1016/j.clim.2020.108427

8. Adhikari S, Meng S, Wu Y et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;9(1). doi:10.1186/s40249-020-00646-x

9. de Koning E. Ec.europa.eu. https://ec.europa.eu/health/sites/health/files/ern/docs/ev_20200512_co02_en.pdf. Published 2020. Accessed June 10, 2020.

10. Maddaloni E, Buzzetti R. Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics. Diabetes Metab Res Rev. 2020:e33213321. doi:10.1002/dmrr.3321

11. Hill M, Mantzoros C, Sowers J. Commentary: COVID-19 in patients with diabetes. Metabolism. 2020;107:154217. doi:10.1016/j.metabol.2020.154217

12. Vetter P, Vu D, L’Huillier A, Schibler M, Kaiser L, Jacquerioz F. Clinical features of covid-19. BMJ. 2020:m1470. doi:10.1136/bmj.m1470

13. Hassan S, Sheikh F, Jamal S, Ezeh J, Akhtar A. Coronavirus (COVID-19): A Review of Clinical Features, Diagnosis, and Treatment. Cureus. 2020. doi:10.7759/cureus.7355

14. Belouzard S, Millet J, Licitra B, Whittaker G. Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein. Viruses. 2012;4(6):1011-1033. doi:10.3390/v4061011