Protein based biomarkers for non-invasive Covid-19 detection

Abstract

COVID-19 has become a substantial lethal disease worldwide, and early diagnosis is a significant concern for this virus. Currently, RT-PCR is being used worldwide for the detection of this virus with human to human transmission. Furthermore, the recent develop biosensor leading to others diagnosis approach but being invasive are painful and time taking. Another possibility can be protein-based biomarkers as an application of biosensors for detection and early diagnostics. Considering the other approach, that is, microfluidics-based biosensor, though being a non-invasive method, will be restricting virus transmission. This review commences with the recent develop biosensor for Covid-19 detection and listing down the available biomarkers with their secretion range comparison of normal to COVID-19 patients through clinical analysis in china and concludes with the future approach for the diagnosis.

Highlights

• •Protein based biomarkers for Non-invasive Covid-19 detection
• •Cost-effective
• •Integration of microfluidics system with this kind of biosensor, so that a minimal amount of sample will be used and the chance of virus transmission remains insignificant

1. Introduction

COVID-19 is a recent outbreak occurred worldwide and created a colossal dysfunction of various activity all around the world [12]. COVID-19 stand for Coronavirus diseases 2019. The infection and spread of this virus were firstly observed in Wuhan city of China, has now affected nearly 200 countries worldwide [10]. Coronaviruses constitute the subfamily Orthocoronavirinae. These are enveloped viruses, positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry with genome size rangeing from approximately 26 to 32 kilobases, one of the largest among RNA viruses [11]. They have characteristic club-shaped spikes that project from their surface. The primary concern related to this virus is early diagnosis, cost-effectiveness and reduce the chance of spread so that working professional also do not get affected while testing. Currently, RT-PCR is being used for testing the virus which is time taking and costly, moreover some of the research group has recently develops biosensor for Covid-19 detection though different approach but they all are invasive and lead to virus particles exposers, to overcome this issue, a biomarker-based biosensor can play a pivotal role, as biomarker are naturally occurring biomolecule specific to particular diseases, such as CYFRA-21 is a protein-based biomarker for oral cancer. Protein-based biomarkers are easy to isolate as compare to a nucleic acid (DNA/RNA) or cell-based biomarker. Moreover, the biomarker isolation and sample preparation are much more comfortable in protein-based biomarker as compared to a nucleic acid or other biomarkers. In the current detection of COVID-19, which is RT-PCR required RNA isolation, purification and processing step, which increase the time of detection and cost of testing. We can locate out such biomarker through proteomics studies from COVID-19 infected patient and find out specific biomarker for COVID-19.

2. Recent develop biosensor

All around the worldwide several research groups are indulged in developing a rapid diagnostic technique for Covid-19 detection, as the current method RT-PCR is time-consuming and costly. To begins, this scenario Qiu and his team develop a Dual-Functional Plasmonic Photothermal Biosensors, in this, they used plasmonic photothermal (PPT) effect and localized surface plasmon resonance (LSPR) with the help of two-dimensional gold nanoislands (AuNIs) which they functionalized with complementary DNA receptors which can perform a sensitive detection of the selected sequences from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [8]. Though this sensor is fast and more accurate as compared to RT-PCR result, still it does not remove the obstacle of virus particles exposure. To improve the detection limit et al., recently develop an immunosensor based on SARS-CoV-2 spike protein based on graphene sheet on FET based system, this sensor has a better limit of detection [9]. However, it lacks the specificity in longer terms if viral strain gets mutated and change its morphology. These are some of the recent development through different research group for the rapid detection of Covid-19 and their various parameters are listed in Table 1 . However, none of them approaches towards the development of non-invasive biosensor, which can be user friendly and cheaper.

Table 1.

Recently develop biosensor and their parameters.

