Advancing flavivirus detection: Role of nanotechnology in eliminating cross-reactivity

Dear Editor,

Flaviviruses are emerging and re-emerging viruses that exhibit epidemic potential and can cause high mortality and morbidity globally.^[1] Flaviviruses are classified as enveloped viruses and have a single-stranded positive-sense genome. These viruses are known to transmit diseases through the bites of mosquitoes and ticks, and these viruses are commonly referred to as arboviruses.^[2] Flavivirus consists of a group of medically significant viruses with pathogenic potential, including dengue virus (DENV), Japanese encephalitis, Zika virus, tick-borne encephalitis, and yellow fever virus.^[3] Among all flaviviruses, dengue itself has been a significant contributor to the cases, with 505,430 reported dengue cases surging to 5.2 million cases in 2019. In 2023, the highest number of dengue cases was reported, with ~6.5 million dengue cases reported across >80 countries, with 7,300 deaths attributed to the disease.^[4] Following the rise in DENV infection, there has also been a notable increase in the number of cases of yellow fever and Zika virus infections. After the DENV, increasing cases of yellow fever and Zika virus infection have also been reported. According to a study, >86,000 cases of yellow fever and 169,734 cases of Zika virus infection have been documented between 2011-2021.^[5]

Diagnosis of flavivirus is usually done by identifying the viral antigen, genome sequencing, virus isolation, and various serological assays. In serological tests, immunofluorescent tests, western blots, and immunoglobulin (Ig)M/IgG antibody-capture enzyme-linked immunosorbent assay are commonly used techniques.^[6] The existence of numerous flaviviruses circulating in endemic places causes cross-reactivity of antibodies, which is one of the main issues faced during serological testing for flaviviruses.^[7] Because the immune system can develop primary and secondary antibodies that react with different flaviviruses, this cross-reactivity makes identification more difficult. Serodiagnosis thus becomes challenging and prone to errors. Particularly in regions where many flaviviruses are co-circulating, false-positive results might happen, making it more difficult to differentiate between infections.^[7]

Nanotechnology can be used as a key tool in addressing the problem of flavivirus cross-reactivity by removing false positives, especially in endemic regions where several flaviviruses are common. Nanotechnology-based solutions are gaining significant attention due to their improvements in sample volume, rapid detection capabilities, and the ability to detect analytes in unusable samples.^[8] The use of nanoparticles has now been widely employed to detect infectious pathogens, providing sensitive, rapid, cost-effective, and highly specific results against different pathogens.^[9] A previous study demonstrated the gold nanoparticles to detect all four serotypes of the (DENV 1-4) and concluded that these nanoparticles greatly enhance the sensitivity and specificity while reducing the test duration from 1-3 days to <5 min.^[8]

The effective use of nanosensors for the rapid diagnosis of the Zika virus was shown in a study conducted by Banerjee et al.^[10] Furthermore, the simultaneous detection of cross-reactive antibodies for the Dengue and Zika viruses is made possible by their magnetic relaxation nanosensors. This invention may be validated for larger samples in endemic regions for quicker identification of pathogens and associated cross-reactive antibodies. Therefore, incorporating nanotechnology-based solutions might greatly improve the quick, cost-effective, highly sensitive, and specific detection of flaviviruses as well as the differentiation of cross-reactive antibodies, particularly in the epidemic region where multiple flaviviruses are prevalent. With this approach, reliable, accurate, and detailed diagnostic outcomes can be achieved that ultimately reduce the chances of misdiagnosis. This, in turn, supports effective disease management where the patient receives the correct diagnosis and aids clinicians in making informed decisions to improve the patient outcome and lastly restrict the spread of disease through proper identification and targeted interventions.