S. No	Techniques Used	Materials used	Limit of Detection	Analytes	Linear Detection Range (LDR)	Incubation Time	Advantage	Limitation	Ref.
1	Surface Plasmon Resonance	Gold nanoislands	0.22 pM	DNA	0.01 pM to 50 μM	–	-Fast responsive	-Sample isolation and purification are time consuming	8
							-Low detection limit
2	Field-effect transistor	Graphene sheet	1.6 × 101 pfu/mL	Protein	1.6 × 101 pfu/ml to 1.6 × 104 pfu/ml	4 h	-Low cost -Highly selective	-Incubation time is more	9

3. Potential biomarkers through clinical studies

Rapid and early diagnosis of any diseases is always a major concern for any country. Currently, the situation related to COVID-19 is enormous, as we do not have any rapid system for early and fast detection of this virus. Several countries are trying to develop a rapid kit based on antibodies or gene for detection. There are other techniques which can resolve out this problem with a more manageable approach and detect the virus rapidly. One of these techniques is biomarker based on sensors, terming biosensors. There are several reported biosensor based on biomarkers which accurately detect particular diseases such as non-invasive biosensor develop by Kumar et al., for oral cancer detection which used CYFRA-21 as a specific biomarker for oral cancer [6], same like these specific biomarkers for COVID-19 can also be used, and biosensor can be made.

Furthermore, the other issue with this virus detection is human to human transmission while detecting. Professional working for the diagnosis are in a major threat to get into the contact of this virus and get affected and to subdue this approach this biomarkers based biosensor can be integrated with microfluidics system which will restrict the sample amount as well as the chance of virus transmission, such as Singh et al., has tried to develop a microfluidics-based biosensor for influenza detection [7]. In this review article, we have listed out the significant biomarkers which were reported in various paper after the clinical studies in COVID-19 patients in china [[1], [2], [3]]. Biomarkers such as Serum amyloid A (SAA) which secreted in a more substantial amount in COVID-19 patient as compared to a healthy patient, Serum ferritin is also a considerable biomarkers from these studies which also shows a potential to detect specifically COVID-19 as there is difference between secretion range and cut off the range, furthermore biosensor based on this approach will be non-invasive that can be user friendly in use so that the need of highly qualified professional limit can be overcome, apart this others biomarkers which can also be considered are listed in Table 2 with the secretion range in healthy patient and COVID-19 infected patient [5]. Lastly, there are some more studies which report some more biomarkers such as IL-10, IL-6 and IL-1beta [4].

Table 2.

List of considerable biomarkers for Covid-19.

S.No.	Biomarker	Normal patient	Affected patient	Biological samples	Ref.
1	Serum ferritin, (ng/mL)	15.0–150.0	800.4 (452.9–1451.6)	Serum	1
2	C-reactive protein,(mg/L)	0.0–1.0	57.9 (20.9–103.2)	Plasma	1
3	Interleukin-2R, (U/mL)	223.0–710.0	757.0 (528.5–1136.3)	Serum	1
4	IL-6 (pg/mL)	0·0–7·0	7·9	Blood	2
5	D-Dimer (μg/mL)	0–0.243	0.4	Plasma	3
6	Serum amyloid A (SAA) (mg/L)	0–10	108.4	Serum/Saliva	3

4. Future prospects and conclusion

Considering the urgent need for rapid detection of COVID-19 the biomarkers based sensor can plays a pivotal role as it will reduce the time to detect, will be cost-effective, and also reduce the chance of virus transmission while diagnosis, we can look forward to the integration of biosensor with microfluidics system.

Through clinical studies of COVID-19 patient biomarkers such as Serum ferritin, Interleukin-2R are found to shows considerable difference in their secretion range of healthy patients and affected patients with COVID-19 diseases, further to develop biomarkers based biosensor such biomarkers can be used and to investigate more specific biomarkers further proteomics analysis can be done. We can also look forward with the integration of microfluidics system with this biosensor so that a minimal amount of sample is used and the chance of virus transmission remains insignificant.

The schematic representation of this review is prepared in Fig. 1 .

Fig. 1.

Schematic representation of biomarkers based biosensor.

Author's contribution

The authors contributed equally in reviewing the work and providing a unique solution to use the biomarkers in biosensors.

Funding

This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.